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Biomedical subjects

C Wright

Publications and source records attributed to C Wright.

At least 217 records · Page 12Linked to original sources
PubMed1991

Node negative breast cancer: the prognostic value of DNA ploidy for long-term survival.

The DNA content of breast tumours from 170 patients who presented between 1978 and 1980 was measured by flow cytometry. The relationship between tumour ploidy and disease outcome was assessed and its association with other prognostic factors evaluated. Compared with those with diploid tumours, patients with aneuploid tumours had significantly earlier relapse and shorter survival (P less than 0.0001). Tumour ploidy was strongly related to grade (P less than 0.001), but there was no significant association between DNA ploidy and c-erb-B-2 expression, lymph node status or tumour size. In lymph node negative and c-erb-B-2 negative patients, aneuploid tumours were associated with a poorer prognosis (P less than 0.001) than diploid tumours. Multivariate analysis showed that tumour ploidy gave independent information on disease free and overall survival. Tumour ploidy may be used as an independent prognostic variable in patients with breast cancer and it may be helpful in defining patients within the node negative or c-erb-B-2 negative groups likely to have a poor outcome who might benefit from adjuvant treatment.

Adult↗
PubMed1991

Long-term survival in breast cancer related to overexpression of the c-erbB-2 oncoprotein: an immunohistochemical study using monoclonal antibody NCL-CB11.

In a previous series we have shown poor short-term (3-5 years) survival for patients with tumours overexpressing the c-erbB-2 oncoprotein. In this study we employed archival paraffin-embedded tissue from patients who underwent mastectomy 10-12 years prior to assessment (n = 187). Immunohistochemical staining was carried out by an indirect immunoperoxidase technique using the novel monoclonal antibody NCL-CB11. Tumours were scored according to intensity of membrane staining. Patient and tumour information was obtained by scrutiny of clinical records. Survival analysis was carried out for both time to relapse and time to death, using the log rank test. Patients with tumours demonstrating intense membrane staining had a poor prognosis compared with the rest, with a steeply sloped survival curve over the first 4 years; the survival difference was still evident at 12 years follow-up (P less than 0.001). The survival advantage for c-erbB-2 negative patients was maintained in lymph node negative patients (P less than 0.001). However, c-erbB-2 status did not influence survival in the node positive group, where all patients had a uniformly poor outlook. These results applied to both time to relapse and time to death. In conclusion, c-erbB-2 status, determined using NCL-CB11, is a powerful prognostic indicator, defining in particular node negative patients with a particularly poor prognosis, and for whom alternative therapeutic strategies may be appropriate.

Antibodies, Monoclonal↗
PubMed1991

p53 expression in human breast cancer related to survival and prognostic factors: an immunohistochemical study.

In a study of 90 breast cancer patients, tumour p53 protein expression was determined by immunohistochemistry using the monoclonal antibody PAb1801. Patient lymph node status and Bloom's grade were determined, and both oestrogen and progesterone status assessed, also by immunohistochemistry. Lymph node status, tumour grade, and progesterone receptor status all had a significant influence on survival. Patients with p53-positive tumours showed poorer survival but this did not achieve significance. p53 protein expression showed a significant relationship to high tumour grade and a weak correlation with negative oestrogen receptor status. The data suggest that p53 protein expression may be a marker of more aggressive carcinomas but that the prognostic power of expression is likely to be weak and unlikely, therefore, to be of clinical value. The results do not resolve whether detectable p53 protein expression represents a random product of dedifferentiation, or an important feature of the malignant phenotype, playing a key role in tumour behaviour. The number of patients in our study is small, however, and investigation of a larger series is clearly indicated.

Antibodies, Monoclonal↗
PubMed1991

Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar.

