Search PubMed⌕ Search

Biomedical subjects

D E Neal

Publications and source records attributed to D E Neal.

At least 19 recordsLinked to original sources
PubMed1997

Androgen regulation of ornithine decarboxylase in human prostatic cells identified using differential display.

Androgens are essential for normal prostate physiology and have a permissive role in the development and progression of prostate cancer. Using the mRNA differential display technique, ornithine decarboxylase (ODC) was identified to be up-regulated by androgens in human prostatic LNCaP cells. On Northern analysis, the induction of ODC expression by 10 nM androgen was rapid and continued up to 48 h exposure with a maximum 6.3-fold up-regulation. The anti-androgen Casodex inhibited the androgen-induced up-regulation of ODC, whereas the protein synthesis inhibitor cycloheximide did not. Together these data suggest that regulation is mediated through the androgen receptor protein and does require secondary protein synthesis, respectively. The kinetics of induction of ODC were almost identical to those of prostate specific antigen. Taken together these data suggest that ODC is directly regulated by androgens in LNCaP cells.

Base Sequence↗
PubMed1997

The expression of waf-1, p53 and bcl-2 in prostatic adenocarcinoma.

OBJECTIVE: To determine the associations between the expression of waf-1 (a cyclin-dependent kinase inhibitor regulated by p53), p53, bcl-2 and tumour progression in prostate cancer. PATIENTS AND METHODS: Samples of prostatic tissue were obtained by biopsy or at prostatectomy from 40 men (mean age 73 years, range 55-88) with histologically confirmed prostate cancer, examined using immunohistochemical staining for the three gene products, and the expression related to the stage, grade, disease progression and survival of the patients. RESULTS: Fifteen of 18 patients whose tumours were positive for waf-1, 10 of 12 positive for bcl-2 and 17 of 19 positive for p53 had disease progression. Fifteen of 19 patients positive for p53 had poorly differentiated tumours compared with 11 of 21 negative for p53 (P < 0.05). A significant number of patients positive for p53 progressed and had a shorter time to progression compared to those negative for p53 (P < 0.05). There was no correlation between either waf-1 and/or bcl-2 staining and clinical grade, stage or tumour progression. CONCLUSIONS: This study confirmed the association of p53 protein accumulation with aggressive behaviour in prostate cancer and identified waf-1 protein in prostatic tumours. There was no evidence that the upregulation of waf-1 was associated with a better outcome in patients with prostate cancer.

Adenocarcinoma↗
PubMed1997

The accuracy of recording of occupational history in patients with bladder cancer.

OBJECTIVE: To determine how accurately information on the occupations of patients with transitional cell carcinoma of the bladder (TCC) was recorded. PATIENTS AND METHODS: Using a semi-structured interview and a standard proforma, 108 patients with TCC of the urinary tract were studied and the results compared with records in their case notes. RESULTS: Case notes were substantially correct in only 39% of patients. Occupations that might have been a significant factor in the aetiology of TCC were omitted in 71% of potentially exposed male patients and no occupational history was recorded in 12% of all patients. CONCLUSIONS: Important clinical information was missing from the case notes that might have been of practical use in determining whether patients might be eligible for financial redress and which might be of use in future clinical research. It is recommended that details of occupational history should be taken using a structured proforma; this could be a suitable topic for regular audit.

Carcinoma, Transitional Cell↗
PubMed1996

C-erbB-2 in bladder cancer: molecular biology, correlation with epidermal growth factor receptors and prognostic value.

PURPOSE: To study the c-erbB-2 oncogene in primary transitional cell bladder cancer. MATERIALS AND METHODS: Ninety-five patients with known clinical follow-up and epidermal growth factor receptor (EGFr) status were studied for expression of c-erbB-2 by immunostaining. Possible mechanisms underlying increased staining for c-erbB-2 protein were investigated by analyzing DNA and RNA encoding c-erbB-2. RESULTS: Strong positive staining for c-erbB-2 was detected in 20 (21%) tumors, with weaker staining in a further 13 (14%). There was no correlation between increased staining for c-erbB-2 and tumor stage, grade, or EGFr status. There was a low rate of amplification of the c-erbB-2 gene (1 of 24) on Southern blotting with a higher rate of elevated c-erbB-2 mRNA (4 of 44) with dot blot hybridization. For pT1 tumors, the rate of recurrence was higher for those tumors which were positive for c-erbB-2. CONCLUSIONS: c-erbB-2 oncoprotein is expressed by a significant proportion of transitional cell tumors of the bladder. In this study, the prognostic significance of c-erbB-2 expression appears limited.

