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Biomedical subjects

David E Neal

Publications and source records attributed to David E Neal.

At least 19 recordsLinked to original sources
PubMed2007

A role for neurotensin in bicalutamide resistant prostate cancer cells.

BACKGROUND: Anti-androgens are administered as a principal treatment for prostate cancer. Aggressive hormone refractory disease is characterized in some cases by the development of a neuroendocrine phenotype. However little attention has been paid to resistance pathways selected for by long-term treatment with non-steroidal anti-androgens. METHODS: Using a resistant sub-line, LNCaP-Bic, we performed a comparative gene expression profiling using cDNA microarrays and target validation by qRT-PCR. Targets were then explored using cell proliferation, cell cycle analysis and in vitro invasion assays using siRNA technology. RESULTS: Neurotensin/Neuromedin N (NTS) was upregulated in the LNCaP-Bic line at both the transcript and protein level. The resistant line was found to have an increased proliferation rate, more rapid cell cycle progression and increased invasiveness through Matrigel. Each phenotypic difference could be reduced using siRNA knockdown of NT. CONCLUSION: Increased expression of NT in bicalutamide resistant prostate cancer cells induces cell proliferation and invasion suggesting that this peptide may contribute to the development of bicalutamide resistant prostate cancer.

Androgen Antagonists↗
PubMed2006

A comparison of socio-demographic and psychological factors between patients consenting to randomisation and those selecting treatment (the ProtecT study).

BACKGROUND: Patient preferences for treatment can pose problems for the conduct of randomised controlled trials: patients with a preference may refuse participation and thereby potentially compromise external validity. Moreover, randomising patients with a preference may affect treatment efficacy and threaten internal validity. AIMS: This study compared baseline characteristics and short-term psychological outcomes of patients who selected their treatment and those who agreed to random allocation. METHODS: Men participating in the prostate testing for cancer and treatment (ProtecT) study and who were randomised to active monitoring (n=138) were compared with those who had refused randomisation and selected this management (n=180). Socio-demographic data were collected at baseline, and anxiety and depression data were collected at baseline and six month follow-up. Socio-demographic characteristics were compared across these two groups in univariable analyses, and then linear regression was used to compare levels of anxiety and depression at follow-up with adjustments for confounders. RESULTS: Participants who selected active monitoring were more affluent (based on occupation details) and had less anxiety at baseline than those who were randomised. There were no differences with respect to age and marital status. Levels of anxiety and depression at six months follow-up were similar across the two groups of men. CONCLUSIONS: This study found some differences at baseline between the socio-demographic and psychological status of those randomised and self-selecting treatment, but no psychological differences at short-term follow-up. Further empirical evidence is required to assess whether preferences impact upon the process and outcome of randomised controlled trials.

Aged↗
PubMed2006

Fournier's gangrene.

BACKGROUND: A 59-year-old man presented with a 4-day history of scrotal pain and swelling and the rapid development of moist, black, foul-smelling lesions on the scrotum and penis. As a liver-transplant recipient, he was immunosuppressed. He also had type 1 (insulin-dependent) diabetes and poor nutrition, which might have compromised immunity further. INVESTIGATIONS: Physical examination, blood and tissue cultures, full blood count, urea and electrolytes, liver function tests, coagulation profile, C-reactive protein, and examination under anesthesia. DIAGNOSIS: Fournier's gangrene originating from an infected cutaneous lesion in an immunocompromised patient. MANAGEMENT: Resuscitation and triple broad-spectrum antibiotics, urgent surgical debridement, serial examinations under anesthesia with further debridements, and split-skin grafting. Phallic reconstruction is planned.

Fournier Gangrene↗
PubMed2006

Measuring the psychosocial impact of population-based prostate-specific antigen testing for prostate cancer in the UK.

