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D Compton

Publications and source records attributed to D Compton.

16 recordsLinked to original sources
PubMed2006

Developmental competence of human in vitro aged oocytes as host cells for nuclear transfer.

BACKGROUND: Improving human nuclear transfer (NT) efficiencies is paramount for the development of patient-specific stem cell lines, although the opportunities remain limited owing to difficulties in obtaining fresh mature oocytes. METHODS: Therefore, the developmental competence of aged, failed-to-fertilize human oocytes as an alternate cytoplasmic source for NT was assessed and compared with use of fresh, ovulation-induced oocytes. To further characterize the developmental potential of aged oocytes, parthenogenetic activation, immunocytochemical analysis of essential microtubule proteins involved in meiotic and mitotic division, and RT-PCR in single oocytes (n = 6) was performed to determine expression of oocyte-specific genes [oocyte-specific histone 1 (H1FOO), growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), zygote arrest 1 (ZAR1)] and microtubule markers [nuclear mitotic arrest (NuMA), minus-end directed motor protein HSET and the microtubule kinesin motor protein EG5]. RESULTS: For NT, enucleation and fusion rates of aged oocytes were significantly lower compared with fresh oocytes (P < 0.05). Cleavage rates and subsequent development were poor. In addition, parthenote cleavage was low. Immunocytochemical analysis revealed that many oocytes displayed aberrant expression of NuMA and EG5, had disrupted meiotic spindles and tetrapolar spindles. One of the six oocytes misexpressed GDF9, BMP15 and ZAR1. Two oocytes expressed EG5 messenger RNA (mRNA), and HSET and NuMA were not detectable. RT-PCR of mRNA for oocyte specific genes and microtubule markers in single aged oocytes. CONCLUSIONS: Thus, aneuploidy and spindle defects may contribute to poor parthenogenetic development and developmental outcomes following NT.

Aging↗
PubMed2003

Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE).

Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.

Aged↗
PubMed2001

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.

Age of Onset↗
PubMed1999

Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.

In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses, leading to a secondarily avascular tumor and massive tumor cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth.

Adenocarcinoma↗
PubMed1999

The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone and in combination, in seasonal allergic rhinitis.

BACKGROUND: Antihistamines effectively treat seasonal allergic rhinitis (SAR), although the ability of this drug class to reduce nasal congestion is limited. Nasal decongestants effectively treat nasal congestion but not the histamine-related components of SAR. Therefore antihistamine/nasal decongestant combinations are commonly used to maximize the treatment of SAR. Fexofenadine HCl is a nonsedating, long-acting H1 receptor antagonist that provides fast and effective relief from SAR. It is well tolerated, with no sedative or cardiotoxic effects. OBJECTIVE: We sought to compare the efficacy and safety of a fexofenadine HCl/pseudoephedrine HCl combination with that of each individual component in the treatment of ragweed allergy. METHODS: In this Canadian multicenter, double-blind, parallel-group study, 651 patients allergic to ragweed were randomized to receive 60 mg of fexofenadine HCl twice daily, 120 mg of sustained-release pseudoephedrine HCl twice daily, or a combination of the 2 drugs (60 mg of fexofenadine HCl/120 mg of sustained-release pseudoephedrine HCl) twice daily for 2 weeks. Efficacy analyses were based on symptom severity. In addition, a health economic assessment was performed. RESULTS: Combination therapy was significantly more effective than pseudoephedrine alone in improving primarily histamine-mediated symptoms (sneezing; rhinorrhea; itchy nose, palate, and/or throat; and itchy, watery, red eyes) and significantly more effective than fexofenadine alone in reducing nasal congestion. Combination therapy also produced greater improvements in daily activities and work productivity compared with the individual components. No serious adverse events were reported in any of the treatment groups. In addition, no clinically significant changes in 12-lead electrocardiogram parameters, vital signs, or clinical laboratory values were observed. CONCLUSION: Combination therapy is more effective than fexofenadine alone or pseudoephedrine alone in relieving the full spectrum of SAR symptoms (ie, both the primarily histamine-related symptoms and nasal congestion).

