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E McDermott

Publications and source records attributed to E McDermott.

At least 37 records · Page 2Linked to original sources
PubMed1998

Doxycycline inhibits elastin degradation and reduces metalloproteinase activity in a model of aneurysmal disease.

PURPOSE: Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes are mediated by increased levels of endogenous metalloproteinases (MMPs) within the aorta, which provide a potential therapeutic target for pharmacologic agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of doxycycline--an MMP inhibitor--to reduce matrix degradation was assessed in a previously described model of aneurysmal disease that used a brief pulse of elastase to induce MMP production and elastin degradation in arterial organ cultures. METHODS: Porcine aortic segments (n = 8) were preincubated in exogenous pancreatic elastase for 24 hours before culture in standard conditions for 13 days with both 1 and 10 mg/L doxycycline. Control segments were cultured both without doxycycline and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereologic analysis of sections stained with Miller's elastin and van Gieson's stain. RESULTS: Stereologic analysis demonstrated a significant preservation of elastin in aorta treated with doxycycline 10 mg/L (p < 0.001) and demonstrated that this preservation was accompanied by a significant reduction in MMP-9 activity (p < 0.02). Immunoblotting for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) showed no decreased production in the doxycycline-treated groups. CONCLUSIONS: Therapeutic ranges of doxycycline significantly inhibited elastin degradation and MMP-9 production within aortic organ cultures. These data suggest that doxycycline may have a potential application in reducing the growth rates of small abdominal aortic aneurysms.

Animals↗
PubMed1998

Assay of matrix metalloproteinases types 1, 2, 3 and 9 in breast cancer.

Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases implicated in cancer invasion and metastasis. Gelatin zymography was performed on 84 human breast carcinomas and seven normal breast tissues. The precursor form of MMP-2 (72 kDa) was found in 11 (12%) samples, while its two activated forms, i.e. 62 kDa and 59 kDa, were found in three (6%) and 34 (40%) samples respectively. In contrast to MMP-2, most of the samples (52%) contained MMP-9 in its precursor form. Using ELISA, MMP-1 levels were found in 12% of the samples while MMP-3 levels were found in only 2% of the samples. Levels of MMP-2, -3 and -9 correlated inversely with numbers of nodal metastases. Neither MMP-2 nor -9 levels were significantly related to patient outcome. However, patients with high levels of a 50-kDa gelatinase band after zymography had a significantly better survival than patients with low levels. This species was never observed in normal breast tissue.

Breast↗
PubMed1997

Plasminogen activator inhibitor type 2 in breast cancer.

The serine protease urokinase plasminogen activator (uPA) is causally involved in cancer invasion and metastasis. Activity of this protease in vivo is controlled principally by two inhibitors, one of which is plasminogen activator inhibitor type 2 (PAI-2). In this study, we show that PAI-2 levels were significantly higher in primary breast carcinomas (n = 152) than benign breast tumours (n = 18). In the primary cancers, PAI-2 levels correlated weakly but significantly with those of uPA and PAI-1, but not with tissue type plasminogen activator (tPA) or uPA receptor (uPAR) levels. Using Northern blotting, mRNA for PAI-2 was found in 28.6% of 49 primary breast cancers. In contrast to findings at the protein level, PAI-2 mRNA levels failed to correlate with those for uPA or PAI-1. After immunocytochemistry with primary cancers, PAI-2 was detected predominantly in the malignant cells of primary carcinomas but was also present in stromal cells. Using the median value as a cut-off point, PAI-2 showed no significant relationship with either disease-free interval or overall survival. However, using an optimum cut-off value, patients with low levels of PAI-2 had a worse outcome than those with a high level. We conclude that, unlike PAI-1, high levels of PAI-2 may be a favourable prognostic marker in breast cancer.

Age Factors↗
PubMed1996

Multiple drug resistance-related messenger RNA expression in archival formalin-fixed paraffin-embedded human breast tumour tissue.

A method is described by which RNA, suitable for reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, can be extracted from formalin-fixed paraffin-embedded (FFPE) tissues and subsequently used for detecting the expression of several genes. Using this technique, RNA can be extracted from specimens, quantified, reverse transcribed and regions of interest amplified and analysed within 36 h. The tissue specimens included in this study were from human breast carcinoma, investigating a range of genes associated with the development and/or maintenance of multiple drug resistance (MDR). This technique, applied to archival tissues, offers great potential for increasing our understanding of alterations in expression levels of genes associated with MDR. The method developed is also applicable to studies on expression of other genes in paraffin-embedded tissues.