Blotting, Southern↗
PubMed1996

Transforming growth factor alpha and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.

We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from 'normal' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with 'normal' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours.

Epidermal Growth Factor↗
PubMed1996

Alterations in expression of the multidrug resistance-associated protein (MRP) gene in high-grade transitional cell carcinoma of the bladder.

Expression of the MRP gene has been demonstrated in vitro to be a casual factor in non-P-glycoprotein-mediated multidrug resistance, and is implicated in resistance to a number of the chemotherapeutic agents currently used in the treatment of high-grade transitional cell carcinoma (TCC) of the bladder (doxorubicin, epirubicin and vinblastine). Using a sensitive RT-PCR-based technique, we have quantified MRP mRNA levels in a series of untreated TCC (n=24), normal bladder (n=5) and control tissue and cell line samples. MRP mRNA was widely expressed and detectable in all samples analysed, with considerable (up to 190-fold) variation observed between individual tumour samples. MRP mRNA levels found in TCC samples were lower than those determined for normal peripheral mononucleocyte (2.3-fold) and testis (4.1-fold) samples, previously reported to be high-expressing tissues, and varied over a similar range to that observed in normal bladder samples. Results indicate that MRP mRNA levels in a greater proportion of high-grade (G3) bladder tumours (55%, 6/11) are significantly reduced (P=0.018) compared with low- and moderate-grade (G1/2) bladder tumours (8%, 1/13), and suggest that MRP mRNA levels frequently become reduced as a consequence of tumour progression to advanced, poorly differentiated disease. No correlation was apparent between MRP and MDR1 mRNA levels, thus providing no evidence to suggest common regulation of the two genes. In a limited number of patients, no evidence was found to support a role for MRP mRNA levels as a determinant of response to chemotherapy in patients being uniformly treated with either cisplatin-methotrexate-vinblastine (n=6) or epirubicin-cisplatin-methotrexate (n=4) regimens. Similarly, no overall pattern of altered MRP mRNA expression was observed following chemotherapy in four patients from whom post chemotherapy biopsies were taken. This study provides a useful pilot investigation regarding the level, variation and pattern of MRP mRNA expression in TCC of the bladder, and suggests that further studies to establish the clinical significance of these variations are required.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Cell adhesion molecules in bladder cancer: soluble serum E-cadherin correlates with predictors of recurrence.

Sera from 40 patients with newly diagnosed bladder cancer (28 superficial tumours (pTa and pT1) and 12 muscle-invasive tumours) were assessed by enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of soluble E-cadherin (sE-cadherin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Corresponding frozen sections of primary tumour were analysed for E-cadherin expression using the monoclonal antibody, HECD-1 and standard immunohistochemistry. Patients with bladder cancer had significantly higher concentrations of sE-cadherin compared with a control group (P = 0.017). No difference was found between the two groups with regard to sE-selection (P = 0.403), sVCAM-1 (P = 0.942) and sICAM-1 (P = 0.092). High levels of sE-cadherin were related to poor histological grade (P = 0.009), number of superficial tumours at presentation (P = 0.008) and a positive 3 month check cytoscopy in superficial disease (P = 0.036). Abnormal E-cadherin expression was associated with increasing tumour stage (P = 0.009) and grade (P = 0.03). There was no correlation between high levels of soluble E-cadherin in sera and abnormal E-cadherin expression by the tumour (P = 0.077). Elevated levels of sE-cadherin are found in sera of patients with bladder cancer and correlate with known prognostic factors.

Aged↗
PubMed1996

bcl-2 overexpression combined with p53 protein accumulation correlates with hormone-refractory prostate cancer.