The hormone dependency of the MCF-7 breast cancer cell line, while extensively tested in liquid culture, has not been previously evaluated under conditions of anchorage-independent growth in serum-free media. Using the soft agar clonogenic assay, we demonstrate that physiologically relevant concentrations of estradiol (E2), progesterone (Pg), and prolactin (PRL) similarly stimulated MCF-7 cell colony formation in the absence of serum. Addition of an anti-insulin-like growth factor-I (IGF-I) antibody inhibited E2- and Pg-stimulated growth, while PRL action was not affected. Similar results were obtained with an anti-IGF-I receptor antibody, except that its inhibitory effect on Pg-induced colony formation was modest and not statistically significant. Administration of either an anti-transforming growth factor-alpha (TGF-alpha) antibody or an anti-epidermal growth factor (EGF) receptor antibody similarly inhibited E2-stimulated MCF-7 cell growth in soft agar, while neither antibody influenced Pg or PRL effects. Addition of TGF-beta 1, -beta 2, -beta 3 similarly suppressed MCF-7 cell colony formation in a dose dependent manner to a degree comparable to that observed with 4-OH-tamoxifen (4-OH-T). Furthermore, the growth inhibitory effect of 4-OH-T was completely reversed by an anti-TGF-beta antibody. We conclude that IGFs and TGF-alpha are important mediators of E2-stimulated MCF-7 cell growth in soft agar. IGFs may also be playing a role in Pg action, while neither growth factor is involved in PRL-stimulated colony formation. Finally, TGF-beta appears to be an important mediator of antiestrogen-induced inhibition of tumor growth.

Agar↗
PubMed1991

The influence of right heart catheterisation on pulmonary arterial pressure in chronic heart failure: relationship to neuroendocrinal changes.

Continuous ambulatory measurement of pulmonary arterial pressure was used to investigate changes following right heart catheterisation in patients with chronic heart failure. Ten males, mean age 56 years, with chronic heart failure, underwent 24 hour pressure recording using a micromanometer tipped catheter with in vivo calibration and frequency modulated recording. Eight patients were taking diuretics and 3 vasodilators. Blood was drawn for catecholamines, plasma renin activity and atrial natriuretic peptide 1 hour before catheterisation (-1 h), at the time of catheterisation (0 h) and 1, 2, 3, 4 and 6 hours later and aldosterone, cortisol and growth hormone at -1, 0 and 6 hours. Analysis of variance was used to determine changes in pulmonary arterial pressure, heart rate and hormones from the time of catheterisation in lying, sitting and standing postures. There was no significant change in pulmonary arterial pressure or heart rate over the 12 hours following or 24 hours after catheterisation in any posture. In the majority of patients plasma noradrenaline, plasma renin activity, atrial natriuretic peptide, aldosterone and cortisol were elevated. There was no significant change in hormone levels during the 6 hours following catheterisation. These findings suggest that the effect of invasive haemodynamic monitoring and chronic medical therapy on central haemodynamics is minor, and that a delay between insertion of catheters and measurement of pressure is unnecessary.

Adult↗
PubMed1991

Double-blind randomised placebo-controlled dose-efficacy study of sustained release verapamil in chronic stable angina.

The efficacy and tolerability of sustained release verapamil (Securon SR) was investigated in twenty-four patients with chronic stable angina. Patients entered four randomised, double-blind treatment periods, each lasting one week of verapamil-SR 240 mg once daily, 360 mg once daily, 240 mg twice daily, and matching placebo. Four patients were withdrawn, but in one instance this was attributable to side effects from verapamil. Among the remaining twenty patients, mean frequency of angina fell from 4.25 episodes during the last five days of placebo to 2.35, 2.6 and 1.3 episodes during respective active treatments (all P less than 0.001). Compared with placebo the median percentage increase in time to 1 mV ST depression during treadmill exercise (12 hours post dose) was significant only with the regimen of verapamil-SR 240 mg given twice daily at +11% (P = 0.04). Total duration of exercise was also significantly longer and maximum ST depression significantly less only with the twice daily treatment (704 + 186 sec vs 648 + 203 sec; P = 0.03, and 1.75 + 0.73 mm vs 2.15 +/- 0.62 mm; P = 0.02). Side effects, predominantly constipation, breathlessness, and swollen ankles, occurred most frequently with verapamil-SR 360 mg. Thus, sustained release verapamil is well tolerated and effective in the treatment of angina. A regimen of 240 mg given twice daily emerges as superior to once daily treatments for 24-hour prophylaxis of angina.

Aged↗
PubMed1991

Time course of naloxone-precipitated withdrawal after acute methadone exposure in humans.

