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Biomedical subjects

C S Foster

Publications and source records attributed to C S Foster.

At least 19 recordsLinked to original sources

Long-term outcome among men with conservatively treated localised prostate cancer.

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10-30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.

Aged↗

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.

Gene Expression Regulation, Neoplastic↗

Brn-3a neuronal transcription factor functional expression in human prostate cancer.

Neuroendocrine differentiation has been associated with prostate cancer (CaP). Brn-3a (short isoform) and Brn-3c, transcriptional controllers of neuronal differentiation, were readily detectable in human CaP both in vitro and in vivo. Brn-3a expression, but not Brn-3c, was significantly upregulated in >50% of tumours. Furthermore, overexpression of this transcription factor in vitro (i) potentiated CaP cell growth and (ii) regulated the expression of a neuronal gene, the Nav1.7 sodium channel, concomitantly upregulated in human CaP, in an isoform-specific manner. It is concluded that targeting Brn-3a could be a useful strategy for controlling the expression of multiple genes that promote CaP.

Blotting, Western↗

Immunomodulatory therapy for Vogt-Koyanagi-Harada patients as first-line therapy.

PURPOSE: To report on the use of immunomodulatory therapy (IMT) in a group of patients with Vogt-Koyanagi-Harada disease (VKH) and to compare the outcomes with those of another group of patients with VKH who were treated for prolonged periods with corticosteroids. METHODS: Treatment regimens and their respective outcomes (visual acuity) were compared for the following groups: prolonged steroid with or without delayed addition of IMT (Group 1) and relatively prompt IMT with or without steroid (Group 2). RESULTS: The average duration of follow-up in Group 1 was 28.9 months and in Group 2 23.4 months. In Group 1, visual acuity deteriorated in three of the five patients (60%) and improved in one (20%). The fifth patient showed improvement in visual acuity in one eye, but decreased visual acuity in the other eye. In Group 2, seven of the eight patients showed improvement in their visual acuities (87.5%); visual acuity deteriorated in one patient (12.5%). CONCLUSIONS: The results suggest that IMT as first-line therapy for VKH is associated with a superior visual outcome when compared to steroid as monotherapy or with delayed addition of IMT.

Adolescent↗

Importance of TURP in diagnosing prostate cancer in men with multiple negative biopsies.

OBJECTIVE: Patients with persistently elevated PSA and multiple negative TRUS guided 12-core biopsies, present a clinical conundrum. We evaluated the efficacy of transurethral biopsy and/or resection in abetting prostate cancer diagnosis. PATIENTS AND METHODS: Eleven patients who had prostate cancer diagnosed only on TURP following TRUS guided (24-48 cores) negative biopsies, including five who underwent radical prostatectomy were assessed. Extent and site of tumour was analysed in relation to the TURP cavity. RESULTS: Mean age was 61.8 years (PSA range: 3.8-20.9 ng/ml.). Patients had TURP for worsening LUTS with chippings diagnosing invasive prostate cancer. Organ confined anterior prostate cancer was diagnosed in five who had radical prostatectomy. CONCLUSION: Anteriorly directed transurethral biopsies and/or TURP help in the diagnosis of prostate cancer in patients with multiple negative biopsies. Patients with anterior prostate cancer tend to have organ-confined disease even with higher PSA.

Aged↗

Cell populations and adhesion molecules expression in conjunctiva before and after bone marrow transplantation.

