Biomedical subjects

A Bergh

Publications and source records attributed to A Bergh.

At least 91 records · Page 5Linked to original sources

PubMed1997

Long-term outcome of conservative therapy in men presenting with voiding symptoms and prostate cancer.

OBJECTIVE: To investigate the outcome of conservative therapy in men presenting with voiding symptoms and prostate cancer. METHODS: A consecutive series of 186 men presenting with voiding symptoms and prostate cancer were treated with transurethral resection (TUR). Examination of the resected tissue revealed 70 nonpalpable prostate cancers and confirmed the clinical suspicion of prostate cancer in 116 palpable tumors; 47 tumors were well differentiated, 87 intermediate and 52 poorly differentiated. Bone scan indicated metastasis in 24 men, all asymptomatic. The men were followed and underwent orchidectomy if symptoms of generalized disease appeared. RESULTS: After a follow-up of 13-21 years, 172/186 (92%) of the men had died, with 80/186 (43%) of the men dying of prostate cancer. The mean life expectancy was 6.3 years (confidence interval 5.4-7.1) compared with 10.2 years of an age-matched control group. In a subgroup of men with clinically localized disease, 26/97 (27%) died of prostate cancer. These men had a mean life expectancy of 7.1 years (confidence interval 6.0-8.3). Tumor stage and grade were highly significant predictors for cause-specific survival in uni- and multivariate analysis. Death from prostate cancer continued to occur beyond 10 years after diagnosis at a decreasing rate. CONCLUSIONS: Patients with prostate cancer causing voiding symptoms at presentation severe enough to necessitate TUR had a less favorable outcome than asymptomatic patients with prostate cancer in previously reported series, even when stratified for stage and grade. It is suggested that voiding symptoms at diagnosis are a putative prognostic factor in prostate cancer.

Age Factors↗

PubMed1996

Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.

Adult↗

PubMed1996

Estrogen induces apoptosis in a rat prostatic adenocarcinoma: association with an increased expression of TGF-beta 1 and its type-I and type-II receptors.

Rats transplanted with the androgen-sensitive Dunning R3327 PAP prostatic adenocarcinoma were castrated and treated with either estrogen or vehicle alone for short periods (4 hr, 12 hr, 24 hr) and for 6 weeks. In these tumors the expression of TGF-beta 1, TGF-beta type-I and type-II receptors (TGF-beta RI, TGF-beta RII) was examined by immunohistochemistry. Apoptotic cells were identified by in situ nick and labelling (TUNEL). Tumor growth was retarded by castration and even more by additive estrogen treatment. The epithelium of the untreated tumors stained weakly for TGF-beta 1 and TGF-beta RI, but TGF-beta RII was not detected. Castration induced moderate TGF-beta 1 immunoreactivity in a major part of the glandular epithelium after 24 hr. After 12 hr already, castration plus estrogen resulted in an intense staining for TGF-beta 1 in the basal epithelial cells, some of which also showed an apoptotic appearance. The percentage of cells having stained positive for TGF-beta 1 was significantly higher in the estrogen-treated groups than in the castrated group after 12 hr, and its elevated TGF-beta 1 level remained at 6 weeks. Notably, the increased immunoexpression of TGF-beta 1 occurred before the onset of induction of apoptosis. In parallel with the upregulation of TGF-beta 1 after castration, the expression of its receptors. TGF-beta RI and RII, was induced and was further enhanced by the additive estrogen treatment. The number of intensely stained TGF-beta 1 tumor cells showed a strong correlation with the number of apoptotic tumor cells identified by TUNEL in the whole material. Furthermore, TGF-beta 1 immunoreactivity co-localized with the presence of apoptotic cells in the estrogen-treated tumors at 6 weeks after castration.

Activin Receptors, Type I↗

PubMed1996

Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.