This study examined naloxone-precipitated withdrawal symptoms from 24 to 168 h after pretreatment with a single 30-mg i.m. dose of methadone in 6 male subjects who were experienced users of opioid drugs but were not currently dependent. The study showed that acute physical dependence signs and symptoms could be reliably precipitated with a small dose of naloxone (0.75 mg/70 kg i.m.) for as long as 96 h (4 days) after a single dose of methadone. The intensity of symptoms at 24 h post-methadone was similar to that observed at 96 h; no precipitated withdrawal effects were observed at 168 h (7 days) after methadone administration. The magnitude of precipitated withdrawal effects at 96 h was not attenuated by the administration of a prior naloxone challenge at 24 h post-methadone. Agonist effects (pupillary constriction; subjective effects) were detectable at 24 h but not at 96 h post-methadone. The results suggest that methadone engenders long-lasting physical dependence effects that can be detected beyond the dissipation of acute agonist effects. Methadone pretreatments may provide a convenient mechanism for the production and examination of long-term mu-opiate receptor physical dependence.

Adult↗
PubMed1991

Acute physical dependence in humans: repeated naloxone-precipitated withdrawal after a single dose of methadone.

This paper reports the intensity and duration of acute physical dependence precipitated by naloxone administration following a single pre-treatment with the opioid against methadone (30 mg/70 kg, i.m.) in six non-dependent human volunteers with histories of prior opioid abuse. In a within-subject cross-over design, challenges of the antagonist naloxone (0.5-1.0 mg, i.m.) were administered at 6, 30 and 54 h, or at only 54 h after methadone pre-treatment. Acute physical dependence, as indicated by physiologic, subjective, and observer rated withdrawal, was seen in all subjects following active naloxone administration, was of nearly uniform intensity for a period of 6-54 h after acute methadone administration, and was not attenuated by prior naloxone administration.

Adult↗
PubMed1991

Role of transforming growth factor-alpha (TGF-alpha) in basal and hormone-stimulated growth by estradiol, prolactin and progesterone in human and rat mammary tumor cells: studies using TGF-alpha and EGF receptor antibodies.

The biological role of transforming growth factor-alpha (TGF-alpha) in basal and hormone-stimulated proliferation of primary human and rat mammary tumor cells was studied using antibodies against TGF-alpha and its receptor. A monoclonal antibody, MAb-425 against human EGF receptor was added to in vitro soft agar, clonogenic cultures of human breast carcinoma cells under basal and estradiol(E2)-stimulated conditions. The antibody had an antagonist effect on colony growth in 4 of 10 tumors and an agonist effect in 4 (72 and 153% of control). E2-stimulated colony growth in 5 tumors (167% of control) and the antibody blocked E2-stimulation in 3 of the 5. Inhibition of E2-stimulated growth in 3 and basal growth in 4 other tumors by the EGF receptor antibody suggest that endogenously secreted TGF-alpha has a role as an autocrine/paracrine growth factor in constitutive and E2-stimulated tumor cell proliferation in a majority of human tumors. A polyclonal antibody against TGF-alpha was used to study the role of TGF-alpha in E2-, prolactin(Prl)- and progesterone(Prog)-stimulated proliferation of NMU(nitrosomethylurea)-induced rat mammary tumor cells under similar culture conditions. TGF-alpha, E2, Prl and Prog stimulated colony growth equally to 176, 187, 168 and 181% of control. The antibody produced significant and similar inhibition of TGF-alpha and E2-stimulated growth (95 and 83%). In contrast, inhibition of Prl- and Prog-stimulated growth by the antibody was only 24 and 37%. The TGF-alpha ligand antibody did not have an agonist or antagonist effect when added alone. Thus, TGF-alpha seems to be a major stimulatory growth factor mediating E2-induced tumor cell proliferation in rat mammary tumors. It is less important in Prl- and Prog-induced tumor growth and not essential for basal growth in these tumors. We conclude that TGF-alpha is a biologically important autocrine/paracrine growth factor in primary human breast cancer cell proliferation and in E2-induced rat mammary tumor growth.

Animals↗
PubMed1991

c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes.

The c-erbB-2 gene is overexpressed in about 20% of human breast cancers. Four hundred and eighty-three cases previously examined by immunohistochemical staining for c-erbB-2 expression were analysed to assess the risk associated with the elevated protein expression. Oncoprotein expression was correlated with increasing tumour grade but not with oestrogen receptor status, nodal involvement, tumour size or age. There was an increased risk of relapse and death associated with c-erbB-2 expression irrespective of nodal involvement. This marker thus appears to be a significant prognostic factor in the early as well as the late stages of breast cancer.