Adolescent↗
PubMed1997

Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.

Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mouse. An Ang1 relative, termed angiopoietin-2 (Ang2), was identified by homology screening and shown to be a naturally occurring antagonist for Ang1 and Tie2. Transgenic overexpression of Ang2 disrupts blood vessel formation in the mouse embryo. In adult mice and humans, Ang2 is expressed only at sites of vascular remodeling. Natural antagonists for vertebrate receptor tyrosine kinases are atypical; thus, the discovery of a negative regulator acting on Tie2 emphasizes the need for exquisite regulation of this angiogenic receptor system.

Amino Acid Sequence↗
PubMed1996

Intracerebroventricular injection of leptin increases thermogenesis and mobilizes fat metabolism in ob/ob mice.

Genetically obese (ob/ob) mice display a number of metabolic alterations, including decreased thermogenesis, hyperphagia, hyperglycemia and increased body fat. A single intracerebroventricular (i.c.v.) injection of these mice with leptin (0.01 to 1 microg) lowered food intake and body weight within 24 h. In addition, i.c.v. administration of leptin increased 22 h energy expenditure while reducing the respiratory quotient (RQ) in a dose-dependent manner. The leptin-induced decrease in RQ suggests a reduction in the fraction of total energy derived from carbohydrate oxidation and a corresponding increase in energy derived from fat oxidation. Our data suggest that leptin controls energy homeostasis through activation of receptor(s) in the central nervous system (CNS) that regulate both food intake and energy metabolism.

Adipose Tissue↗
PubMed1996

RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.

An activated ras oncogene induces a program of differentiation in the human medullary thyroid cancer cell line TT. This differentiation process is accompanied by a marked increase in the transcription of the human calcitonin (CT) gene. We have localized a unique Ras-responsive transcriptional element (RRE) in the CT gene promoter. DNase I protection indicates two domains of protein-DNA interaction, and each domain separately can confer Ras-mediated transcriptional inducibility. This bipartite RRE was also found to be Raf responsive. By affinity screening, we have cloned a cDNA coding for a zinc finger transcription factor (RREB-1) that binds to the distal RRE. The consensus binding site for this factor is CCCCAAACCACCCC. RREB-1 is expressed ubiquitously in human tissues outside the adult brain. Overexpression of RREB-1 protein in TT cells confers the ability to mediate increased transactivation of the CT gene promoter-reporter construct during Ras- or Raf-induced differentiation. These data suggest that RREB-1 may play a role in Ras and Raf signal transduction in medullary thyroid cancer and other cells.

Adult↗
PubMed1992

Regulation of human calcitonin gene transcription by cyclic AMP.

Transcription of the human calcitonin (CT) gene is markedly increased by cAMP in the TT line of medullary thyroid carcinoma. This response is conferred by 5' flanking DNA sequences located between -132 and -252 relative to the transcription initiation site. Within this region are an upstream cyclic AMP response element (CRE), a downstream CRE flanked by two octamer motifs, and two adjacent C-rich AP2-like sequences. In transfection experiments in TT cells, the downstream CRE, combined with CT promoter sequences, generated 70% of the maximal cAMP response. The upstream CRE and the C-rich elements conferred 10 and 30% of this response, respectively. In gel mobility shift assays, specific TT cell proteins bound to each of these sequences. Therefore, the cAMP response of the CT gene is complex, requiring multiple elements acting in concert.

Base Sequence↗
PubMed1992

Human calcitonin gene regulation by helix-loop-helix recognition sequences.

