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Biomedical subjects

S Nicholson

Publications and source records attributed to S Nicholson.

At least 73 records · Page 4Linked to original sources
PubMed1990

Epidermal growth factor receptor (EGFr) as a marker for poor prognosis in node-negative breast cancer patients: neu and tamoxifen failure.

Analysis of EGFr and ER was performed on tumour samples from 231 patients with operable breast cancer followed for up to 6 yr after surgery. The median duration of follow-up in patients still alive at the time of analysis was 45 months. Thirty-five percent of patients (82) had tumours greater than 10 fmol/mg 125I-EGF binding (EGFr+) and 47% (109) had cystolic ER concentration greater than 5 fmol/mg (ER+), with a marked inverse relationship between EGFr and ER (P less than 0.00001). EGFr was second only to axillary node status as a prognostic marker for all patients both in terms of relapse-free and overall survival (P less than 0.001, logrank EGFr+ vs EGFr-). For patients with histologically negative axillary nodes EGFr was superior to ER in predicting relapse and survival (P less than 0.01 and P less than 0.005, respectively, compared to P less than 0.1 and P less than 0.1, logrank). In a multivariate (Cox model) analysis only EGFr, out of EGFr, ER, size and grade, was predictive for either relapse-free or overall survival for patients with node-negative disease (P = 0.052 and P = 0.026, respectively). The correlation of neu expression with response to tamoxifen in patients with recurrent disease was assessed immunochemically. Response rate was reduced in the presence of neu from 50 to 17% for ER+ cases and from 26 to 0% for ER- cases.

Biomarkers, Tumor↗
PubMed1990

Epidemiology and hepatitis C virus in Victoria.

Parenterally transmitted non-A, non-B (NANB) hepatitis virus or hepatitis C virus is a common cause of both acute and chronic hepatitis. Using a recently developed enzyme-linked immunosorbent assay we looked at the prevalence of antibodies to hepatis C virus (anti-HCV) in a number of groups. People with haemophilia (75.6%) and intravenous drug users (61.9%) had the highest prevalence, while homosexual men attending a sauna (34.1%) and prisoners (30.8%) had a moderately high prevalence of anti-HCV. A lower prevalence of antibody was detected in female prostitutes (10.4%), institutionalised mentally retarded subjects (9.5%), homosexual men requesting human immunodeficiency virus (HIV) testing through their local doctor (8.8%), dialysis patients (5.9%), renal transplant patients (6.9%), and patients referred from a sexually transmitted diseases clinic (6.2%). The lowest prevalence of anti-HCV was recorded in women attending a provincial hospital for antenatal care (0.4%). The predominance of anti-HCV in groups of people exposed to blood-borne and sexually transmitted infections suggests that these routes may be primarily involved in the spread of hepatitis C virus infection.

Adult↗
PubMed1990

Expression of the neuron-specific glycoprotein GP50 by granule cell cultures.

The expression and properties of the neuron-specific glycoprotein, GP50, by neonatal rat granule cells grown in primary tissue culture were studied using the monoclonal antibody MabSM-GP50. GP50 was expressed by granule cells in culture but not by astrocytes or PC12 cells that had been induced to differentiate with nerve growth factor. Immunocytochemical staining of granule cell cultures demonstrated that immunoreactivity was concentrated in the cell body. Although the amount of GP50 increased slowly throughout the culture period the maximum level of expression in vitro was markedly lower than that observed in cerebellum of the comparable age. Radiolabelling of cell surface proteins by lactoperoxidase-catalyzed iodination demonstrated that GP50 was expressed on the surface of granule cells. Following phase-partitioning of granule cells in the presence of Triton X-114, 75% of GP50 was found to be present in the detergent phase, indicating that it is an integral membrane protein. Sucrose density gradient centrifugation of Triton X-100 extracts of granule cells resolved GP50 into two components with sedimentation coefficients of 3.6S and 7.3S. The 3.6S species (Mr 42,000 Da) accounted for greater than 80% of the total, indicating that GP50 is present predominantly in a monomeric form within the membrane. These properties are similar to those of GP50 expressed in P12 cerebellum but contrast with the behavior of GP50 from mature brain, in which the 7.3S, hydrophilic form is the predominant species. The results suggest that the mature expression of GP50 may be dependent upon the histotypic pattern of development which occurs in vivo.

