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Biomedical subjects

D E Neal

Publications and source records attributed to D E Neal.

At least 109 records · Page 6Linked to original sources
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↗
PubMed1997

Ca2+ mobilization in cultured human bladder smooth muscle cells in response to hypotonic stimuli.

The effects of hypotonic solutions on intracellular Ca2+ were determined on primary cultures of human detrusor smooth muscle cells. In the presence of external Ca2+, changing from a solution containing 290 mosmol l-1 to one containing 240 mosmol l-1 (80% normal tonicity) activated a rise in intracellular Ca2+. If the exposure to 240 mosmol l-1 was followed by exposure to 150 mosmol l-1 (50% normal tonicity) a further increase in Ca2+ was noted. Exposure to hypotonic solutions which contained nominally zero Ca2+ also resulted in a rise in intracellular Ca2+, suggesting that mechanical perturbation of the surface membrane can mobilize Ca2+ directly from intracellular stores. Stimulation of cells with a brief exposure to agonist (histamine, 5 microM) in the nominal absence of external Ca2+ produced a release of Ca2+ from intracellular stores. Under these conditions the response to a subsequent hypotonic stimulation was small or absent. These observations suggest that hypotonic stress induces a mobilization of Ca2+ from the same store as that activated by agonist. Detailed analysis of data from individual bladders revealed that there were significant differences between cells cultured from normal bladders and those from bladders with detrusor instability. On exposure to 240 mosmol l-1 cells from unstable bladders gave larger responses than cells from normal bladders. However, exposure of cells from unstable bladders to a subsequent stimulus of 150 mosmol l-1 resulted in a smaller rise in Ca2+ than was observed with normal cells. Overall, these data suggest that isolated detrusor smooth muscle cells are sensitive to membrane stretch by hyposmotic solutions and that the mechanisms involved include the direct mobilization of intracellular Ca2+. The data also suggest that there may be differences in the responsiveness of cells isolated from stable and unstable bladders.

Arachidonic Acid↗
PubMed1997

Bronchial dilatation in patients with HIV infection: CT assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage.

OBJECTIVE: Symptoms of airway disease occur in patients infected with HIV, and bronchiectasis has been reported in patients with AIDS. We evaluated thin-section thoracic CT scans in HIV-positive individuals for bronchial dilatation and correlated imaging findings with pulmonary function abnormalities and findings at bronchoalveolar lavage (BAL). SUBJECTS AND METHODS: Sixty-one subjects, 50 of whom were HIV-positive and 11 of whom were HIV-negative, underwent thin-section CT, BAL, and pulmonary function tests. Two radiologists evaluated the CT scans on two separate occasions for bronchial dilatation in each lobe. BAL and pulmonary function test data in the subjects with bronchial dilatation were compared with such data in subjects with normal bronchi seen on CT scans. RESULTS: Eighteen of the 50 HIV-positive subjects and none of the HIV-negative subjects had bronchial dilatation revealed by CT. Subjects with bronchial dilatation revealed by CT had significantly higher BAL neutrophil counts (p = .014) and significantly lower diffusing capacity (p = .003) than did subjects with normal bronchi revealed by CT. CONCLUSION: Bronchial dilatation is commonly revealed by CT scans of HIV-positive individuals. The association of elevated levels of BAL neutrophils and decreased diffusing capacity with bronchial dilatation that we found in this study suggests that the neutrophil may be associated with airway damage and lung destruction in patients who are infected with HIV.

Adult↗
PubMed1996

TENS: a treatment option for bladder dysfunction.

To ascertain the mode of action and benefits of transcutaneous electrical nerve stimulation (TENS) in detrusor overactivity, stress incontinence and interstitial cystitis, an English-language literature search using Medline (1984-1995) was undertaken with detrusor instability, incontinence, interstitial cystitis, neuromodulation, transcutaneous electrical nerve stimulation and urodynamics as keywords and the material so identified was reviewed. The mode of action of TENS and optimal stimulation parameters in bladder dysfunction remain unclear. Lack of strict selection criteria and deficient reporting of subjective and objective outcomes precluded full assessment of therapeutic efficacy. A beneficial effect was evident in some studies of detrusor overactivity and interstitial cystitis. A trial of TENS in detrusor overactivity and interstitial cystitis refractory to conventional therapy would seem justified. Continued experimental research and further clinical studies will lead to refinement of the treatment modality.

Cystitis, Interstitial↗
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↗