By catalyzing the rate-limiting step in adipose tissue lipolysis, hormone-sensitive lipase (HSL) is an important regulator of energy homeostasis. The role and importance of HSL in tissues other than adipose are poorly understood. We report here the cloning and expression of a testicular isoform, designated HSLtes. Due to an addition of amino acids at the NH2-termini, rat and human HSLtes consist of 1068 and 1076 amino acids, respectively, compared to the 768 and 775 amino acids, respectively, of the adipocyte isoform (HSLadi). A novel exon of 1.2 kb, encoding the human testis-specific amino acids, was isolated and mapped to the HSL gene, 16 kb upstream of the exons encoding HSLadi. The transcribed mRNA of 3.9 kb was specifically expressed in testis. No significant similarity with other known proteins was found for the testis-specific sequence. The amino acid composition differs from the HSLadi sequence, with a notable hydrophilic character and a high content of prolines and glutamines. COS cells, transfected by the 3.9-kb human testis cDNA, expressed a protein of the expected molecular mass (M(r) approximately 120,000) that exhibited catalytic activity similar to that of HSLadi. Immunocytochemistry localized HSL to elongating spermatids and spermatozoa; HSL was not detected in interstitial cells.

Amino Acid Sequence↗

PubMed1996

Pretreatment p53 immunoreactivity does not infer radioresistance in prostate cancer patients.

PURPOSE: To test, in a clinical context, the hypothesis that p53 aberrations, assessed by immunoreactivity, are related to radioresistance as suggested by several experimental studies. METHODS AND MATERIALS: Sixty patients with prostate cancer who underwent transurethral resection of the prostate or biopsy prior to definitive external beam therapy were retrospectively identified. The endpoint in the study was cancer specific survival. The nuclear accumulation of the aberrant p53 protein was evaluated by immunohisto-chemistry with the pantropic, monoclonal Ab-6 anti-p53 antibody (clone DO-1) on pretreatment biopsies. Immunoreactivity was related to stage, grade, and cancer-specific survival. RESULTS: There was a correlation between p53 immunoreactivity and low tumor stage (p < 0.001), but no relation between p53 status and grade was found. Moreover, no significant difference was found in cancer-specific survival between the p53 positive tumors (109 months) and the p53 negative tumors (99 months). CONCLUSIONS: No disadvantage regarding survival was seen for patients with p53 immunoreactive tumors, implicating that p53 immunoreactivity does not infer radioresistance in prostate cancer. This suggests that the p53 inactivation may be a less important determinant of tumor response to radiotherapy in some human cancers than in the previously studied experimental situations. Thus, other mechanisms may be more important in determining outcome after radiation. However, the series is small and data should be interpreted with caution.

Aged↗

PubMed1996

Expression of transforming growth factor-beta 1 in rat ventral prostate and Dunning R3327 PAP prostate tumor after castration and estrogen treatment.

BACKGROUND: In normal prostate, TGF-beta 1 is associated to castration induced apoptosis. Combined castration and estrogen treatment, but not castration alone, induces apoptosis in the Dunning R3327 PAP adenocarcinoma. METHODS: TGF-beta 1 expression in rat ventral prostate (VP) and Dunning R3327 PAP tumor was studied after castration and estrogen treatment, using competitive RT-PCR, in situ hybridization and immunohistochemistry. RESULTS: TGF-beta 1 mRNA level was 6 times higher in the tumor than in the VP. Combined castration and estrogen treatment increased TGF-beta 1 mRNA levels in the tumor from day 3, while castration did not. The TGF-beta 1 expression was located in the epithelial cells. CONCLUSIONS: The Dunning R3327 PAP tumor contains high levels of TGF-beta 1, which are further increased by combined castration and estrogen treatment. However, since this increase is not apparent until day 3, TGF-beta 1 probably does not contribute to the known induction of apoptosis in the tumor at day 1 after combined castration and estrogen treatment.

Adenocarcinoma↗

PubMed1996

Bcl-2 immunoreactivity in prostate tumorigenesis in relation to prostatic intraepithelial neoplasia, grade, hormonal status, metastatic growth and survival.