Animals↗
PubMed1990

Prognostic significance of the estrogen-regulated protein, cathepsin D, in breast cancer. An immunohistochemical study.

Expression of the estrogen-regulated lysosomal protease, cathepsin D, was studied in a series of 94 breast cancers using an immunohistochemical technique. Granular staining of tumor cell cytoplasm was detected in 62 cases. Positive staining was associated with a significant increase in overall time to relapse and when survival was analyzed in terms of intensity of cathepsin D staining there was a significant trend for both increased time to relapse and increased length of survival. The presence of estrogen receptor was associated with positive cathepsin D immunostaining, and in the subgroup of estrogen receptor-positive tumors cathepsin D staining was associated with significantly prolonged survival; this was not the case for estrogen receptor-negative tumors. Positive cathepsin D immunostaining was associated with significant prognostic advantage in patients with confirmed lymph node metastasis but not in node-negative patients. It is suggested that cathepsin D expression reflects the functional integrity of the estrogen response pathway. Cathepsin D may prove a clinically useful adjunct to assessment of estrogen receptor status.

Adult↗
PubMed1990

Expression of the oestrogen regulated pNR-2 mRNA in human breast cancer: relation to oestrogen receptor mRNA levels and response to tamoxifen therapy.

The pNR-2 mRNA is regulated by oestrogens in cell lines established from metastatic human breast cancer cells. The levels of the pNR-2 and oestrogen receptor RNAs have been measured in 96 tumour samples from patients undergoing surgery for breast cancer. Oestrogen receptor mRNA was detected in 90% of the 60 primary breast tumour samples from patients not receiving endocrine therapy at the time of surgery, whereas the pNR-2 RNA was detected in 57%. In primary tumours the expression of pNR-2 was entirely dependent upon oestrogen receptor RNA expression. When the 60 primary tumours were considered, pNR-2 and oestrogen receptor mRNA levels were significantly correlated. There was no significant correlation for pNR-2 positive tumours. pNR-2 mRNA levels were similar in tumours of pre- and post-menopausal patients and were independent of tumour differentiation and nodal status. Oestrogen receptor and pNR-2 mRNA levels were also measured in 21 tumour samples from patients receiving primary tamoxifen therapy. Eleven of these had shown an objective response and a significantly larger number of tumours from these patients contained pNR-2 mRNA than from patients who did not respond (chi 2 = 6.08, P less than 0.025).

Breast Neoplasms↗
PubMed1990

Humoral immune responses in mice using gamma inulin preparations as adjuvants for hepatitis B vaccines.

There is an urgent need for new, powerful adjuvants suitable for use with sub-unit and peptide vaccines in humans. We have measured the humoral immune response in BALB/c mice to vaccine formulations using recombinant HBsAg antigens, and gamma inulin and alum adjuvants. Using Merck, Sharpe & Dohme (MSD) HBsAg at 10 micrograms/mL, high levels of anti-HBs were generated and geometric mean S/N ratios of 88, 133 and 107 were obtained for alum absorbed vaccine, gamma inulin, and a mixture of the two adjuvants, respectively. A dilution series produced ED50 values of 0.08, 0.15 and 0.22 micrograms/mL respectively. In a second series of experiments comparing alum and algamulin (a complex of gamma inulin and alum), MSD HBsAg induced anti-HBs levels of 81 and 52, and ED50 values of 0.3 and 0.4 when used in conjunction with alum and algamulin, respectively. SKF HBsAg induced anti-HBs levels of 126 and 111 with alum and algamulin, and ED50 values of 0.11 and 0.075. The class, subclass and level of antibody produced in mice boosted with a second dose of vaccine at 21 days was also examined. Both alum and gamma inulin induced higher levels of total antibody, IgG1 and minor IgG subclasses than algamulin, or HBsAg alone. Overall, gamma inulin appears to be an equivalent adjuvant to alum, although their mechanisms of action are different. Mixtures or complexes of the two adjuvants appear to be less effective in inducing humoral immune responses in mice than either alone.

Adjuvants, Immunologic↗
PubMed1989

Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer.

