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Biomedical subjects

E Boyd

Publications and source records attributed to E Boyd.

At least 19 recordsLinked to original sources
PubMed2005

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-small-cell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9-8.7 days and a steady-state volume of distribution of approximately 60 ml kg(-1). Clearance was 3.6-5.7 ml(-1) day(-1) kg(-1). These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

Animals↗
PubMed2001

The application of comparative genomic hybridization as an additional tool in the chromosome analysis of acute myeloid leukemia and myelodysplastic syndromes.

In acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) there are frequently complex karyotypes with multiple structurally altered chromosomes, many of which are marker chromosomes of unknown origin. The aim of this study was to apply comparative genomic hybridization (CGH) to cases of AML or MDS in transformation submitted for routine cytogenetic analysis to investigate whether this approach would yield any further information and, if possible, to predict which cases would benefit from CGH analysis. Nineteen cases with AML or MDS in transformation were analyzed. CGH revealed nine cases with gains or losses of chromosomal material. In six of these cases the chromosomal location of this material was not apparent from cytogenetic analysis especially when multiple markers were present. By using fluorescence in situ hybridization (FISH) with specific libraries for the chromosome regions that showed discordance between CGH and conventional cytogenetics, we were able to identify the chromosome location of material within the karyotype. In this group of six patients, four cases of an unbalanced translocation involving regions of chromosomes 5 and 17 were characterized. Three of these cases had additional abnormalities, including two cases with regions of amplification in which oncogenes are located (MYC, MLL) and one case with a dic(7;21)(p10;p10). In all six cases it was possible to characterize complex chromosomal aberrations such as derivative chromosomes, marker chromosomes, and ring chromosomes. This study demonstrates that CGH can detect true gain and loss of critical chromosome regions more accurately than conventional karyotyping in cases with very complex karyotypes, and can thus prove useful in predicting prognosis and pinpointing areas of the genome that require further study. Also, CGH can be a useful technique to identify the origin of marker chromosomes, and it can assist in choice of probes for confirmatory FISH, when there is no clue provided from the analysis of G-banded chromosomes.

Acute Disease↗
PubMed2000

Spondylocarpotarsal synostosis syndrome and cervical instability.

Spondylocarpotarsal synostosis syndrome is a recently delineated autosomal recessive condition comprising short stature with short trunk, failure of normal spine segmentation resulting in block vertebrae and fusion of posterior elements, carpal and/or tarsal coalition, scoliosis, lordosis, pes planus, dental enamel hypoplasia, decreased range of motion or dislocation of the elbow, renal anomalies, and hearing loss. The vertebral segmentation defects may involve noncontiguous areas of the cervical, thoracic, and lumbar spine. Odontoid hypoplasia was noted in two cases. We report on a sporadic case of spondylocarpotarsal synostosis in a 5-year-old girl with hypoplasia of C1 and odontoid and subluxation of C2 upon C3. This brings the number of well-documented cases of spondylocar- potarsal synostosis to 19, and is the first documenting cervical spine instability. Careful evaluation for this complication should be considered in other cases.

Abnormalities, Multiple↗
PubMed2000

Meningeal worm in deer from western Nebraska.

One hundred seventy-eight white-tailed deer (Odocoileus virginianus) and 275 mule deer (Odocoileus hemionus) collected from locker plants in the western 2/3 of Nebraska (USA) in November 1997 were examined for the meningeal worm (Parelaphostrongylus tenuis). Parelaphostrongylus tenuis was identified in 17 (10%) of 168 white-tailed deer and in one (<1%) of 273 mule deer. This is the first naturally occurring infection of P. tenuis recorded in a mule deer.

Animals↗
PubMed1999

Trends in prenatal diagnosis of Down syndrome and other autosomal trisomies in Scotland 1990 to 1994, with associated cytogenetic and epidemiological findings.