Adult↗
PubMed1996

Further evidence for genetic anticipation in familial rheumatoid arthritis.

OBJECTIVE: To determine whether preliminary evidence supporting features of genetic anticipation in familial rheumatoid arthritis (RA) could be replicated in independent and larger samples. METHOD: Data were obtained from records of 59 multicase families from the Arthritis and Rheumatism Council (ARC) National Repository in Manchester, 65 multicase families from Cleveland, Ohio, USA, and 253 consecutive patients with RA attending clinics in Nottingham. RESULTS: Mean ages of disease onset in the parents affected with RA were consistently greater than those in the probands. In the ARC data, the mean age difference in disease onset between the affected mother and proband pairs was 16.0 years (95% confidence interval (CI) 7.2 to 24.8 years, n = 11); in the Cleveland data it was 7.8 years (95% CI 0.9 to 14.7 years, n = 24), and in the Nottingham data it was 10.4 years (95% CI 2.8 to 18.0 years, n = 28). Similar results were found in the limited number of father-proband pairs. Unlike the findings of earlier work, there was no correlation between proband age at disease onset and age of the parent at conception of the proband. CONCLUSION: In independent and larger familial RA data sets, features of genetic anticipation were replicated. Our findings support the case for further research at a molecular level into genetic anticipation in those families with two successive generations affected by RA.

Adult↗
PubMed1996

Urokinase plasminogen activator as a predictor of aggressive disease in breast cancer.

Urokinase plasminogen activator (uPA) is a multifunctional protein involved in both extracellular proteolysis and signal transduction. uPA usually mediates its actions while attached to a membrane-bound receptor, termed uPAR. In this study, uPA and its receptor were measured at both protein and mRNA levels in breast cancer. At both levels, concentrations of uPA were significantly correlated with those for uPAR. uPA levels also correlated significantly with cathepsin B and cathepsin D but not with cathepsin L, MMP-8 or MMP-9 levels. Irrespective of the cut-off point used (e.g., median, tertile or quartile values), uPA was a significant prognostic marker for breast cancer.

Blotting, Northern↗
PubMed1995

Urokinase plasminogen activator and urokinase plasminogen activator receptor in breast cancer.

Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. uPA mediates its action while attached to a membrane-bound receptor (uPAR). In this investigation we show that uPAR levels correlate with uPA levels in human breast cancers. uPAR levels, however, do not correlate with other components of the plasminogen activator system such as tissue-type plasminogen activator (t-PA), PAI-I or PAI-2. In addition, uPAR levels showed no correlation with tumor size, axillary-node status or estrogen-receptor status. On the basis of an optimum cut-off point, patients with breast cancers containing high levels of uPAR had a worse prognosis than patients with low levels of the receptor. However, as a prognostic marker in breast cancer, uPAR was not as strong as uPA. Our results are consistent with data from model systems suggesting that both uPA and uPAR are necessary for metastasis.

Breast Neoplasms↗
PubMed1995

Assay of matrix metalloproteases types 8 and 9 by ELISA in human breast cancer.

Results from model tumour systems suggest that either increased levels of certain metalloproteases (MMPs) or decreased levels of their inhibitors correlate with metastatic potential. In this study, levels of two MMPs, i.e. MMP-8 and -9, and their inhibitor tissue inhibitor of metalloprotease type 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in human breast tumours. Levels of MMP-8 and -9 correlated significantly with each other, but neither MMP correlated with urokinase plasminogen activator. Levels of both MMP-8 and -9 were also significantly related to levels of TIMP-1. In contrast, neither MMP correlated with plasminogen activator inhibitor. No relationship was found between MMP-8, MMP-9 or TIMP-1 and either tumour size or metastasis to axillary nodes. MMP-8 and -9 levels were inversely related to levels of oestrogen receptors. MMP-8 but not MMP-9 levels were also inversely correlated with progesterone receptor levels. It is concluded that the assay for MMP-8 and -9 described here will permit the evaluation of these proteases as prognostic markers in cancer.

Biomarkers, Tumor↗
PubMed1994

Urokinase plasminogen activator as a prognostic marker in different subgroups of patients with breast cancer.