Adult↗
PubMed1991

Expression of mutant p53, c-erbB-2 and the epidermal growth factor receptor in transitional cell carcinoma of the human urinary bladder.

Expression of the p53, the epidermal growth factor receptor (EGFr; c-erbB-1) and c-erbB-2 proteins was studied in 82 patients with primary transitional cell carcinoma of the bladder using an immuno-histochemical method. Strong or moderate staining was found in 18% of tumours for p53 with weaker staining in a further 36% giving a total of 54% of tumours stained for p53. Strong staining was found in 15% of tumours for c-erbB-2 and in 31% for the EGFr. Tumours invading the bladder muscle were significantly more likely to be strongly stained positively for p53 and/or EGFr compared with superficial tumours: only 15% of invasive tumours were stained negatively for both p53 and EGFr. No statistical association was found between p53 and EGFr expression. Weakly positive associations were found between the expression of c-erbB-2 and p53 and between muscle invasive tumours and increased expression of c-erbB-2. Alterations in the expression of p53, c-erbB-1 and c-erbB-2 were found frequently in human transitional cell carcinoma of the urinary bladder and may be of clinical use in defining patient sub-groups of differing prognosis.

Aged↗
PubMed1991

Epidermal growth factor receptor (EGFr); results of a 6 year follow-up study in operable breast cancer with emphasis on the node negative subgroup.

More accurate criteria are required for the selection of patients with node-negative breast cancer for systemic adjuvant therapy. Expression of epidermal growth factor receptor (EGFr) has been shown previously to be inversely related to oestrogen receptor (ER) in patients with operable breast cancer and to be associated with a poorer prognosis. Analysis of EGFr and ER was performed on tumour samples from 231 patients with operable breast cancer followed for up to 6 years 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 with greater than 10 fmol mg-1 I125-EGF binding (EGFr+) and 47% (109) and cystolic ER concentrations greater than 5 fmol mg-1 (ER+), with a marked inverse relationship between EGFr and ER (P less than 0.00001). In a univariate analysis 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, log rank). 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, log rank). 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 = 0.05 and P = 0.026 respectively). EGFr has been shown to be a marker of poor prognosis for patients with node-negative breast cancer. Since patients with EGFr+ tumours are unlikely to respond to hormone therapy it may be possible to select them for trials of systemic adjuvant chemotherapy.

Breast Neoplasms↗
PubMed1991

Therapeutic implications of dynamic coronary stenosis in patients with single vessel coronary artery disease.

Ten patients with proven single-vessel coronary artery disease and a positive exercise test for ischaemia were investigated to establish the importance and therapeutic implications of dynamic coronary stenosis in such patients. All patients interrupted their anti-anginal therapy and under took serial exercise testing in an attempt to identify variability in the ischaemic threshold. Ergonovine testing was performed in nine patients and all underwent 48 h of ambulatory ST segment monitoring while treatment was discontinued. Patients then entered a randomized double-blind study of atenolol and nifedipine; treadmill exercise testing and 48 h of ambulatory ST segment monitoring were performed at the end of each treatment phase. Six (60%) patients showed evidence of variability in coronary vasomotor tone four of whom developed significant ST segment changes during administration of ergonovine; a further two had greater than 30% variability in time to onset of ischaemia during serial treadmill exercise testing. Atenolol significantly increased the time to ischaemia on exercise testing, both in the group as a whole and in the subgroup with evidence of altered vasomotor tone when compared with no therapy, and led to a non-significant reduction in the frequency and duration of ischaemia during the patients' daily lives. Nifedipine, conversely, did not significantly increase time to ischaemia on exercise testing or reduce the frequency or duration of ambulatory ischaemia in either the whole group or the subgroup. With evidence of altered vasomotor tone when compared to no therapy however it was beneficial in terms of reduction in chest pain and requirement for glyceryl trinitrate during daily life.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Eradication of colonization by methicillin-resistant Staphylococcus aureus by using oral minocycline-rifampin and topical mupirocin.