The present report summarizes findings on 670 cases of autosomal trisomy diagnosed in Scotland, with actual or expected dates of delivery in 1990 to 1994 inclusive. Cases were notified by cytogenetic service laboratories. There were 277 prenatal and 369 postnatal diagnoses and 24 spontaneous losses. Excluding the latter, numbers diagnosed with trisomy 21, trisomy 18, trisomy 13, and other trisomies were, respectively, 470 (72.8%), 108 (16.7%), 36 (5.6%), and 32 (5.0%). Estimated maternal age-specific birth rates for trisomy 21 were close to published values from other jurisdictions. However, comparisons with a clinically based national register of congenital anomalies suggested that 3-4% of Down syndrome births were never karyotyped, most being early neonatal deaths. There was a striking increase over the period in the proportion of cases detected prenatally, associated with increased maternal serum screening in mothers <35 years old. Over the 3 final years (1992-1994), prenatal screening followed by elective termination was estimated to reduce the birth rate in trisomy 21 by 24% in mothers aged <35 years, by 57% in older mothers, and by 35% in all mothers. The crude incidence per 1,000 births fell from 1.08 in 1990-1991 to 0.77 in 1992-1994, in spite of an upward shift in the overall maternal age distribution. For trisomies 18 and 13, the estimated overall reductions in the birth rate over the whole 5-year period were respectively, 26 and 17%. In free trisomy 18, there was a significant reduction in the sex ratio (male/female) to 0.65, in line with earlier studies.

Abnormalities, Multiple↗
PubMed1999

Two years' prospective experience using fluorescence in situ hybridization on uncultured amniotic fluid cells for rapid prenatal diagnosis of common chromosomal aneuploidies.

A probe was generated from the YAC clone 831B9 that was suitable for the prenatal detection of trisomy 21 using fluorescence in situ hybridization (FISH). This probe was initially tested on a series of 650 unselected amniotic fluid samples prior to the karyotype being available. 630 were correctly identified as having two copies and 13 samples were correctly scored as having three copies of chromosome 21. Seven samples failed to produce a result. A trial was then initiated, reporting to clinicians the interphase FISH results before cytogenetic analysis had been performed. During the first 18 months of this trial 1504 samples were tested: 1467 were correctly identified as disomic and 35 samples were correctly scored as trisomic for chromosome 21. Two samples failed to produce a result. A chromosome 18 specific probe (LI.84) was employed where there was a relevant clinical indication (181 samples) and 10 samples were correctly scored as having three copies of chromosome 18. Thus, this approach appears to be reliable and is popular with both clinicians and patients due to the speed of the result. However, it does not replace chromosomal analysis on cultured cells, which detected a range of abnormalities besides the trisomies and triploidies detected by FISH.

Amniotic Fluid↗
PubMed1998

Most Jacobsen syndrome deletion breakpoints occur distal to FRA11B.

Recent studies have identified a (CCG)n repeat in the 5' untranslated region of the CBL2 protooncogene (11q23.3) and have demonstrated that expansion of this repeat causes expression of the folate-sensitive fragile site FRA11B. It has also been demonstrated that FRA11B is the site of breakage in some cases of Jacobsen syndrome (JS) involving terminal deletions of chromosome 11q. We report on 2 patients with JS and a 46,XX,del(11)(q23.3) karyotype. In both cases, microsatellite and fluorescence in situ hybridization analyses indicated that the deletion breakpoint was approximately 1.5-3 Mb telomeric to FRA11B. There was no evidence of expansion of the CBL2 (CCG)n repeat in the parents of either patient. The deleted chromosome was of paternal origin in both cases, although it was of maternal origin in the cases reported to be caused by FRA11B. These findings and those in previously reported patients suggest that the breakpoint for most 11q deletions in JS patients is telomeric to FRA11B, which raises the possibility that there may be other fragile sites in 11q23.3 in addition to FRA11B. These findings also support previous evidence that there may be a propensity for breakpoints to differ depending on the parental origin of the deleted chromosome.