The Bcl-2 protein prolongs cell survival by overriding apoptosis. To explore the role of Bcl-2 in prostate tumorigenesis, immunoreactivity for Bcl-2 was examined in untreated and androgen-deprived tumours and lymph node metastasis. Following the transurethral resection, 150 untreated patients were maintained under surveillance until death or for a minimum of 11 years, and castration was performed at symptomatic progression. The Bcl-2 index (BI) was defined as the percentage of immunoreactive cells in a tumour. The mean BI was 12 in the untreated tumours, and BI was significantly higher in high-grade tumours, mean BI 17, than in low-grade tumours, mean BI 6. There was no correlation between BI and stage or metastatic disease, nor did BI predict cancer-specific survival. In 16 androgen-deprived, but non-relapsed tumours, the mean BI was 54, at a mean time of 22 months after castration, indicating a permanent increase of Bcl-2 protein expression after androgen withdrawal. In six patients, tissues from the prostate tumour and obturator lymph node metastasis were available. Four primary tumours immunostained for Bcl-2, but only one metastasis stained. Foci of highgrade prostatic intraepithelial neoplasia (PIN) were present in 44 of the 150 untreated tumours. All PIN foci were intensely immunoreactive for Bcl-2, and mean BI was 79, suggesting that Bcl-2 protein expression is associated with early prostate tumorigenesis.

Aged↗

PubMed1996

Leydig cells secrete factors which increase vascular permeability and endothelial cell proliferation.

Adult intact control rats, and animals treated with human chorionic gonadotrophin (hCG) or with ethane dimethane sulphonate (EDS) to deplete Leydig cells, were injected with bromodeoxyuridine (BrdU) to label proliferating cells. Apoptotic cells were visualized by in-situ end labelling (ISEL) of fragmented DNA. Three per cent of testicular endothelial cells were labelled with BrdU and few were apoptotic in intact testes. The BrdU endothelial cell labelling index was increased by hCG-treatment and decreased in Leydig cell-depleted testes. Immunohistochemical staining showed that Leydig cells and testicular macrophages contain immunoreactive vascular endothelial growth factor (irVEGF). The ability of testicular cells to stimulate angiogenesis was studied further by transplanting interstitial cells or seminiferous tubule segments under the kidney capsule. A prominent vascular network was observed around interstitial cell grafts, but not around tubule grafts. Treatment of transplanted rats with human chorionic gonadotrophin (hCG, 50 i.u.) resulted in an accumulation of PMN-leukocytes and an increase in vascular permeability in the remaining testis and in interstitial cell grafts. Interstitial cells from Leydig cell-depleted (EDS-treated) testes were also transplanted under the kidney capsule. This type of graft caused only a discrete stimulation of angiogenesis, and there was no increase in vascular permeability around the graft after hCG treatment. It is suggested that Leydig cells secrete angiogenic factors and that they are the source of the inflammation mediator(s) produced in the testis after hCG treatment. The high proliferation rate in endothelial cells suggests continuous remodelling of the testicular microvasculature, but the functional significance of this remains unknown.

Animals↗

PubMed1996

Human chorionic gonadotrophin-induced testicular inflammation may be related to increased sensitivity to interleukin-1.

Treatment of adult male rats with human chorionic gonadotrophin (hCG) results in an inflammation-like response in the testicular microcirculation. Polymorphonuclear (PMN) leukocytes accumulate in venules and vascular permeability is increased. The mechanism behind this response was studied. Treatment with an interleukin-1 receptor antagonist partly prevented the hCG induced accumulation of PMN leukocytes 4 h after treatment. Human recombinant interleukin-1 alpha (IL-1 alpha) and beta (IL-1 beta), serotonin, and histamine were injected intratesticularly on one side and saline injected on the contralateral side in both intact and hCG-pretreated adult rats. A low dose of IL-alpha (a dose that did not increase vascular permeability in unstimulated testes) increased vascular permeability in the testes of animals treated with hCG 4, 6 or 8 h earlier, but it was without effect in testes from rats treated with hCG 0,1, 2, 16 or 32 h prior to IL-1 injection. The sensitivity to the pro-inflammatory effect of locally injected IL-1 beta was also increased by hCG treatment. There was no increase in vascular permeability after local injection of a large dose of histamine or serotonin in either saline- or in hCG-pretreated animals. Hypothetically, the hCG-induced inflammation-like increase in testicular vascular permeability could be related to increased sensitivity to constitutively produced mediators such as IL-1.