Human calcitonin (CT) gene transcription is regulated by proximal 5' flanking sequences which mediate cAMP-induced expression, and by a distal basal enhancer region. Using transient expression of CT-CAT constructs, we showed that the basal enhancer is active in a CT-producing small cell lung cancer cell line (DMS53) and the thyroid C cell derived tumor line, TT, but is inactive in non-CT-producing cell lines. In deletional and direct mutational analyses of the distal enhancer region, disruption of two elements resembling recognition sequences for the helix-loop-helix (HLH) family of transcriptional regulatory proteins resulted in a significant loss of basal transcriptional enhancer action. These results suggest that HLH recognition motifs may mediate a significant portion of constitutive CT gene transcriptional activity in these cells. Nuclear protein extracts from DMS53 cells formed specific binding complexes with oligonucleotides containing two of these candidate enhancer sequences. However, proteins capable of binding to these CT gene HLH consensus recognition sites were not restricted to CT-producing cells. We conclude that members of the HLH protein family, some expressed ubiquitously and some expressed or activated in a tissue-restricted fashion, may combine to enhance CT gene transcription in tumor cells of neuroendocrine derivation.

Base Sequence↗
PubMed1991

Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA.

The plasma cholesteryl ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high density lipoproteins (HDL) to triglyceride-rich lipoproteins and plays a major role in the catabolism of HDL. Lipoprotein lipase (LPL) is the rate-limiting enzyme for hydrolysis of circulating triglyceride and is involved in HDL formation. We show that tissues containing LPL are major sources of CETP mRNA in several mammalian species, including some with low cholesteryl ester transfer activity in plasma. In hamsters, adipose tissue and heart were found to be the richest sources of both CETP and LPL mRNA; in situ hybridization studies showed that the same cell types (i.e. adipocytes or myocytes) contained CETP and LPL mRNA in these tissues. Isolated adipocytes synthesized active CETP. Dietary studies revealed a complex pattern of response of CETP mRNA levels in different tissues, which showed partial similarity to the changes in LPL mRNA abundance. However, high cholesterol diets resulted in increased CETP mRNA abundance in adipose tissue, heart, and skeletal muscle, without equivalent changes in LPL mRNA. Plasma HDL cholesteryl ester levels showed strong inverse correlations with CETP mRNA abundance in adipose tissue. The results suggest a conserved function of CETP in adipose tissue and heart, such as a co-ordinate action with LPL to enhance HDL turnover. Although there is considerable overlap in the tissue- and cell-specific pattern of CETP and LPL gene expression, dietary studies revealed only limited parallelism in response at the mRNA level. The increase in CETP mRNA in peripheral tissues in response to increased dietary cholesterol suggests that local induction of CETP synthesis may help to recycle cholesterol deposited in these tissues during lipolysis of dietary lipoproteins.

Adipose Tissue↗
PubMed1991

Effects of acyl-CoA: cholesterol O-acyltransferase inhibition on cholesterol absorption and plasma lipoprotein composition in hamsters.

1. The ACAT inhibitors, CL 277082 and SA 58-035 were administered for 7 days to hamsters fed diets containing 0.5% cholesterol. 2. Both agents inhibited cholesterol absorption, decreased hepatic. VLDL and IDL cholesterol esters, plasma HDL and HDL apoE and A-I. 3. In addition, CL 277082 treatment produced significant decreases in plasma cholesterol, VLDL apoB and plasma IDL. 4. The cholesteryl esters in VLDL and LDL but not HDL were more polyunsaturated in CL 277082 treated animals. 5. These results support the hypothesis that ACAT inhibition in the cholesterol fed hamster results in an inhibition of dietary cholesterol absorption, thus limiting the cholesterol supply required for the hepatic production of triglyceride-rich lipoproteins.

Absorption↗
PubMed1990

Differential utilization of calcitonin gene regulatory DNA sequences in cultured lines of medullary thyroid carcinoma and small-cell lung carcinoma.

Regulation of expression of the human calcitonin gene was found to differ between two tumor lines of different tissue origin, medullary thyroid carcinoma (TT line) and small-cell lung carcinoma (DMS53 line). Distal 5' DNA elements between -750 and -2000 exhibited a stronger basal activity in DMS53 than in TT cells, whereas proximal DNA sequences between -132 and -252 mediated a dramatic cyclic AMP response in TT but not DMS53 cells.

Calcitonin↗