Changes in penile length after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy.

Although reports have shown evidence for penile length (PL) shortening after radical prostatectomy (RP), the association between neoadjuvant androgen deprivation therapy (NADT) and PL after RP has yet to be determined. This study evaluates chronological changes in PL after NADT and RP. Stretched PLs (SPLs) of 143 patients, 41 of whom had undergone NADT, were measured before, 10 days after, and 1, 3, 6, 9, 12, 18, and 24 months after RP. Chronological erectile function and testosterone levels were then evaluated. SPL was shortest 10 days after RP in both the NADT (-) and NADT (+) groups and gradually recovered in length thereafter. SPL in the NADT (-) group was significantly longer than that in the NADT (+) group before RP. However, no significant differences in SPLs were found between both groups 6 months after RP. Although all subjects in the NADT (+) group had testosterone levels of <50 ng/dL before RP, such levels increased after RP. Before RP, the NADT (-) group was found to have significantly better erectile function than the NADT (+) group. However, differences in erectile function between the NADT (-) and NADT (+) groups after RP were not significant. This report is the first to show that among patients with prostate cancer, those who underwent NADT had greater PL recovery after RP than those who did not. Data regarding PL recovery after NADT and RP obtained in this study could be useful for patients with prostate cancer who plan to undergo such procedures.

Effects of testosterone replacement therapy on metabolic syndrome among Japanese hypogonadal men: A subanalysis of a prospective randomised controlled trial (EARTH study).

We investigated the effects of testosterone replacement therapy (TRT) on metabolic factors among hypogonadal men with a metabolic syndrome. From the study population of the EARTH study, which was a randomised controlled study in Japan, 65 hypogonadal patients with a metabolic syndrome, comprising the TRT group (n = 32) and controls (n = 33), were included in this study analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 12 months. Waist circumference, body mass index, body fat volume and blood pressure were measured in all patients at baseline and at 12 months. In addition, blood biochemical data, including total cholesterol, triglyceride (TG), HDL cholesterol, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) levels, were also evaluated. Changes in these categories from baseline to 12 months were compared between the TRT and control groups, with significant differences observed in waist circumference, body fat percentage, FPG, TG and HbA1c levels. No significant differences were observed in other parameters. TRT for 1 year was associated with improvements in some metabolic factors among Japanese men with hypogonadism and metabolic syndrome.

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease.

Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult-onset Still's disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6.1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non-carriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low-frequency variants of MEFV gene may be one of the susceptibility factors of AOSD.

MEFV gene polymorphisms and TNFRSF1A mutation in patients with inflammatory myopathy with abundant macrophages.

Inflammatory myopathy with abundant macrophages (IMAM) has recently been proposed as a new clinical condition. Although IMAM shares certain similarities with other inflammatory myopathies, the mechanisms responsible for this condition remain unknown. Patients with familial Mediterranean fever (FMF) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) also often develop myalgia. We therefore investigated the polymorphisms or mutations of MEFV and TNFRSF1A genes in patients with IMAM to identify their potential role in this condition. We analysed the clinical features of nine patients with IMAM and sequenced exons of the MEFV and TNFRSF1A genes. The patients with IMAM had clinical symptoms such as myalgia, muscle weakness, erythema, fever and arthralgia. Although none of the patients were diagnosed with FMF or TRAPS, seven demonstrated MEFV polymorphisms (G304R, R202R, E148Q, E148Q-L110P and P369S-R408Q), and one demonstrated a TNFRSF1A mutation (C43R). These results suggest that MEFV gene polymorphisms and TNFRSF1A mutation are susceptibility and modifier genes in IMAM.

Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy.

Great advances in tissue androgen analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) have made it possible to evaluate the tissue androgen content from a single needle prostate biopsy specimen. In this study, we investigated if pre-treatment androgen content in prostate biopsy specimens could predict their response to primary androgen deprivation therapy (ADT) and future castration-resistant prostate cancer (CRPC). One-hundred and sixty-five prostate cancer patients who received primary ADT were enrolled. They had received multiple core prostate needle biopsy at diagnosis, and an additional one needle biopsy specimen was obtained for tissue androgen determination using LC-MS/MS. The patients' prostate specific antigen (PSA) values were periodically followed during the treatment and patients were determined to have CRPC when their PSA value increased continuously to 25% above the nadir and a 2.0 ng/mL increase. A significant correlation was found between PSA value decline velocity (PSA half-time) after ADT and pre-ADT tissue androgen content. Twenty-three patients were determined to have CRPC. These CRPC patients had a significantly high concentration of tissue T (p < 0.01) and low concentration of tissue 5α-dihydrotestosterone (DHT) (p < 0.01), resulting in a higher tissue T/DHT ratio (p < 0.001). A multivariate Cox proportional hazard model revealed the pre-ADT tissue T/DHT ratio and Gleason score as independent predictors for CRPC development. By using the two statistically significant variables, the relative risk of CRPC development could be calculated. The results of this study suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT. Further studies are required for the clinical application of T/DHT ratio evaluation.

miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo.

Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized microRNA (miRNA) arrays to screen for differentially expressed miRNAs in paclitaxel-resistant cell lines established in vitro. We observed concordant upregulation of miR-135a in paclitaxel-resistant cell lines representing three human malignancies. Subsequently, the role of miRNA-135a was evaluated in an in vivo model of paclitaxel resistance. In this model, mice were inoculated subcutaneously with a non-small cell lung carcinoma cell line and treated with paclitaxel for a prolonged period. In paclitaxel-resistant cell lines, established either in vitro or in vivo, blockage of miR-135a sensitized resistant cell lines to paclitaxel-induced cell death. We further demonstrated a correlation between paclitaxel response and miR-135a expression in paclitaxel-resistant subclones that were established in vivo. The paclitaxel-resistant phenotype of these subclones was maintained upon retransplantation in new mice, as shown by decreased tumor response upon paclitaxel treatment compared with controls. Upregulation of miR-135a was associated with reduced expression of the adenomatous polyposis coli gene (APC). APC knockdown increased paclitaxel resistance in parental cell lines. Our results indicate that paclitaxel resistance is associated with upregulation of miR-135a, both in vitro and in vivo, and is in part determined by miR-135a-mediated downregulation of APC.

Risedronate prevents persistent bone loss in prostate cancer patients treated with androgen deprivation therapy: results of a 2-year follow-up study.

Androgen deprivation therapy (ADT) for prostate cancer (PCa) causes bone loss. Although we reported previously that risedronate significantly recovers bone mineral density (BMD) for up to 12 months, there have been no reports with longer follow-up periods to date. This study extended our earlier series extending the follow-up period to 24 months. Eligible patients had histologically confirmed PCa without lumbar spine metastasis and underwent ADT. Lumbar spine BMD, urinary deoxypyridinoline (uDPD) and serum bone alkaline phosphatase were measured at 6, 12 and 24 months. Among the total of 96 patients, we analyzed 26 and 18 patients in risedronate administration and control groups, respectively. BMD relative to the young adult mean ratio, uDPD and serum bone alkaline phosphatase of the risedronate administration group recovered significantly after 24 months compared with the control group (P<0.0001, P=0.0001, and P<0.0001, respectively). Transient blurred vision, malaise and vertigo were observed in 1 patient each among the 46 patients treated with risedronate within 28 days after first administration. Oral administration of risedronate is safe and effective for the recovery of ADT-induced bone loss in PCa patients even at 24 months after commencement of treatment.

The relationship of serum and salivary cortisol levels to male sexual dysfunction as measured by the International Index of Erectile Function.

To evaluate the biomarkers of sexual function, we investigated the relationship between questionnaire responses and biological hormones such as testosterone (T) and cortisol (F) in serum and saliva. The study population included 105 men aged 30-72 years (mean: 49+/-4.5, median: 49). Levels of all serum hormones (Total-T, Free-T, Bioavailable-T, Total-F and Bioavailable-F) and salivary hormones (Saliva-T and Saliva-F) were measured directly by liquid chromatography/tandem mass spectrometry. The International Index of Erectile Function (IIEF) was used as a questionnaire to evaluate sexual dysfunction. Free-T and Bioavailable-T showed significant inverse correlations with age (P<0.01). In the group not taking antidepressants, the levels of Bioavailable-F and Saliva-F showed significant inverse correlations with a portion of the IIEF score (P<0.05). However, reductions in Bioavailable-T and Saliva-T showed no association with the IIEF score. In the group taking antidepressants, these hormone levels showed no correlation with IIEF.

A case of IgG4-related autoimmune disease with multiple organ involvement.