Animals↗

PubMed1996

p53 immunoreactivity as prognostic marker for cancer-specific survival in prostate cancer.

OBJECTIVES: The objective of this study was to evaluate the role of p53 immunoreactivity as a prognostic marker in prostate cancer. METHODS: The nuclear accumulation of the aberrant p53 protein was determined by immunohisto-chemistry on surgical specimens and related to stage, grade and cancer-specific survival in 186 prostate cancer patients treated with transurethral resection and subsequent surveillance. RESULTS: There was a significant correlation between p53 staining and grade: 2% of the highly differentiated, 8% of intermediately, and 21% of the poorly differentiated tumors stained. Patients with p53-positive tumors had a significantly shorter survival (52 months) than the p53-negative group (123 months). However, in a Cox multiple regression analysis of p53 status, tumor stage, grade, metastasis and age, p53 lost its significance as an independent predictor. CONCLUSIONS: p53 is a rare and late event in prostate cancer, indicating that other molecular mechanisms may be of greater importance in the development of prostate cancer. The predictive value of p53 apparently depends on its association with high grade and advanced stage, and it is not a useful prognostic marker in prostate cancer. However, p53 status could play a role in the evaluation of patients prior to radiotherapy since p53 inactivation may produce radioresistant tumors.

Adult↗

PubMed1996

5-Hydroxytryptamine--a local regulator of testicular blood flow and vasomotion in rats.

The effects of 5-hydroxytryptamine (5-HT), 5-HT2 receptor antagonists (ritanserin and ketanserin), histamine and substance 48/80 on testicular blood flow and microcirculation were studied in adult rats. The substances were administered by topical application on the testicular surface and by intratesticular injections, and blood flow was measured by radioactive microspheres and with a laser Doppler flowmeter. Blood flow was decreased by 5-HT in a dose-dependent manner and vasomotion in the testis was inhibited, suggesting that it could be involved in the physiological regulation of the testicular vasculature. The 5-HT antagonists did not significantly influence flow or vasomotion in intact testes. Histamine did not cause any major effects on testicular blood flow. Substance 48/80 caused degranulation of testicular mast cells, and reduced testicular blood flow and vasomotion suggesting that testicular mast cells, possibly by releasing 5-HT, could be involved in the local control of the testicular vasculature.

Administration, Topical↗

PubMed1995

Effects of estrogens and progestogens on the membrane permeability and growth of human prostatic carcinoma cells (PC-3) in vitro.

The effects of estrogens and progestogens in the management of prostatic adenocarcinoma are generally believed to be related to their suppressive effect on the hypothalamic-pituitary-testicular axis, but other mechanisms have also been suggested. The present study was designed to investigate if an androgen-insensitive human prostatic cancer cell line (PC-3) is sensitive to estrogens or progestogens and to elucidate possible mechanisms of action. Both estrogens and progestogens in high doses (10(-5) M) suppressed tumor cell growth. At these high doses medroxyprogesterone acetate (MPA) most effectively reduced the uptake of 86rubidium chloride, indicating the strongest effect on ion transport and membrane permeability. Effects on rubidium transport were also seen after estrogen treatment. It is suggested that estrogens and progestogens have direct cytotoxic effects on prostatic carcinoma cells in vitro, possibly by an effect on the cell membrane.

Adenocarcinoma↗

PubMed1995

Differentiation-stage specific expression of oncoprotein 18 in human and rat prostatic adenocarcinoma.