We were interested to analyse the composition of the cellular infiltrate and adhesion molecules expression in the conjunctiva before and at least one hundred days after autologous and allogenic bone marrow transplantation (BMT) and its relation with the presence of dry eye. We used immunohistochemistry on cryopreserved human conjunctiva with monoclonal antibodies to T-lymphocytes (CD3, CD4 and CD8), B-lymphocytes (CD19), macrophages (CD14), natural killer cells (NK, CD57), intercellular adhesion molecule 1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), lymphocyte function associated antigen-1 (LFA-1), very late antigen-4 (VLA-4), interleukin 2 receptor (IL2r, CD25) and HLA-DR. Our autologous recipients had no graft-versus-host disease (GVHD) but allogenic patients had chronic GVHD. After autologous BMT the conjunctiva had significantly more: (1) T lymphocytes (CD3+, CD4+, CD8+) in the epithelium; (2) CD4+ and CD14+ cells in the stroma; and (3) VLA-4 expression in the stroma than before BMT. After allogenic BMT, the conjunctiva exhibited a significant increase of: (1) CD3+ and CD14+ cells in the epithelium; (2) T lymphocytes (CD3+, CD4+, CD8+) and CD14+ cells in the stroma; and (3) VLA-4 and LFA-1 expression in the stroma than before BMT. After the engraftment, the comparison between autologous and allogenic recipients revealed that: (1) there were no significant differences in adhesion molecule expression; (2) the epithelium of autologous recipients had significantly more CD3+ cells; and (3) the stroma of allogenic patients had significantly more CD3+ and CD8+ cells. Among allogenic recipients, CD14+ cells were significantly increased both in the epithelium and in the stroma of patients with signs or symptoms of dry eye in comparison with patients without ocular involvement. Additionally, those having keratoconjunctivitis sicca (KCS) had CD4/CD8 ratios significantly higher than those without KCS. In conclusion, in the conjunctiva after autologous BMT a subclinical cell mediated immune reaction seems to take place. The conjunctivitis of chronic GVHD is complex, with T cells and macrophages dramatically contributing to the process.

Acute Disease↗

A potential novel marker for human prostate cancer: voltage-gated sodium channel expression in vivo.

Functional expression of voltage-gated sodium channel alpha-subunits (VGSCalphas), specifically Nav1.7, is associated with strong metastatic potential in prostate cancer (CaP) in vitro. Furthermore, VGSC activity in vitro directly potentiates processes integral to metastasis. To investigate VGSCalpha expression in CaP in vivo, immunohistochemistry and real-time PCR were performed on human prostate biopsies (n>20). VGSCalpha immunostaining was evident in prostatic tissues and markedly stronger in CaP vs non-CaP patients. Importantly, RT-PCRs identified Nav1.7 as the VGSCalpha most strikingly upregulated (approximately 20-fold) in CaP, and the resultant receiver-operating characteristics curve demonstrated high diagnostic efficacy for the disease. It is concluded that VGSCalpha expression increases significantly in CaP in vivo and that Nav1.7 is a potential functional diagnostic marker.

Biomarkers, Tumor↗

Ocular toxoplasmosis in pregnancy.

PURPOSE: To describe the course of ocular toxoplasmosis during pregnancy. METHODS: This study was a retrospective, non-comparative case series of four pregnant women who were treated for ocular toxoplasmosis during pregnancy. RESULTS: All of the participants had severe and treatment-resistant toxoplasmic retinochoroiditis during pregnancy, leaving three of them with decreased visual acuity in spite of aggressive therapy. Delivery of the infant appeared to help the recovery in two patients. CONCLUSIONS: Pregnant state may provoke the recurrence of ocular toxoplasmosis.

Adult↗

Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers.

This study has tested the hypothesis that comparison of protein and mRNA expression for ERalpha and ERbeta1 by human breast cancers provides novel information relating to the clinical and pathological characteristics of human breast cancers. Expression of ERalpha and ERbeta1 was identified in 167 invasive cancers from postmenopausal women treated only with endocrine therapy. The cohort included 143 cases receiving only adjuvant Tamoxifen following surgery. ERalpha and ERbeta1 expression was analysed by immunohistochemistry and reverse transcription RT-PCR and compared with clinical progression of individual cancers. ERalpha protein was closely associated with the corresponding RNA detected by RT-PCR (Chi-square, P<0.001). In contrast, ERbeta1 protein and mRNA were inconsistent. Although an association was identified between ERalpha and ERbeta mRNAs (Chi-square, P<0.001) and between ERalpha protein and ERbeta1 mRNA (Chi-square, P<0.027), no association was identified for the ERalpha and ERbeta1 proteins detected by immunohistochemistry. ERbeta1 was not associated with outcome. However, in the absence of ERalpha, ERbeta1 protein expression was associated with elevated cell proliferation. There was a trend for the ERbeta1 protein-positive cases to have a worse outcome, both within the group as a whole as well as within the ERalpha-positive Tamoxifen-treated cases. This study has confirmed the hypothesis that expression of ERalpha is an important determinant of breast cancer progression, and has further demonstrated that ERbeta1 may play a role in the response of breast cancers to endocrine therapy.