Abnormalities, Multiple↗
PubMed1998

Mosaic supernumerary ring chromosome 19 identified by comparative genomic hybridisation.

We report the use of comparative genomic hybridisation (CGH) to define the origin of a supernumerary ring chromosome which conventional cytogenetic banding and fluorescence in situ hybridisation (FISH) methods had failed to identify. Targeted FISH using whole chromosome 19 library arm and site specific probes then confirmed the CGH results. This study shows the feasibility of using CGH for the identification of supernumerary marker chromosomes, even in fewer than 50% of cells, where no clinical or cytogenetic clues are present.

Aged↗
PubMed1998

A new strategy for cryptic telomeric translocation screening in patients with idiopathic mental retardation.

Cryptic unbalanced chromosome rearrangements in the telomeric bands of human chromosomes constitute a significant cause of "idiopathic" mental retardation. Here, we have described a new strategy based upon comparative genomic hybridisation (CGH) to screen for these abnormalities. A modified CGH analysis showed three unbalanced cryptic rearrangements in five patients from three families. These chromosome abnormalities and their balanced forms in the relatives were then confirmed by fluorescence in situ hybridisation (FISH). This study describes a new approach to the diagnosis of cryptic translocations between the G band negative ends of chromosomes and confirms the significant contribution of cryptic telomeric rearrangements to idiopathic mental retardation.

Child, Preschool↗
PubMed1997

Locus heterogeneity, anticipation and reduction of the chromosome 2p minimal candidate region in autosomal dominant familial spastic paraplegia.

We examined 11 Caucasian pedigrees with autosomal dominant 'uncomplicated' familial spastic paraplegia (SPG) for linkage to the previously identified loci on chromosomes 2p, 14q and 15q. Chromosome 15q was excluded for all families. Five families showed evidence for linkage to chromosome 2p, one to chromosome 14q, and five families remained indeterminate. Homogeneity analysis of combined chromosome 2p and 14q data gave no evidence for a fourth as yet unidentified SPG locus. Recombination events reduced the chromosome 2p minimum candidate region (MCR) to a 3 cM interval between D2S352 and D2S367 and supported the previously reported 7 cM MCR for chromosome 14q. Age of onset (AO) was highly variable, indicating that subtypes of SPG are more appropriately defined on a genetic basis than by AO. Comparison of AO in parent-child pairs was suggestive of anticipation, with a median difference of 9.0 years (p<0.0001).

Adolescent↗
PubMed1997

Identification of variant translocations in chronic myeloid leukemia by fluorescence in situ hybridization.

We studied two cases of chronic myeloid leukemia (CML) having variant complex translocations detected by trypsin G-banding and fluorescence in situ hybridization (FISH). Application of dual color- (DC-) FISH using abl and bor cosmid probes permitted us to detect the bor-abl fusion event on both interphase nuclei and metaphase spread. Furthermore, FISH using combinatorial hybridization (centromeric-library and library-library probes) demonstrated the content and the position of the translocations in CML patients with variant (complex type) Ph-positive rearrangements. FISH analysis appears to be superior than conventional cytogenetic analysis.

Chromosomes, Human, Pair 6↗
PubMed1996

A practical strategy for detection of major chromosome aneuploidies using ratio-mixing fluorescence in situ hybridization.

We describe the use of ratio-mixing FISH to visualize simultaneously probe sets specific for chromosomes 13, 18 and 21 as well as both sex chromosomes in uncultured lymphocytes and amniocytes. This method has the advantage of a smaller sample requirement than uni-colour FISH and potential for analysis of a larger number of chromosome aneuploidies using a minimum number of different probe haptenization and detection systems. An unselected series of uncultured lymphocytes and amniocytes was used to investigate the reliability of ratio-mixing FISH for diagnostic applications. The results indicate that the five-colour ratio-mixing FISH is a reliable technique and can be used for simultaneous detection of major aneuploidies. However, as a diagnostic approach, the strategy of using a three-colour ratio-mixing FISH and a dual colour to detect the five clinically important aneuploidies on two slides from the same sample, appears to be simpler and more practical.