OBJECTIVE: To evaluate the psychosocial impact of participation in a population-based prostate-specific antigen (PSA) testing programme, akin to screening, and to explore the relationship between urinary symptoms reported before PSA testing and the response to the subsequent PSA result. PATIENTS AND METHODS: This prospective questionnaire study was nested within the case-finding component of the ProtecT (prostate testing for cancer and treatment) feasibility study (ISRCTN20141297). Men aged 50-69 years from 18 general practices in three cities in the UK completed the Hospital Anxiety and Depression Scale (HADS), the Short Form-12 (SF-12) Health Survey, and the International Continence Society 'male' (ICSmale) questionnaires before giving consent for a PSA test in a community clinic (baseline). Men with an 'abnormal' PSA result returned for further investigation (including biopsy) and repeated these questionnaires before biopsy. RESULTS: At baseline, study participants had similar levels of anxiety and depression to the general male population. There was no increase in the HADS scores, or reduction in the SF-12 mental health component summary score, on attendance at the biopsy clinic after receiving an 'abnormal' PSA result. Urinary symptoms were associated with levels of anxiety and depression before receiving a PSA result (baseline), but were not associated with anxiety and depression at biopsy independently of baseline scores. Therefore changes in anxiety or depression at biopsy did not appear to differ between those with and without urinary symptoms. CONCLUSIONS: This study confirms the findings of other studies that the deleterious effects of receiving an abnormal PSA result during population screening are not identified by generic health-status questionnaires. Comparisons with outcomes of studies measuring cancer-specific distress and using qualitative research methods raise the question of whether a prostate cancer screening-specific instrument is required. However, a standardized measure of anxiety identified differences at baseline between those who did and did not report urinary symptoms. These findings suggest that it might be advisable to better inform men undergoing PSA testing about the uncertain relationship between urinary symptoms and prostate cancer, to minimize baseline levels of psychological distress.

Aged↗
PubMed2005

Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors.

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.

Amino Acid Sequence↗
PubMed2005

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

Androgens↗
PubMed2004

Evaluation of the therapeutic potential of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in preclinical models of bladder cancer.

The epidermal growth factor receptor (EGFR) is associated with aggressive phenotypes and is an independent predictor of stage progression and mortality in bladder cancer. Gefitinib ('Iressa,' ZD1839) is an orally active EGFR-tyrosine kinase inhibitor. The objective of this study was to evaluate the in vitro and in vivo effects of gefitinib in the EGFR-expressing human bladder cancer cell lines 253J B-V, RT-112, and T24. EGFR expression was 3- and 2-fold higher in 253J B-V and RT-112, respectively, compared with T24 cells. Ten microm gefitinib inhibited EGFR, p42/44 extracellular signal-regulated kinase (ERK), and Akt/protein kinase B phosphorylation in all three of the cell lines. Inhibition of ERK by gefitinib was significantly greater in 253J B-V compared with RT-112 and T24 cells (9:2:1 in 253J B-V:RT-112:T24), whereas inhibition of Akt phosphorylation was less in 253J B-V compared with RT-112 and T24 cells (1:9:30 in 253J B-V:RT-112:T24). When cultured in serum-free medium supplemented with epidermal growth factor, 10 microm gefitinib inhibited DNA synthesis in T24 and RT-112 cells, whereas 1 microm gefitinib was sufficient to inhibit DNA synthesis in 253J B-V cells. Similarly, in the presence of serum, 10 microm gefitinib induced a significant reduction in S-phase and viable cell number in T24 and RT-112 cells, whereas 1-10 microm gefitinib caused a dose-dependent effect on these phenotypes in 253J B-V cells. Gefitinib significantly enhanced the ability of ionizing radiation to reduce colony forming ability in 253J B-V and RT-112 cells. In nude mice, a daily oral dose of 150 mg/kg gefitinib induced regression of tumors produced by 253J B-V cells growing at s.c. sites and suppression of tumors produced by these cells at orthotopic sites but had no effect on tumors produced by RT-112 cells growing at s.c. sites. The data indicates that gefitinib has potential therapeutic value, alone or in combination with ionizing radiation, in a subset of EGFR-expressing bladder cancers. However, there is a differential response to gefitinib in these EGFR-expressing bladder cancer cell lines. Although gefitinib can inhibit phosphorylation of EGFR, ERK, and Akt, and inhibit growth of bladder cancer cells in vitro, it does not necessarily inhibit growth of bladder cancer cells in vivo. It is likely that optimized therapy approaches will require an accurate "molecular" diagnosis allowing effective, selective, tailored therapeutic strategies to be designed.

Animals↗
PubMed2004

CD133, a novel marker for human prostatic epithelial stem cells.

Stem cells are clonogenic cells with self-renewal and differentiation properties, which may represent a major target for genetic damage leading to prostate cancer and benign prostatic hyperplasia. Stem cells remain poorly characterised because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying cells, which have a more restricted proliferative potential. Human CD133 antigen, also known as AC133, was recently identified as a haematopoietic stem cell marker. Here we show that a small population (approximately 1%) of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously shown to be a marker of stem cells in prostate epithelia. alpha(2)beta(1)(hi)/CD133(+) cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential and can reconstitute prostatic-like acini in immunocompromised male nude mice.