Oncoprotein 18 (Op18) is an intracellular phosphoprotein that has been shown to be overexpression in a number of human malignancies. In the present report we have studied the pattern of Op18 expression on normal, hyperplastic, and malignant prostatic tissue as well as in rat prostatic tumor lines. One of the objectives of the present work was to establish whether the level of Op18 expression can be used as a prognostic marker in human prostatic adenocarcinoma. To that end, sections from normal, hyperplastic, and malignant human prostatic tissue were examined by immunohistochemistry for expression of Op18. In the normal and hyperplastic prostate, Op18 expression was observed in basal glandular epithelial cells, whereas the columnar luminal epithelial cells were not stained by the anti Op18 antibodies. In highly differentiated prostatic cancers occasional epithelial cells were stained, while in poorly differentiated tumors most of the epithelial cells contained Op18 immunoreactivity. The staining pattern was similar in the primary prostatic tumor and in the regional lymph node metastases. Most importantly, a limited survey of prostatic cancer patient samples (n = 40) showed a significant correlation between the fraction of Op18 immunoreactive cells and survival. Studies of a rat prostatic tumor model, showed that only a few cells were stained in the highly differentiated Dunning R3327PAP tumor, while most cells were stained in the anaplastic AT1 rat prostatic tumor. Interestingly, castration of rats resulted in an increased Op18 immunoreactivity, within 14 days, in the highly differentiated rat R3327PAP prostatic tumor. In conclusion, the level of Op18 expression seems to be related to cellular differentiation, histological grade, and survival in prostatic cancers. These findings show that Op18 immunoreactivity may be useful as a prognostic marker in prostatic cancer. In addition it may help in the differentiation between highly differentiated prostatic tumors and non-malignant conditions.

Adenocarcinoma↗

PubMed1995

Epidermal growth factor receptor content in rat prostatic adenocarcinoma: effects of endocrine treatment.

Epidermal growth factor receptor (EGF-R) was studied in Dunning prostatic cancer models using competitive binding assays and solution hybridization assay. EGF-R-binding capacity and mRNA were demonstrated in a hormone-sensitive R3327 prostatic tumor from both control and castrated animals while no such activity was found in the hormone-independent AT-1 tumors. Castration induced no quantitative changes in the EGF-R. Estrogen treatment induced a significant reduction of the binding capacity of EGF-R and its mRNA. It was concluded that EGF-R is present in the androgen-sensitive Dunning prostatic tumor models (R3327), but that the androgen-insensitive, undifferentiated AT-1 tumor lacks EGF-R expression. Endocrine treatment has no significant effect on the EGF-R in these tumor models.

Adenocarcinoma↗

PubMed1995

Localization and quantity of hyaluronan in urogenital organs of male and female rats.

The histochemical distribution of hyaluronan was analysed in various urogenital organs of male and female (non-pregnant and pregnant) rats by use of a hyaluronan-binding protein and avidin biotin/peroxidase staining. Microwave-aided fixation was used to preserve the extracellular location of hyaluronan. The concentrations of hyaluronan in the different tissues were measured with a highly sensitive radio-assay. Hyaluronan accumulated predominantly in the connective tissue around smooth muscle fibres and in the subepithelial lamina propria. Abundant hyaluronan also occurred in perivascular and perineural connective tissue. In the female urogenital organs, hyaluronan content was high in the vagina and urinary bladder, and highest in the vagina during pregnancy. In the uterus, the surface epithelium of the endometrium stained intensely. In the ovary, the zona pellucida of the oocyte and the theca interna cell layer of the follicles and the follicular fluid of mature follicles exhibited prominent staining. The corpus luteum was devoid of hyaluronan, whereas enlarged corpora lutea of pregnancy exhibited weak, patchy staining. In male urogenital organs, staining for hyaluronan was absent from the testis and epididymis, whereas the erectile connective tissue of the penis stained intensely. The hyaluronan concentrations were high in penile tissue and urinary bladder, while testis, epididymis and the ductus deferens contained only little hyaluronan.

Animals↗

PubMed1995

Expression of multiple forms of brain cytochrome P450.