Aneuploidy↗
PubMed1996

Down syndrome with partial duplication and del (21) syndrome: study protocol and call for collaboration. Study I: Clinical assessment.

We report on the clinical and cytogenetic assessment of five cases of Down syndrome phenotype with either a partial duplication of chromosome 21 or a normal karyotype, and we quote a case of del (21q) syndrome. Down syndromes with a partial duplication of chromosome 21 (as well as cases of del (21q), which are partly the phenotypic countertype of trisomy 21) are of paramount importance in the understanding of genes involved in the phenotype of Down syndrome. The goal is to find the relevant genes implicated in the main traits of Down syndrome (i.e. mental retardation, Alzheimer disease, and serious visceral malformations). Such a goal, in our opinion, cannot be reached just by publishing the genotype and the phenotype of a small cohort of patients: 1. a sufficient number of accurate cases is needed, and 2. data have to be computerized for definite conclusions to be reached. The main aims of this report are to present our study protocol and to invite colleagues to participate in a collaborative study in order to collect a maximum of these (rare) cases.

Adolescent↗
PubMed1996

The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4.

1. The novel tri-aryl ethane CDP840, is a potent and selective inhibitor of cyclic AMP phosphodiesterase type 4 (PDE 4) extracted from tissues or recombinant PDE 4 isoforms expressed in yeast (IC50S: 4-45 nM). CDP840 is stereo-selective since its S enantiomer (CT 1731) is 10-50 times less active against all forms of PDE 4 tested while both enantiomers are inactive (IC50S: > 100 microM) against PDE types 1, 2, 3 and 5. 2. Oral administration of CDP840 caused a dose-dependent reduction of interleukin-5 (IL-5)-induced pleural eosinophilia in rats (ED50 = 0.03 mg kg-1). The eosinophils in pleural exudates from CDP840-treated animals contained higher levels of eosinophil peroxidase (EPO) than cells from control animals, suggesting a stabilizing effect on eosinophil degranulation. CDP840 was approximately equi-active with the steroid dexamethasone in this model and was 10-100 times more potent than the known PDE 4-selective inhibitors rolipram and RP73401. The activity of CDP840 was not influenced by adrenalectomy, beta-sympathomimetics or beta-sympatholytics. 3. Antigen-induced pulmonary eosinophilia in sensitized guinea-pigs was reduced dose-dependently by CDP840 (0.01-1 mg kg-1, i.p.) and intracellular EPO levels were significantly higher. CDP840 was more potent in these activities than CT1731 or rolipram and comparable in potency to RP73401. 4. Rolipram or CDP840 were less active than dexamethasone in preventing neutrophil accumulation, or exudate formation in carrageenan-induced pleurisy in rats and thus do not exhibit general anti-inflammatory activity. 5. In sensitized guinea-pigs, aerosols of the antigen ovalbumin caused a dose-dependent bronchoconstriction demonstrated by an increase in pulmonary inflation pressure. Administration of CDP840 (0.001-1.0 mg kg-1, i.p.), 1 h before antigen challenge, resulted in dose-dependent reduction in response to antigen. This activity was not due to bronchodilatation since higher doses of CDP840 (3 mg kg-1) did not significantly change the bronchoconstrictor response to histamine. Rolipram was approximately 10 times less active than CDP840 in preventing antigen-induced bronchoconstriction. 6. These results confirm the observations that selective PDE 4 inhibitors reduce antigen-induced bronchoconstriction and pulmonary eosinophilic inflammation. CDP840 is more potent than rolipram in inhibiting native or recombinant PDE 4. Unlike the recently described potent PDE 4 inhibitor RP73401, CDP840 is more active than rolipram in the rat IL-5 model following oral administration. The novel series of tri-aryl ethanes, of which CDP840 is the lead compound, could be the basis of an orally active prophylactic treatment for human asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Familial Wolf-Hirschhorn syndrome resulting from a cryptic translocation: a clinical and molecular study.