A 52-year-old male was admitted with autoimmune pancreatitis (AIP), showing mononuclear cell infiltration in both the pancreas and salivary glands with both normal sialography and anti-SS-A/SS-B antibodies. Although the AIP improved with glucocorticoid treatment, subsequent abdominal computed tomography (CT) revealed a nodular shadow in the bilateral kidneys, which was confirmed as interstitial nephritis by renal biopsy. The patient's serum immunoglobulin G4 (IgG4) level was 10 times higher than the upper limit of the normal range. IgG4-positive mononuclear cell infiltration was detected in the salivary gland, pancreas, and kidney. A new entity proposed as 'IgG4-related autoimmune disease' was considered.

Different expression of androgen receptor coactivators in human prostate.

OBJECTIVES: To investigate the expression of androgen receptor (AR) coactivators in the human prostate for a better understanding of androgen action in prostate cancer. METHODS: Using reverse transcriptase-polymerase chain reaction, we examined the expression levels of AR coactivators (ARA55, SRC1, ARA54, TIF2, RAC3) in four prostate cancer cell lines (DU145, PC3, LNCaP, and LN-TR2), nine benign prostatic tissue samples, and 21 prostate cancer tissue specimens. RESULTS: In the cell lines, SRC1 was expressed ubiquitously at almost equal amounts. Contrary to this, ARA55, ARA54, TIF2, and RAC3 displayed cell line-specific expression. In the LN-TR2 cells, established from LNCaP cells by long-term treatment with tumor necrosis factor-alpha, the expression levels of ARA55 and TIF2 were much higher than those in the LNCaP cells. In every prostatic tissue specimen, the expression levels of TIF2 and RAC3 were very low. The expression levels of ARA55 and SRC1 were higher in the cancer specimens with a higher grade or poor response to endocrine therapy than in those with a lower grade or good response to endocrine therapy. CONCLUSIONS: Prostate cancer cells express AR coactivators. Long-term stimulation by tumor necrosis factor-alpha could increase ARA55 and TIF2 expression in LNCaP cells. The different expression of coactivators may contribute to the different response of prostate cancer to androgenic stimulation or endocrine therapy.

Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone.

Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-kappaB ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, osteoclast numbers were elevated at the bone/tumor interface in the vehicle-treated mice compared with the normal values in the OPG-treated mice. Furthermore, OPG had no effect on CaP cell viability, proliferation, or basal apoptotic rate in vitro. These results emphasize the important role that osteoclast activity plays in the establishment of CaP skeletal metastases, including those with an osteoblastic component.

Long-term exposure of tumor necrosis factor alpha causes hypersensitivity to androgen and anti-androgen withdrawal phenomenon in LNCaP prostate cancer cells.

BACKGROUND: One of the mechanisms through which prostate cancers relapse during anti-androgen therapy may involve adaptation to low concentrations of androgen induced by anti-androgen therapies. Recent studies from our laboratory have reported that tumor necrosis factor-alpha (TNFalpha) is secreted from prostate cancer epithelial cells and LNCaP cells. We hypothesized that TNFalpha changes androgen-sensitivity in LNCaP cells. METHODS: We cultured LNCaP cells for more than 3 months in the presence of 50 ng/ml TNFalpha and established TNFalpha-resistant LNCaP cells (LN-TR2). Sensitivity to androgen was examined by the cell proliferation assay. We also transfected LNCaP and LN-TR2 cells with a luciferase reporter plasmid driven by prostate-specific antigen (PSA) promoter and compared PSA promoter activity. Nuclear localization of AR protein that binds to target genes was also examined by Western blotting. RESULTS: LN-TR2 cells had increased sensitivity to dihydrotestosterone (DHT) (i.e., proliferation and PSA promoter activation) than LNCaP cells. Total AR mRNA and AR protein levels were decreased in LN-TR2 cells. However, LN-TR2 cells demonstrated increased levels of nuclear AR compared to LNCaP cells. At 1 nM DHT, the anti-androgen bicalutamide stimulated LN-TR2 and inhibited LNCaP proliferation. CONCLUSIONS: Long-term exposure of TNFalpha causes hypersensitivity to DHT in LNCaP and this was associated with increased nuclear AR protein. Furthermore, hypersensitivity to androgen caused anti-androgen withdrawal phenomenon in the presence of DHT although bicalutamide itself did not stimulate LNCaP proliferation without androgen. This result may be one possible mechanism for the anti-androgen withdrawal phenomenon.

[Prospects for molecular research in urological oncology: bladder cancer].