Seventy-seven men with histologically proven and newly diagnosed prostate cancer we investigated for the presence of bcl-2 protein overexpression and p53 protein accumulation 1 immunohistochemistry. Forty-five men had evidence of locally advanced and metastatic disease and we treated by means of hormone manipulation. Twenty-eight patients either failed to respond to initial hormone manipulation or relapsed within 37 months from diagnosis (median 20 months). Of the 77 cancers, 37 (48% showed bcl-2 overexpression at diagnosis. Twenty-seven of those were treated with androgen ablation and 2 (74%) had hormone-refractory disease (P = 0.0128). Twenty-three of 77 men (29.8%) had nuclear staining for p53 protein. Twenty-one of those were treated with hormone manipulation and 14 (66.6%) showed hormone resistance (P = 0.0012). Seventeen patients had both bcl-2 overexpression and p53 protein accumulation, 16 of whom were hormonally treated, with 13 (81.2%) having hormone-refractory disease (P < 0.0001). These findings suggest that the combined detection of p53 protein accumulation and bcl-2 overexpression may be useful in predicting hormone resistance in prostate cancer. By deregulating programmed cell death, alteration in these genes may prevent patients from responding to androgen ablation, or allow them to escape hormonal control of the disease.

Adenocarcinoma↗
PubMed1996

Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer.

The mdm2 oncogene encodes a 90-kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts in a range of human cancers and their absence in normal tissues. Transfection of NIH 3T3 cells with each of these forms gave foci of morphologically transformed cells. A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encoding the p53 binding domain, but retain carboxyterminal zinc-finger domains. These observations suggest a reassessment of the transforming mechanisms of mdm2 and its relation to p53.

3T3 Cells↗
PubMed1996

The role of the nurse practitioner in a urology service.

OBJECTIVE: To evaluate the role of the nurse practitioner in urology and to determine the impact on the work of junior doctors. METHODS: Written criteria were defined before the postholder was appointed and subsequent performance was assessed against these criteria. Training was provided and the quality of work was assessed by direct observation. Senior House Officers (SHOs) were asked whether the post had increased their opportunities to attend theatre, outpatients and post-graduate training sessions and had decreased the number of 'inappropriate' tasks they had to perform. RESULTS: The nurse practitioner accomplished all the tasks that were defined before the appointment. The assessment of patients in pre-admission and haematuria clinics was satisfactory. The continuity of information, care of patients and counselling for patients receiving complex surgery were improved. Sixty-three per cent of all patients seen in the pre-admission clinic and all patients in a haematuria clinic were assessed initially by the nurse practitioner. Because the nurse practitioner was involved in setting up intravenous drug administration and infusions, administrative tasks and in obtaining results from the laboratory, the number of 'inappropriate' tasks performed by the SHOs decreased and they were able to attend more sessions of training and education. CONCLUSIONS: The nurse practitioner in clinical urological practice constitutes an effective use of resources and relieves junior medical staff from other tasks, allowing them to receive a more focused training. In addition, the quality of patient care was thought to be improved in some areas. The framework of a job plan for a nurse practitioner is described.

Humans↗
PubMed1996

Peptide growth factors in the prostate as mediators of stromal epithelial interaction.

Peptide growth factors play a role in the maintenance of normal prostatic growth and differentiation (Fig. 2). It seems likely that the androgen sensitivity of human prostate is mediated by the production of peptide growth factors from stromal cells which act as the direct intermediate of androgen action on epithelial cells. TGF-beta 1 inhibition of epithelial cells is opposed by the stimulatory action of EGF, IGF and FGFs to maintain an equilibrium of epithelial cell numbers. The indirect mitogenic action of androgens appear to act by down-regulation of TGF-beta 1 and possibly EGF receptors. There is also interaction with the effects of IGF-II, produced by prostatic stromal cells and acting on epithelial cells to increase proliferation. The growth of normal prostatic fibroblasts is under the control of bFGF and TGF-beta 1. However, although our understanding of the actions of these growth factors in the normal prostate has improved over the last decade, their role in the development and maintenance of prostate cancer is less clearly defined. TGF-beta 1, classically considered to be inhibitory for epithelial cells, may be up-regulated in prostatic tumours, stimulating growth. Alternatively, autocrine production of such growth factors by tumour cells may lead to loss of inhibitory effects from exogenous TGF-beta 1, a mechanism also witnessed with TGF-alpha and bFGF. The role of EGF in the development of prostate cancer is confusing because results from the use of different cell types and experimental conditions is contradictory. It may be that a switch in the production of the predominant EGFr ligand from EGF to TGF-alpha is an important feature in the development and maintenance of the malignant phenotype. The presence of TGF-alpha autocrine loops has been shown clearly in some tumour cell lines. This switch in the production of a particular ligand may also be a feature of IGFs in prostate cancer. IGF-II may be replaced by IGF-I during malignant progression, both of which are able to act via the type 1 receptor. This change in IGF expression appears to be accompanied by altered expression of the IGF-BP2, with less detectable within prostatic tissues but elevated serum levels [58]. Basic FGF is normally produced by prostatic fibroblasts but is also produced by some prostatic cancer cell lines [64]. However, as with all growth factors, the expression of the bFGF protein and its receptor is dependent on the cell line examined. The autocrine and paracrine control of normal and abnormal prostatic growth by growth factors is important in determining their role in the development and maintenance of prostate cancer. Better understanding of such mechanisms is essential for the development of novel therapeutic strategies in the control and treatment of prostate cancer.