BACKGROUND: Urokinase plasminogen activator (uPA) is a serine protease involved in cancer invasion and metastasis. Previously, uPA was shown to be an independent prognostic marker in breast cancer. The aim of this study were to evaluate uPA as a prognostic marker in different subgroups of patients with breast cancer. METHODS: Urokinase plasminogen activator was assayed by enzyme-linked immunosorbent assay in detergent extracts of human breast tumors. RESULTS: Using both disease free interval (DFI) and overall survival (OS) as end points, uPA was an indicator of prognosis in the following groups of patients: those with positive axillary nodes, those who were estrogen receptor (ER)-positive, women younger than 50 years of age, and women older than 50 years of age. For patients with negative axillary lymph nodes, uPA was a significant prognostic marker using DFI as an end point and was almost statistically significant (P = 0.055) using OS as end point. In patients who were ER-negative, uPA levels showed no significant relationship with patient outcome. CONCLUSIONS: Urokinase plasminogen activator is a significant prognostic marker in most of the major subgroups of patients with breast cancer and may be a marker for patients with negative axillary lymph nodes.

Animals↗
PubMed1992

Enzyme-linked immunosorbent assay of c-erbB-2 oncoprotein in breast cancer.

Amplification or increased expression of the c-erbB-2 gene has previously been reported to be a prognostic marker for breast cancer. Gene amplification is usually measured by Southern blotting, whereas increased protein expression is usually detected by immunocytochemistry. We measured c-erbB-2 protein with an enzyme-linked immunosorbent assay (ELISA). High concentrations of oncoprotein were found in 25 of 161 (16%) primary breast cancers and in 3 of 6 (50%) breast cancer metastases. High concentrations were not found in normal breast tissue or benign breast tumors. In the primary cancers, high concentrations of c-erbB-2 protein were found more frequently (a) in estrogen receptor-negative tumors than in estrogen receptor-positive tumors, (b) in progesterone receptor-negative tumors than in progesterone-positive tumors, and (c) in axillary node-positive cancers than in node-negative cancers. Patients with tumors containing high amounts of the c-erbB-2 protein had a significantly shorter (P less than 0.001) disease-free interval and overall survival rate than did patients with low amounts. We conclude that assay of c-erbB-2 protein by ELISA is simple, rapid, and quantitative and offers important prognostic information in breast cancer.

Biomarkers, Tumor↗
PubMed1991

Cathepsin D concentration in breast cancer cytosols: correlation with biochemical, histological, and clinical findings.

Cathepsin D (CD, EC 3.4.23.5) is a lysosomal protease induced by estrogen in certain estrogen receptor (ER)-positive breast cancer cell lines but produced constitutively by ER-negative cell lines. Our aims in this investigation were to study the distribution of CD in human breast cancers and to relate its concentrations to various biochemical, histological, and clinical characteristics. The concentrations of CD were significantly higher in breast carcinomas than in either normal breast tissues or benign breast tumors. In primary carcinomas, CD concentrations did not correlate with the concentrations of ER or with the estrogen-inducible protease t-PA. However, CD concentrations did correlate weakly but significantly with both UK-PA antigen and UK-PA activity. Also, CD concentrations did not correlate with either tumor stage or axillary node status but did correlate significantly with tumor grade. Patients with cancers containing high concentrations of CD had a significantly shorter overall survival than did patients with low concentrations of the enzyme.

Breast Neoplasms↗
PubMed1987

Influence of spinal and general anaesthesia on haemostasis during total hip arthroplasty.

One hundred and one patients with osteoarthritis were randomly allocated to undergo total hip arthroplasty under either spinal (subarachnoid) or general anaesthesia. Venous blood was sampled before, during and after surgery and on the 5th day after operation to study the haemostatic mechanism. There were no preoperative differences between the two anaesthetic groups. Although there was pronounced individual variability, similar patterns of change in coagulation, platelets and fibrinolysis were seen in both groups. However, there were significant differences between the two groups in platelet count, thrombin production, and Factor VIIIRAg in the intra- and immediate postoperative periods. Also, compared with general anaesthesia, there was less intraoperative activation of fibrinolysis, as measured by the euglobulin clot lysis time, with spinal anaesthesia. These differences suggest slight modification of the haemostatic response to surgery with spinal anaesthesia, which could be consistent with a neuroendocrine mechanism. By the 5th day both groups exhibited a very similar "hypercoagulable" postoperative state.

Aged↗