AC133 Antigen↗
PubMed2004

Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer.

BACKGROUND: Histone deacetylase 1 (HDAC1) is a co-repressor involved in differentiation and proliferation control. It is upregulated in malignant compared to benign tissue, and targets a number of transcription factors including p53. METHODS: By immunohistochemistry, HDAC1 protein expression was investigated in human prostate specimens and the CWR22 mouse xenograft model. Flow cytometry and deconvolution immunofluorescence were also performed. RESULTS: HDAC1 was upregulated in pre-malignant and malignant lesions, with the highest increase in expression in hormone refractory (HR) cancer. Using the CWR22 xenograft model we showed androgen dependent regulation of HDAC1. HDAC1 overexpression led to a significant increase in proliferation and a shift towards the undifferentiated cytokeratin (CK) profile in a PC3M derivative clone constitutively expressing HDAC1. CONCLUSION: This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence.

Androgens↗
PubMed2004

Putative involvement of the histone acetyltransferase Tip60 in ribosomal gene transcription.

Tip60 is a histone acetyltransferase (HAT) implicated in a wide range of cellular functions, including mRNA synthesis and DNA repair. In the present report we propose a model based on which Tip60 is actively involved in ribosomal gene transcription through acetylation of UBF, a ribosomal specific transcription factor, as well as through its direct recruitment to the human ribosomal gene promoter, as shown by chromatin immunoprecipitation experiments. Electron microscopy studies revealed that Tip60 resides in sites of active rDNA transcription within the nucleolus, while it co-localizes with UBF as shown by confocal microscopy. In addition, in vivo transcription assays demonstrated that the nucleolar fraction of Tip60 localizes to sites of newly synthesized rRNA. Finally, functional assays established that Tip60 complexes with, and targets UBF for acetylation. The present study underlines the importance of acetylation in rDNA transcription and directly implicates Tip60 in the process of ribosomal gene transcription.

Acetyltransferases↗
PubMed2004

Screen-detected prostate cancer and the insulin-like growth factor axis: results of a population-based case-control study.

Higher circulating levels of IGF-I have been associated with increased risk of prostate and some other cancers. Most research on prostate cancer has been based on men with symptoms or identified following treatment of benign disease. However, increasing numbers of cancer cases are now detected in asymptomatic men following prostate-specific antigen (PSA) tests. We therefore used a population-based case-finding exercise using the PSA test to examine whether associations between the IGF axis and cancer risk were apparent in this population. A matched case-control study was conducted among 7,383 men (50-70 years) receiving a PSA test as part of a case-finding exercise. Assays of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were performed on cases and 2 controls matched on age, recruitment center and calendar time. Analyses were based on 176 cases and 324 matched controls. The risk of prostate cancer increased across quartiles of IGF-I (highest vs. lowest quartile, OR = 2.34; 95% CI = 1.26-4.34; p(trend) = 0.02) and IGF-II (OR = 1.78; 95% CI = 0.94-3.15; p(trend) = 0.09). Controlling for smoking history and IGFBP-3 strengthened associations with cancer for both IGF-I (OR = 3.00; 95% CI = 1.50-6.01; p(trend) 0.005) and IGF-II (OR = 2.02; 95% CI = 1.07-3.84; p(trend) = 0.04) Associations between the IGFs and cancer risk were stronger for advanced cases. Our findings suggest that both IGF-I and IGF-II are associated with an increased risk of screen-detected prostate cancer.

Aged↗
PubMed2004

Measurement of insulin-like growth factor axis does not enhance specificity of PSA-based prostate cancer screening.