Sections of formalin-fixed, paraffin-embedded tissue from 185 primary breast carcinomas were stained immunohistochemically using a polyclonal antibody against the c-erbB-2 oncoprotein. Positive staining, which is known to correlate with gene amplification, was associated with earlier relapse, shorter postrelapse survival, and shorter overall survival. Lymph node, epidermal growth factor receptor, and estrogen receptor status, tumor size, and histological grade also had prognostic significance but, applying multivariate analysis, only lymph node status was a more important predictor of relapse-free and overall survival than staining for the oncoprotein. Positive staining was correlated with negative estrogen receptor status and high histological grade, but there was no association with either lymph node or epidermal growth factor receptor status or tumor size. Expression of the c-erbB-2 oncoprotein appears to be an important independent indicator of prognosis in human breast cancer.

Analysis of Variance↗
PubMed1989

Expression of epidermal growth factor receptors associated with lack of response to endocrine therapy in recurrent breast cancer.

Epidermal growth factor receptors (EGFR) and oestrogen receptors (ER) were analysed in 221 patients with primary operable breast cancer by means of radioligand assays. After median follow-up of 24 months (range 3-60 months), there had been recurrences in 99 patients, of whom 72 (median age 56 years, range 32-77 years) received tamoxifen alone as first-line treatment for recurrence. 20 patients (28%) showed a response to this therapy and 52 (72%) did not. Of 32 ER-positive tumours, 12 (37.5%) showed an objective response to tamoxifen compared with only 2 of 40 (5%) ER-negative tumours (p less than 0.005). Of 35 EGFR-positive tumours, 3 (8.5%) achieved an objective response compared with 11 of 37 (30%) EGFR-negative tumours (p less than 0.05). Only 1 of 28 EGFR-positive, ER-negative tumours achieved an objective response. Including patients whose disease remained stable for more than 6 months with the responders, however, EGFR status was a better predictor of response to tamoxifen; 15 of 37 EGFR-negative patients and 5 of 35 EGFR-positive patients responded (p less than 0.01), compared with 13 of 32 ER-positive and 7 of 40 ER-negative patients (not significant). EGFR expression is a highly significant marker of poor prognosis in patients with breast cancer; it appears to be as good a predictor as ER for objective response and better for overall response to endocrine therapy on relapse.

Adult↗
PubMed1989

Epidermal growth factor receptors in breast cancer: association with early relapse and death, poor response to hormones and interactions with neu.

Epidermal growth factor receptors (EGFRs) were measured in 221 primary breast cancers by ligand binding with 125I-labelled EGF, and high-affinity sites were quantitated. There was a highly significant inverse relationship between oestrogen receptor (ER) and EGFR (15 EGFR-positive [EGFR+]ER+ and 92 EGFR-negative [EGFR-]ER+: 54 EGFR- ER- and 60 EGFR+ ER-). The relapse-free survival and overall survival were significantly shorter for EGFR+ vs EGFR- tumours (P less than 0.001) by about 2 yr in the case of relapse-free survival. When ER- tumours were substratified by EGFR status, the EGFR- ER- tumours had a prognosis almost as good as the ER+ tumours. In 31 of 184 cases, high expression of neu, correlating with amplification, was found. Expression of neu conferred similar poor prognosis to EGFR expression in all prognostic subgroups. Coexpression of neu and EGFR had an additive adverse effect. Epidermal growth factor receptors (EGFR) and oestrogen receptors (ER) were analysed in 221 patients with primary operable breast cancer by means of radioligand assays. After median follow-up of 24 months (range 3-60 months), there had been recurrences in 99 patients, of whom 72 (median age 56 yr, range 32-77 yr) received tamoxifen alone as first-line treatment for recurrence. 14 patients (19%) showed a response to this therapy and 58 (81%) did not. Of 32 ER+ tumours, 12 (37.5%) showed an objective response to tamoxifen compared with only 2 of 40 (5%) ER- tumours (P less than 0.005). Of 35 EGFR+ tumours, 3 (8.5%) achieved an objective response compared with 11 of 36 (30%) EGFR tumours (P less than 0.05). Only 1 of 28 EGFR+, ER- tumours achieved an objective response. Including patients whose disease remained stable for more than 6 months with the responders, however, EGFR status was a better predictor of response to tamoxifen; 15 of 37 EGFR- patients and 5 of 35 EGFR+ patients responded (P less than 0.01).