Antineoplastic Agents, Hormonal↗

Increased risk of malignant progression in benign proliferating breast lesions defined by expression of heat shock protein 27.

Heat shock protein 27 (hsp-27) is a regulator of oestrogen receptor (ER) expression and a modulator of intracellular homeostasis. In this laboratory, Shaaban et al demonstrated the importance of ER-alpha, together with Ki67, in enhancing the progression of benign breast lesions of defined morphological types. To better understand the mechanisms by which ER-alpha promotes breast neoplasia, this study was performed to test the hypothesis that the roles of ER-alpha and hsp-27 may be defined by their quantitative expression in proliferative breast lesions of varying histological risk. The expression of hsp-27 was identified using a specific monoclonal antibody and analysed to assess the proportion of positive epithelial cells using digitised morphometric image analysis. The expression of ER-alpha was analysed by immunohistochemistry and Western blotting in a variety of benign (HUMA121) and malignant mammary cell lines, including ER-alpha(+) (MCF7, ZR-75, T47D) and ER-alpha(-) (MDA-MB 231) breast cancer cell lines. The data confirm that, during progression from normal through proliferative breast lesions to in situ cancer, there was a significant increase in both the proportion and the optical density of the epithelial cells expressing hsp-27. The mean levels of expression ranged from 7.4% of the total number of epithelial cells in normal lobules to 25.17% of epithelial cells in hyperplasias of usual type (HUT) to 61.1% of epithelial cells in ductal carcinoma in situ (P<0.001). The study has confirmed the expression of hsp-27 to be closely associated with ER-alpha(+) expression, and that its regulated expression occurs early along the mammary oncogenic pathway, supporting the initial hypothesis. It is our proposal that the differential expression of hsp-27 modulates the phenotypic behaviour of morphologically benign epithelial cells and hence may be an important determinant in initiating, or promoting, a population of human mammary cancers.

Biomarkers, Tumor↗

Relationship between upregulated oestrogen receptors and expression of growth factors in cultured, human, prostatic stromal cells exposed to estradiol or dihydrotestosterone.

This study investigated the hypothesis that, in benign prostatic hyperplasia (BPH), upregulated oestrogen receptors (ER) and the action of androgens differentially regulate expression of stromal growth factors. Eight human prostatic stromal cell strains were subjected to a procedure to upregulate their ER by exposing them to 1 micromol 17beta-estradiol for 10 days followed by passage and growth in the absence of steroids. Four of the cell strains instead received 100 nmol dihydrotestosterone for 48 h. Immunoexpression of ERalpha, AR and six growth factors was quantified by flow cytometry in each case. Expression of ERalpha was significantly increased in six of eight cell strains. Expressions of six growth factors (FGF-2, FGF-7, IGF-1, TGF-beta1 NGF and e NOS) were elevated but only for FGF-7 was it significant. There was a significant positive correlation between the change in ERalpha and the change in FGF-2 and FGF-7, but not the other growth factors. Exposure to dihydrotestosterone reduced expression of ERalpha and all six growth factors, compared with oestrogen-treated cells but not significantly. It is concluded that upregulated ERalpha in prostatic stroma may have a greater modulating influence on synthesis of certain growth factors than the direct action of androgens and, by enhancing synthesis of FGF-2 and FGF-7, could play a significant role in the development of BPH.

Dihydrotestosterone↗

Effect of peripheral biopsies in maximising early prostate cancer detection in 8-, 10- or 12-core biopsy regimens.