This report consists of a description of our research findings relating to the mechanism of cancer metastasis and target molecules for early diagnosis or cancer therapy. First, we investigated the significance of metastasis-related genes expressed to various extents in three human bladder cancer cell lines using two in vivo models. The relationship between the gene expression pattern and the behavior of cancer cells implicated a loss of E-cadherin expression as a critical factor in facilitating the progression of bladder cancer. Second, we examined the expression of human telomerase reverse transcriptase (hTERT) mRNA in voided urine samples in patients with bladder cancer. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a higher positive rate as compared with cytological examination, suggesting that the expression of hTERT in urine samples may be a useful diagnostic marker for bladder cancer. Finally, we searched for a molecule to which antisense can be applied as a treatment modality. The 150 kDa oxygen regulated protein (ORP 150), a kind of heat shock proteins, functions as a molecular chaperone in the endoplasmic reticulum. We demonstrated that the adenoviral-mediated antisense ORP150 cDNA transfer resulted in the suppression of vascular endothelial growth factor (VEGF) expression and tumor growth in vivo. In addition, the significant correlation between ORP150 and matrix metalloproteinase 2 (MMP-2) expression was observed in bladder cancer, suggesting that ORP150 functions as a molecular chaperon to MMP-2 secretion for tumor invasion. Anti-sense ORP150 may therefore have a potentially stronger antitumor effect because of its multitargeting capability as a molecular chaperone.

Tumor necrosis factor-alpha represses androgen sensitivity in the LNCaP prostate cancer cell line.

PURPOSE: Prostate tumor progression is characterized by development of androgen independence and a heterogeneous distribution of the androgen receptor (AR). Tumor necrosis factor alpha (TNFalpha) has been demonstrated to contribute to the progression of several cancers and thus may play a role in prostate cancer progression. Accordingly, we examined if prostate cancers express TNFalpha and the effect of TNFalpha on androgen sensitivity and AR expression in LNCaP prostate cancer cells. MATERIALS AND METHODS: Immunohistochemical analysis of prostate tissues, ELISA, and northern blotting of LNCaP cell lines were carried out for detection of tumor necrosis factor-alpha (TNFalpha). To see the effect of TNFalpha on androgen receptor (AR), western blotting and northern blotting were performed after extraction of total protein and total RNA from LNCaP cells. Regulation of androgen-sensitivity by TNFalpha was investigated with cell proliferation assay and luciferase assay using PSA promoter after transfection of LNCaP cells. RESULTS: Immunohistochemical analysis demonstrated that TNFalpha protein was strongly expressed in epithelial cells of prostate cancer tissue but not in normal prostatic tissue. Basal level of TNFalpha in cell culture medium from LNCaP cells was very low. However, 12-O-tetradecanoylphorbol 13-acetate (TPA) induced TNFalpha secretion into medium up to 1600 pg/ml/day. Furthermore, 24 hr. post-TPA treatment TNFalpha mRNA levels were increased 15-fold compared to pre-treatment levels. TNFalpha (0 to 30 ng./ml. for 4 days) repressed AR protein and mRNA levels in a dose-dependent fashion in LNCaP cells. Pre-treatment of cells with actinomycin D treatment revealed that repression of mRNA levels was exerted at the post-transcriptional level. TNFalpha inhibited the ability of 10-9 M dihydrotestosterone (DHT) to induce LNCaP cell proliferation and activation of the prostate specific antigen (PSA) gene promoter. This inhibition was partially reversed by overexpression of transgenic androgen receptor. CONCLUSIONS: TNFalpha is present and inducible in prostate cancer cells and short-term TNFalpha diminishes androgen-sensitivity in LNCaP cells through down-regulation of AR protein and mRNA levels. These results suggest that TNFalpha may play a role in the initiation of an androgen-independent state in prostate cancer through its ability to inhibit AR sensitivity in prostate cancer.

Comparative molecular analysis of HTLV-I proviral DNA in HTLV-I infected members of a family with a discordant HTLV-I-associated myelopathy in monozygotic twins.