OBJECTIVES: To examine whether measurement of insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein (IGFBP)-2 or IGFBP-3, alone or in combination, enhanced the specificity of prostate cancer detection among men with a prostate-specific antigen (PSA) level of 3 ng/mL or greater beyond that achieved by the free/total PSA index. METHODS: Cross-sectional analysis was performed on blood samples taken from 597 asymptomatic men (79% of those biopsied) participating in a community case-finding exercise. All men had a total PSA level of 3 ng/mL or greater and had undergone prostate biopsy. Assays of IGF-I, IGF-II, IGFBP-2, IGFBP-3, and free and total PSA were performed. The predictive performance of a range of measures was assessed using receiver operating characteristic analyses and compared with the free/total PSA index, for all biopsies and for men with a PSA level of 3 to 10 ng/mL. The overall test performance was summarized using the area under the receiver operating characteristic curve (AUC). RESULTS: Of the 597 men, 185 (31.0%) had prostate cancer identified at biopsy. When all biopsies were included, the performance of the free/total PSA index (AUC 0.73) was significantly greater than for IGF-I (AUC 0.59; P <0.0001), IGF-I/PSA ratio (AUC 0.65; P = 0.002), IGF-I + IGFBP-3 (AUC 0.59; P <0.0001), IGF-II (AUC 0.66; P = 0.002), and IGF-II + IGFBP-3 (AUC 0.67; P = 0.05). The combined measurement of free/total PSA, IGF-II, and IGFBP-3 resulted in a slight improvement in performance (AUC 0.76; P = 0.01). The results were similar when the analyses were restricted to men with an initial PSA level of 3 to 10 ng/mL. CONCLUSIONS: We found no evidence that measurement of the IGF axis enhances the specificity of prostate cancer detection in clinical practice beyond that achievable using the free/total PSA index.

Adenocarcinoma↗
PubMed2004

Serum insulin-like growth factor-I is positively associated with serum prostate-specific antigen in middle-aged men without evidence of prostate cancer.

We have examined the relationship between serum insulin-like growth factor-I (IGF-I) and prostate-specific antigen in 367 healthy men without evidence of prostate cancer and found a positive association (P = 0.05). In men without prostate cancer, serum prostate-specific antigen is closely related to prostate size, and our findings, therefore, suggest that IGF-I may induce prostatic epithelial proliferation. Higher circulating levels of IGF-I have been associated with increased risk of both prostate cancer and possibly benign prostatic hyperplasia. Greater rates of cell proliferation induced by IGF-I may be a key biological pathway underlying these disorders.

Age Distribution↗
PubMed2003

Control of human PIRH2 protein stability: involvement of TIP60 and the proteosome.

Murine PIRH2 (mPIRH2) was recently identified as a RING finger-containing ubiquitin-protein isopeptide ligase that interacts with both p53 and the human androgen receptor. mpirh2 is a p53-responsive gene that is up-regulated by UV, and mPIRH2 protein has the capacity to polyubiquitylate p53, perhaps leading to p53 destruction. mpirh2 therefore has properties similar to those of the oncogene mdm2. Here, we have identified human PIRH2 (hPIRH2) as a TIP60-interacting protein. To investigate its regulation, we characterized hPIRH2 in parallel with hPIRH2 variants possessing mutations of conserved RING finger residues. We observed that wild-type hPIRH2 is an unstable protein with a short half-life and is a target for RING domain-dependent proteasomal degradation. Accordingly, we found that hPIRH2 was ubiquitylated in cells. The TIP60-hPIRH2 association appeared to regulate hPIRH2 stability; coexpression of TIP60 enhanced hPIRH2 protein stability and altered hPIRH2 subcellular localization. These results suggest that hPIRH2 activities can be controlled, at the post-translational level, in multiple ways.

Acetyltransferases↗
PubMed2003

The scaffolding protein RACK1 interacts with androgen receptor and promotes cross-talk through a protein kinase C signaling pathway.

The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, functions as a ligand-dependent transcription factor that regulates genes involved in cell proliferation and differentiation. Using a C-terminal region of the human AR in a yeast two-hybrid screen, we have identified RACK1 (receptor for activated C kinase-1) as an AR-interacting protein. In this report we found that RACK1, which was previously shown to be a protein kinase C (PKC)-anchoring protein that determines the localization of activated PKCbetaII isoform, facilitates ligand-independent AR nuclear translocation upon PKC activation by indolactam V. We also observed RACK1 to suppress ligand-dependent and -independent AR transactivation through PKC activation. In chromatin immunoprecipitation assays, we demonstrate a decrease in AR recruitment to the AR-responsive prostate-specific antigen (PSA) promoter following stimulation of PKC. Furthermore, prolonged exposure to indolactam V, a PKC activator, caused a reduction in PSA mRNA expression in prostate cancer LNCaP cells. Finally, we found PKC activation to have a repressive effect on AR and PSA protein expression in androgen-treated LNCaP cells. Our data suggest that RACK1 may function as a scaffold for the association and modification of AR by PKC enabling translocation of AR to the nucleus but rendering AR unable to activate transcription of its target genes.

Active Transport, Cell Nucleus↗