OBJECTIVE: To assess the cancer detection rate per individual core biopsy in a 12-core protocol and develop an optimal biopsy regimen for detecting early prostate cancer. PATIENTS AND METHODS: The study included 445 new patients who had a 12-core transrectal ultrasonography (TRUS)-guided prostatic biopsy over a 40-month period. The 12- core biopsy protocol included parasagittal sextant and six peripheral biopsies. The cancer detection rate per individual core was evaluated to give an optimal biopsy protocol. RESULTS: Prostate cancer was detected in 142 patients (31.9%). Parasagittal sextant biopsy would have failed to detect 40 (28.2%) of the cancers. Among the various possible biopsy protocols, the optimum 10-core biopsy strategy excluding the parasagittal mid-zone biopsies from the 12-core protocol achieved a cancer detection rate of 98.6%. CONCLUSION: The cancer detection rate increased from 71.8% for parasagittal sextant biopsies to 88.7% by adding peripheral basal biopsies (8-biopsy protocol); 98.6% of cancers in the series would have been detected with a 10-biopsy strategy omitting the parasagittal mid-zone biopsies. Thus we recommend a 10-core protocol incorporating six peripheral biopsies in patients with elevated age- specific prostate-specific antigen levels (2.6-10.0 ng/mL) for maximising cancer detection.

Adult↗

Post-genomic applications of tissue microarrays: basic research, prognostic oncology, clinical genomics and drug discovery.

Tissue microarrays (TMAs) are an ordered array of tissue cores on a glass slide. They permit immunohistochemical analysis of numerous tissue sections under identical experimental conditions. The arrays can contain samples of every organ in the human body, or a wide variety of common tumors and obscure clinical cases alongside normal controls. The arrays can also contain pellets of cultured tumor cell lines. These arrays may be used like any histological section for immunohistochemistry and in situ hybridization to detect protein and gene expression. This new technology will allow investigators to analyze numerous biomarkers over essentially identical samples, develop novel prognostic markers and validate potential drug targets. The ability to combine TMA technology with DNA microarrays and proteomics makes it a very attractive tool for analysis of gene expression in clinically stratified tumor specimens and relate expression of each particular protein with clinical outcome. Public domain software allows researchers to examine digital images of individual histological specimens from TMAs, evaluate and score them and store the quantitative data in a relational database. TMA technology may be specifically applied to the profiling of proteins of interest in other pathophysiological conditions such as congestive heart failure, renal disease, hypertension, diabetes, cystic fibrosis and neurodegenerative disorders. This review is intended to summarize the strengths and weaknesses of TMA technology which will have an increasingly important role in the laboratories of the post-genomic era.

Animals↗

Correlation of mRNA for oestrogen receptor beta splice variants ERbeta1, ERbeta2/ERbetacx and ERbeta5 with outcome in endocrine-treated breast cancer.

This study has been performed to test the hypothesis that different oestrogen receptor beta (ERbeta) splice variants may be important determinants of clinical parameters, including outcome, in post-menopausal women with breast cancer receiving adjuvant endocrine treatment but no chemotherapy. Splice variants ERbeta1, ERbeta2 and ERbeta5 have been analysed by semi-quantitative RT-PCR in a cohort of 105 patients with primary breast cancer. Clinical correlates included age, grade, size, nodal status, ERalpha, progesterone receptor, Ki67, relapse-free survival (RFS) and overall survival (OS). Seventy per cent of cases were ERbeta1 positive, 69% ERbeta2 positive and 70% ERbeta5 positive. Within the cohort, 47% were positive for all three variants while 10% were negative for all three. ERbeta1 exhibited no discernible relationship with disease outcome. ERbeta2 and ERbeta5 expression was significantly associated with better RFS (P<0.005), and ERbeta2 with better OS (P=0.0002). In multivariate analysis, ERbeta2 (P=0.006), nodal status and the level of Ki67 expression were independent predictors for RFS while ERbeta2 (P=0.0008) and Ki67 status were independent predictors for OS. In the ERalpha-positive cases, or in the subset of those receiving adjuvant tamoxifen, ERbeta2 was significantly associated with good RFS (P<0.0005) and was the only independent marker of OS. We conclude that precise identification of splice variants of ERbeta are more important assessors than is ERbeta1 alone of the biological status of individual breast cancers, and hence in predicting their response to endocrine therapy.

Alternative Splicing↗

Expression and cellular localization of Na,K-ATPase isoforms in the rat ventral prostate.