Adult↗
PubMed1989

Duplex ultrasonography of the fetal aorta, umbilical artery, and placental arcuate artery throughout normal human pregnancy.

A cross-sectional duplex study of blood flow in the fetal aorta, umbilical artery, and arcuate arteries of 111 normal subjects was performed once at between 20 and 42 weeks gestation. Peak systolic velocity, end-diastolic velocity, mean velocity, and volume flow were measured in the fetal aorta, and systolic to diastolic (S/D) ratios were measured in all three vessels. Velocities show an inverse exponential (Y = Exp [1/X x B + C]) increase with gestational age, reaching a plateau just before term, while S/D ratios in the aorta and umbilical arteries show a linear decrease. Such findings are at variance with some published data. Our results suggest a reduction in fetal placental resistance at term and provide useful data concerning normal fetal and placental circulations.

Aorta↗
PubMed1988

Relationship of membrane-bound tissue type and urokinase type plasminogen activators in human breast cancers to estrogen and epidermal growth factor receptors.

The total plasminogen activator (PA) activity and the activities of urokinase type (uPA) and tissue type (tPA) plasminogen activators were measured in 43 primary human breast cancer homogenates. The majority of the PA activity was found in the 100,000 X g crude membrane pellets (log mean of 490 milli-IU/mg of protein, +1169, -346), and little PA activity was present in the cytosolic supernatant (log mean of 19 milli-IU/mg of protein, +168, -17). The activities of total PA and of each type of PA were compared to the estrogen receptor (ER) and epidermal growth factor receptor (EGFR) status of the tumors and to their histological grade. Total PA activity and uPA activity were not significantly different in any group of tumors stratified according to receptor status or tumor grade. Tissue type PA levels, however, were significantly lower in ER-negative compared with ER-positive tumors and in EGFR-positive compared with EGFR-negative tumors (P less than 0.01 and less than 0.05, respectively). The tPA activity was also related to grade, decreasing with worsening differentiation (P = 0.04). The ER-negative tumors were further stratified into EGFR-positive and -negative subgroups. Only the ER-negative tumors possessing EGFR had significantly lower tPA levels than the ER-positive tumors (P less than 0.01). Low tPA levels in breast cancers were, therefore, associated with ER negativity combined with EGFR positivity and may be an indication of poorer differentiation and prognosis.

Breast Neoplasms↗
PubMed1988

Quantitative assays of epidermal growth factor receptor in human breast cancer: cut-off points of clinical relevance.

Epidermal growth factor receptor (EGFr) assays were performed by 3 different methods on 246 human primary breast carcinomas. Scatchard analyses of multipoint binding data on 19 of the first 209 tumours, performed by a displacement method, demonstrated that the majority of tumours exhibited 2 classes of binding site, the high-affinity site with an affinity constant (KD) of mean 2 nmol/l (SD 1.3, range 0.44-7 nmol/l), and a low-affinity site, KD mean 9.5 nmol/l (range 6-15.5 nmol/l). Scatchard analysis of multipoint assays using increasing concentrations of 125I-labelled EGF showed that saturation of the high-affinity site occurred in the majority of saturation of the high-affinity site occurred in the majority of tumours at a concentration of labelled EGF of I nM. Comparison of the KD values of the high-affinity site obtained from displacement assays with those obtained by increasing labelled EGF showed that the KD was significantly higher (p = 0.0002) when measured by the latter method. There was no difference in binding capacity of the high-affinity or low-affinity sites by the 2 methods. A 2-point assay with I nM labelled EGF (specific activity approx. 80-130 microCi/microgram) correlated with quantitative values for the high-affinity site from Scatchard analysis (p less than 0.02). There was a strong inverse relationship between EGFr greater than 10 fmol/mg membrane protein (2-point assay) and ER (dextran-coated charcoal method), Chi-squared 2 X 2 contingency table test = 34.027, p less than 0.0001. Follow-up data from 135 patients revealed a strong inverse relationship between EGFr greater than 10 fmol/mg membrane protein and oestrogen receptor (ER) status and a positive correlation with early recurrence and death. Our data describe a reproducible assay for EGFr and show that a cut-off point at 10 fmol/mg allows clinically useful application.

Binding Sites↗