We present three cousins who have normal karyotypes, despite having clinical features of Wolf-Hirschhorn syndrome. Fluorescence in situ hybridisation techniques confirmed that all three relatives were monosomic for the distal short arm of chromosome 4 and that a cryptic translocation involving chromosomes 4 and 11 was segregating within the family. Segregation analysis indicated that the risk of an affected child being born to a parent carrying the translocation was 15%. Molecular analysis showed that loci D4S111 and D4S115 were not deleted in the proband, thus excluding these loci from the "Wolf-Hirschhorn critical region". Surprisingly, DNA studies also suggested that the translocation breakpoint on chromosome 4 was within the region of a preexisting paracentric inversion.

Abnormalities, Multiple↗
PubMed1995

New members of the 3 beta-hydroxysteroid dehydrogenase gene family.

Several bands of hydridization are detected when southern blots of human genomic DNA are proved with cDNA of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) type I. Two experimental approaches were adopted to estimate the size of the 3 beta-HSD gene family. Firstly, primer designed to amplify 3 beta-HSD type I and II genes were found on occasion to amplify DNA products of appropriate length but which were resolved as distinct sequences by denaturing gradient gel electrophoresis (DGGE). Five of these novel bands were cloned and their sequences were found to be closely related to 3 beta-HSD types I and II. Secondly, 57 genomic clones were selected from two lambda genomic libraries by hybridization with exonic probes of 3 beta -HSD type I. These were screened for novel members of the gene family by pcr amplification using various combinations of PCR primers to the type I and II genes, particularly those primers that previously amplified novel PCR products from genomic DNA. Amplification products from (lambda) clones were screened for novel sequences by DGGE. As a result of these approaches, at least five new members of the 3 beta-HSD gene family were found, one of which locates to the 3 beta -HSD type I and II gene cluster on 1p13. The existence of additional closely related but distinct members of the gene family should be recognized as a potential complication when screening PCR fragments for mutations in the type I and II genes. DGGE was found to be an exceedingly rapid means of screening amplification products from (lambda) clones to search for novel members of the gene family.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

The human 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) gene cluster on chromosome 1p13 contains a presumptive pseudogene; 3 beta-HSD and CYP17 do not segregate with dominantly inherited hirsutism.

Four hirsute females from a family exhibiting idiopathic dominant hirsutism were examined. Basal blood levels of delta 5 and delta 4 steroids were within the normal range, but ACTH stimulation led to increases in 17-hydroxypregnenolone and dehydroepiandrosterone that were significantly above control levels. Using polymorphic genetic markers, the genes for cytochrome P450c1717 encoded by CYP17, and the type I and II forms of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) were found not to segregate with hirsutism in this family, though a base substitution was detected in the 3' end of exon 1 of the gene for 3 beta-HSD type I in three of the four patients investigated. Analysis of PCR patients amplification products by denaturing gradient gel electrophoresis (DGGE) and sequencing revealed a novel homologue of exon 3 of 3 beta-HSD. DNA of one of the affected patients was used to create a genomic library in lambda gem 11 and clones containing the novel homologue were obtained and partially sequenced. The equivalent clone was obtained from a genomic library of an unrelated normal individual. The sequences of the clones from patient and control were identical and homologous to exons 2-4 of human 3 beta-HSD types I and II. No difference was found in the PCR primer sites that flanked the exons 3 homologue which led to its detection on DGGE gels. In both clones, stop codons and deletions were identified in the exon 4 homologue, leading to the deduction that the sequence comes from a pseudogene, which we call 3 beta-HSD psi 1. The pseudogene mapped to chromosome 1p13. It was concluded that dominantly inherited idiopathic hirsutism in this rare kindred was not due to deficiencies in 3 beta-HSD types I, II, or psi or of CYP17).

3-Hydroxysteroid Dehydrogenases↗