OBJECTIVE: To determine the expression and plasma membrane domain location of isoforms of Na,K-ATPase in the rat ventral prostate. MATERIALS AND METHODS: Ventral prostate glands from adult male rats were dissected, cryosectioned (7 micro m) and attached to poly-l-lysine coated glass slides. The sections were then fixed in methanol and subjected to indirect immunofluorescence and immunoperoxidase procedures using a panel of well-characterized monoclonal and polyclonal antibodies raised against known Na,K-ATPase subunit isoforms. Immunofluorescence micrographs were digitally captured and analysed by image analysis software. RESULTS: There was expression of Na,K-ATPase alpha1, beta1, beta2 and beta3 subunit isoforms in the lateral and basolateral plasma membrane domains of prostatic epithelial cells. The alpha1 isoform was abundant but there was no evidence of alpha2, alpha3 or gamma isoform expression in epithelial cells. The alpha3 isoform was not detected, but there was a relatively low level of alpha2 isoform expression in the smooth muscle and stroma. CONCLUSION: Rat prostate Na,K-ATPase consists of alpha1/beta1, alpha1/beta2 and alpha1/beta3 isoenzymes. These isoform proteins were located in the lateral and basolateral plasma membrane domains of ventral prostatic epithelial cells. The distribution and subcellular localization of Na,K-ATPase is different in rodent and human prostate. Basolateral Na,K-ATPase probably contributes to the establishment of transepithelial ionic gradients that are a prerequisite for the uptake of metabolites by secondary active transport mechanisms and active citrate secretion.

Animals↗

Prostatic stem cells.

Multipotent cells within the epithelial compartment, together with phenotypically 'plastic' mesenchyma cells (stromal stem cells), provide a repository of protected genetic information from which the structure, stability and functionality of the prostate gland can be maintained. However, mere preservation of cells in a non-dividing state is insufficient to provide the necessary reservoir of information from which the structure and function of the prostate gland can be retained or recreated. Rather, there is a constant dynamic interaction, at the level of information exchange, between stem cells (whether epithelial or mesenchymal) and their surrounding environment (both humoral and physical). Thus, with respect to epithelial stem cells, these reside within environmental 'niches' which allow their controlled and limited proliferation while preserving genomic integrity. Similar 'mesenchymal niches' are also predicted to occur, although not yet identified, thus providing the multipotent source from which the full spectrum of stromal phenotypes might be regenerated. Recent data from studies of the haematopoietic and hepato-biliary systems indicate that the potential scope of stem cells far exceeds the immediate phenotypic complement of those tissues within which they originate, being dependent upon their precise environment as well as their genomic integrity.

Cell Differentiation↗

Upregulation of estrogen and androgen receptors modulate expression of FGF-2 and FGF-7 in human, cultured, prostatic stromal cells exposed to high concentrations of estradiol.

This study was performed to develop an experimental model in which expression of estrogen receptors (ER) by human prostatic stromal cells could be reproducibly enhanced relative to similar cells with low ER expression. The second aim was to characterise changes in expression of ER, androgen receptor (AR), FGF-2 and FGF-7 in stromal cells exposed to high and low concentrations of estradiol and testosterone mimicking the different sex hormone levels between young and elderly men. Five strains of human prostatic stromal cells, isolated from BPH resections, were grown in steroid-free medium plus 1 micromol 17beta-estradiol. After 10 days, cells were passaged and grown in the same medium without estradiol until confluent. In a second study four cell strains were exposed to high and low concentrations of 17beta-estradiol and testosterone for 10 days. Cells were labelled with fluorescent antibodies to ERalpha, AR, FGF-2 and FGF-7 and the fluorescence intensity measured by flow cytometry. Following exposure to 1 micromol estradiol, stromal cells showed reduced expression of AR and ERalpha but after passage without estradiol they showed a 25% increase in both receptors over controls. Different combinations of sex hormones induced inconsistent changes with respect to expression of ER, AR and FGFs in the various cell-strains. However, there was a highly significant correlation between AR, ER and FGF-2 and FGF-7, which was cell strain-specific. Thus, changes in sex hormone balance per se may not be solely responsible for the observed increases in prostatic ER levels in BPH. Since expression of ER is correlated with synthesis of FGF-2 and FGF-7, it is likely that increases in stromal ER may mediate the synthesis of stromally-derived growth factors which contribute to the aetiopathogenesis of benign prostatic hyperplasia.

Culture Techniques↗