Cell Division↗
PubMed1996

Breast and prostate cancer in the relatives of men with prostate cancer.

OBJECTIVE: To assess the risk of breast, ovarian and prostate cancer in the families of men with prostate cancer. PATIENTS AND METHODS: A case-control study was performed by interviewing patients with prostate cancer and obtaining detailed information on family histories of cancer. Controls were hospital-based patients, of a similar age to the cases, with bladder cancer or benign prostatic hypertrophy. RESULTS: A total of 209 cases and 322 controls were interviewed; of the cases, 22.5% had family members with a history of one or more of breast, ovarian or prostate cancers, compared with 15.2% of controls (P < 0.05). The odds ratio (OR) of having prostate cancer when there was a positive family history was 8.22 and the OR of a female relative of a patient with prostate cancer having breast cancer was 1.51. There was no apparent increased risk of ovarian or any other cancer. CONCLUSIONS: We confirm previous reports of an increased incidence of prostate cancer in the families of men with prostate cancer and report a similarly increased incidence of breast cancer in female relatives. We suggest that detailed family histories be taken routinely and intend to analyse blood samples provided from this study for genetic abnormalities.

Age of Onset↗
PubMed1996

The effect of prostatectomy on symptom severity and quality of life.

OBJECTIVE: To determine the effectiveness of prostatectomy in reducing symptom severity and bother and in improving disease-specific and general quality of life. PATIENTS AND METHODS: A prospective, cohort study was performed in National Health Service and private hospitals in the Northern, Wessex, Mersey, and South-West Thames Health Regions which comprised 5276 men undergoing prostatectomy recruited by 101 of the 106 (96%) surgeons (specialist and non-specialist) performing prostatectomy during a 6-month period. Patients were assessed using the American Urological Association (AUA) Symptom Index Score, the AUA symptom bother score, disease-specific and generic quality-of-life scores, the occurrence of adverse events (urinary incontinence, erectile impotence and retrograde ejaculation) and three global (general) questions on the results of their treatment. The outcome was assessed 3 months after surgery. RESULTS: Prostatectomy was effective in reducing both symptoms (initial mean score 20.1 reduced to 7.4, P < 0.001) and symptom bother (initial mean score 14.4 reduced to 4.3, P < 0.001). Not all men experienced a good reduction in symptoms; 121 (3.9%) were worse, 301 (9.6%) were the same, and 721 (23%) experienced only slight improvement. The type of operation, grade of principal operator and use of pre-operative investigations were not associated with the extent of symptomatic improvement. Changes in symptom severity were highly correlated with changes in bothersomeness++ and disease-specific quality of life but not with generic quality of life. A third of men who were continent before surgery reported some incontinence 3 months later, although only 6% found it a problem. Two-thirds of men experienced retrograde ejaculation and 31% experienced some erectile impotence following surgery. CONCLUSIONS: Prostatectomy is effective in reducing symptoms in most men. Men who experience a substantial reduction in symptoms were more likely to report a favourable outcome. The study confirmed that approximately one-third of men reported an unfavourable result 3 months after their operation.

Aged↗