In an attempt to control the spread of methicillin-resistant Staphylococcus aureus (MRSA) within a spinal cord injury unit, we investigated the mode of transmission and implemented a multidisciplinary approach for control that consisted of grouping of patients into cohorts, contact isolation, and antibiotics. Surveillance cultures of patients and nose and hand cultures of medical personnel were performed. Of 11 colonized patients, 6 had MRSA isolates that shared a similar plasmid profile and antibiogram, raising the possibility of interpatient spread of the organism. Medical personnel had no evident role in transmitting MRSA. All patients' pretherapy MRSA isolates were susceptible to minocycline and, except for one, to rifampin. Time-kill studies showed an indifferent interaction of these two antibiotics. Ten colonized patients received a 2-week oral course of 100 mg of minocycline twice daily and 600 mg of rifampin once daily, while the 11th patient was treated for only 1 week. Patients with colonization of the nares also had twice daily nasal application of 2% mupirocin for 5 days. Colonization with MRSA cleared in 10 of 11 patients (91%) and 20 of 21 sites (95%). When the individual circumstances of a medical facility justify eradication of MRSA colonization, a multidisciplinary approach that includes antibiotic therapy with oral minocycline and rifampin, along with topical mupirocin for those with nasal carriage, may be successful.

Administration, Oral↗
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

Adsorption of aminopyridines to phosphatidylserine membranes.

Aminopyridines belong to the class of compounds which facilitate synaptic transmission at low calcium concentration, an effect associated with the block of K+ channels, enhanced entry of calcium into presynaptic terminals and greater release of transmitter. We have measured the zeta-potential of phosphatidylserine vesicles in the presence of aminopyridines and some related compounds in order to relate the strength of association of the aminopyridines with their biological effectiveness. The dependence of zeta-potential on the concentration of aminopyridines was analyzed in terms of the Langmuir-Stern-Grahame adsorption model. The rank order of the association constants (in M-1) obtained in the study was as follows: 3,4-diaminopyridine (6.5), 4,5-diaminopyrimidine (3.8), 4-aminopyridine (2.6), 3-aminopyridine (1.8), 2-aminopyridine (1.6), 4-dimethylaminopyridine (0.5), 4-aminopyridine methiodide (0.2), and, as control, calcium (12.1). The comparison of association constants with published results of the electric potential maps obtained by the CNDO/2 method suggests that binding to phosphatidylserine membrane increases with the density of excess charge on the protonated aminopyridine ring. We find that the sequence of potencies of aminopyridines in blocking K+ channels, in releasing transmitter, and in the shifts of calcium concentration dependence of synaptic transmission are about the same as the sequence of association constants with the phosphatidylserine membrane. Assuming that the binding domain for aminopyridines in the presynaptic terminal has similar adsorption properties as the phosphatidylserine membrane, we estimate the electric potential difference between the domain and the external solution to be between -300 and -340 mV.

Adsorption↗
PubMed1990

Role of insulin-like growth factor-related peptides in the estradiol-, prolactin-, and progesterone-stimulated growth of N-nitrosomethylurea-induced rat mammary tumors in soft agar.

The present experiments were designed to test the role of insulin-like growth factor-related peptides (IGF-RPs) in hormonally stimulated N-nitrosomethylurea (NMU)-induced mammary tumor colony formation in soft agar. To evaluate production of IGF-RP by NMU cells, we tested the abilities of a monoclonal antibody directed against insulin-like growth factor I (alpha sm 1.20B) and of a polyclonal antibody raised against the insulin-like growth factor I (Ab 134) to inhibit the colony-stimulating effects of conditioned media (CM) obtained from estradiol (E2)-, prolactin (PRL)-, and progesterone (Pg)-treated NMU-induced rat mammary tumors. Both Abs abolished the colony-stimulating action of genuine insulin-like growth factor I while having no effect when added alone or with control CM. The addition of either alpha sm 1.20B or Ab 134 (but not that of an irrelevant Ab) consistently blocked the colony-stimulating action of E2-CM, PRL-CM, and Pg-CM, suggesting that IGF-RPs are produced by NMU mammary tumor cells exposed to these hormones. Next, we directly tested the role of IGF-RPs as mediators of hormonally stimulated growth. We indeed observed that the addition of alpha sm 1.20B markedly inhibited the colony-stimulating actions of E2, PRL, and Pg added to NMU mammary tumor cells in soft agar in the absence of serum. We conclude that, in our experimental system, IGF-RPs not only are produced upon exposure to E2, PRL, and Pg, but also are important mediators of hormonally stimulated growth.

Animals↗