Multiple forms of cytochrome P450 (P450) in brain tissue have been demonstrated to be expressible in brain tissue using polymerase chain reaction (PCR) techniques, Northern blotting, hydroxylation activity assessment and cloning approaches. The antidepressant drug imipramine is metabolized by brain microsomes to multiple products by pathways inhibitable by quinidine, 7,8-benzoflavone, and ketoconazole, well-known inhibitors of P450-catalyzed reactions. Moreover, PCR studies revealed that a number of P450s are expressible in brain tissue and in glioma C6 cells. Quantitative PCR studies further demonstrated the response of many of these forms to induction in agreement with hydroxylation activity results.

Animals↗

PubMed1995

DNA fragmentation induced by the antimitotic drug estramustine in malignant rat glioma but not in normal brain--suggesting an apoptotic cell death.

Estramustine, a combination of 17 beta-oestradiol and nor-nitrogen mustard, has been shown to be metabolised and to induce specific antiproliferative effects in malignant glioma, including arrest of glioma cells in the G2/M phase of the cell cycle, damage to cell membranes and DNA and induction of free oxygen radicals. To evaluate further the effects of estramustine, an in vivo rat glioma model using inbred BD-IX rats and the BT4C cell line was set up. In order to detect cells with fragmented DNA, tumour and brain specimens were, following fixation for histological examination, processed for in situ end labelling (ISEL) with biotin-labelled nucleotides. Fresh tissue fragments were also used for DNA integrity analysis on agarose gels. It was demonstrated that estramustine induced clusters of ISEL-positive cells and a pronounced typical fragmentation of DNA 0.5-8 h after treatment. In tumours examined 24 or 94 h after estramustine treatment, and in untreated tumours, only occasional single ISEL-positive cells were scattered in the tumour. DNA from normal brain tissue did not display any visible sign of fragmentation. These changes are indicative of programmed cell death induced by estramustine in glioma cells but not in normal brain tissue. Further studies are, however, needed to establish in detail the mechanism of cell death following treatment with the antimitotic drug estramustine.

Animals↗

PubMed1995

Castration plus oestrogen treatment induces but castration alone suppresses epithelial cell apoptosis in an androgen-sensitive rat prostatic adenocarcinoma.

The positive effect of castration in prostatic cancer patients is considered to be related to the induction of apoptosis in androgen-dependent tumour cells. However, castration apparently does not induce apoptosis in the highly differentiated, androgen-sensitive Dunning R3327PAP rat prostatic adenocarcinoma. To elucidate potential mechanisms of apoptotic induction in this tumour model, rats with subcutaneously implanted tumours were treated with vehicle (I), castration+vehicle (C) or castration + 50 micrograms of oestradiol benzoate per day s.c. (C + E2). The effects on tumours were examined by morphometry, in situ end labelling (ISEL) of apoptotic cells and immunohistochemically with monoclonal antibodies to proliferating cell nuclear antigen (PCNA) at different time points up to 168 h after castration. Castration inhibited tumour growth and decreased the epithelial cell apoptotic rate (from 12 h) and epithelial cell proliferation rate (from 72 h) compared with that in the I group. Tumour volume, volume densities of epithelium and stroma and stroma cell proliferation rate remained constant in the C group during the study period. C + E2 treatment resulted in increases in cell proliferation in the stroma (from 12 h) and in the volume density of stroma (from 24 h) compared with that in the C and I groups. The number of apoptotic epithelial cells was increased (from 24 h), and this was followed by decreases in the volume density of epithelium (from 24 h), the epithelial cell proliferation rate (from 72 h) and the total tumour volume (from 72 h). We conclude that in the Dunning R3327PAP tumour model C + E2 treatment is more effective than castration alone. C+E2 treatment, in contrast to C, is able to induce tumour cell death and to decrease total tumour volume. The mechanism behind this effect is unknown, but it could be related to stimulatory effects of E2 in the tumour stroma.

Adenocarcinoma↗