In order to elucidate the underlying mechanisms of a discordant case with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monozygotic twins, we investigated HTLV-I tax sequences of 10 - 18 polymerase chain reaction-based clones each derived from peripheral blood mononuclear cells of the twins as well as their infected mother and an elder brother who also suffered from HAM/TSP. Sequence comparison revealed that three of the infected individuals including a twin with HAM/TSP shared the consensus tax sequence identical to the reference, ATK-1, but that of another healthy twin was different at five nucleotide positions including three nonsynonymous changes from ATK-1. This finding strongly suggested that different HTLV-I strains infected the monozygotic twins and the difference in infected proviral sequences determined the discordant clinical outcomes. Transfection and subsequent reporter assays failed to show a significant difference in transactivation activity on HTLV-I LTR and NF-kappaB elements between the products of the two sequences. Two HAM/TSP patients (a twin and elder brother) among three members infected with the ATK-1 type virus shared a paternal HLA allele which was absent in the healthy individual (mother). Genetic analysis of sequence variation in the tax sequences of the discordant twins showed that the Dn/Ds ratio was high in the healthy twin but low in the twin with HAM/TSP, implying the presence of more intense selection forces in the carrier. Our findings strongly suggested that a particular combination of HTLV-I strains with an HLA genotype would be a risk for HAM/TSP.

Up-regulation of human T lymphotropic virus type 1 (HTLV-1) tax/rex mRNA in infected lung tissues.

HTLV-1 has been implicated in certain pulmonary diseases. We previously demonstrated that expression of HTLV-1 tax/rex mRNA, encoding the transcriptional transactivator Tax, was closely associated with infiltration of activated T lymphocytes into lung tissue. To explore mechanisms of tax/rex expression in the lung, tax/rex mRNA expression and proviral DNA load were compared between peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage cells (BALC) from four patients with HTLV-1-associated myelopathy (HAM/TSP) and 13 carriers with various pulmonary symptoms. Semiquantitative detection of tax/rex mRNA strongly suggested that the lung was a preferential site for its expression. Proviral DNA loads in non-HAM/TSP carriers were variable but correlated well between PBMC and BALC in each individual, and revealed no relationship with tax/rex mRNA expression. In contrast, both cell groups from four HAM/TSP patients expressed detectable tax/rex mRNA accompanied by high proviral DNA load. The ratio of tax/rex mRNA expression to proviral DNA load was higher in BALC than in PBMC in three of four carriers and in three of four HAM/TSP patients, suggesting up-regulation of tax/rex mRNA in infected lung tissue. To analyse differences in distribution of HTLV-1 quasispecies between the two tissues, phylogenetic analysis was performed for sequence sets of the proviral tax open reading frame (ORF: 1059 bp) derived from PBMC and BALC of two infected individuals. Sequences derived from the two tissues distributed similarly to branches of phylogenetic trees, and there was no evidence of selective distribution of certain quasispecies in the lung. Our results suggest the presence of tissue-specific conditions that activate viral expression in infected cells in the lung. Constitutive exposure of this tissue to foreign antigens leading to up-regulation of basal viral promoter activity is likely to be one such mechanism.

Epigenetic regulation of androgen receptor gene expression in human prostate cancers.

Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. Heterogenous expression of androgen receptor (AR), which appears to be related to variable responses to endocrine therapy in prostate cancer (PCa) may also be due to epigenetic factors. The methylation status of the 5' CpG island of the AR in 3 prostate cancer cell lines and 10 primary and 14 hormone-refractory PCa samples was determined using the bisulfite PCR methods. In DU145, CpG-rich regions of the AR were hypermethylated. By an immunohistochemical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylation-specific PCR analysis showed aberrant methylation of AR 5'-regulatory region in 20% of 10 primary and 28% of 14 hormone-refractory PCa samples. To clarify the effect of epigenetic regulation on AR expression, we treated three prostate cancer cell lines with a demethylating agent, 5-aza-2'-deoxycytidine (azaC), and a histone deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of AR mRNA was detected after treatment with azaC and/or TSA. Our results suggest that epigenetic regulations including CpG methylation and histone acetylation may play important roles in the regulation of the AR.

Results of conservative treatment of upper urinary tract transitional cell carcinoma.

BACKGROUND: The treatment preserving the kidney for upper urinary tract tumor is still controversial. The indications and results of conservative treatment remain to be elucidated. Experiences of this type of treatment are reported. METHODS: Between April 1981 and March 1998, 14 patients with upper urinary tract transitional cell carcinoma were treated with renal preserving methods. Five were elective and nine were imperative cases. Treatments performed were partial nephrectomy, partial ureterctomy with or without adjuvant chemotherapy, endoscopic tumor resection and topical bacillus Calmette-Guerin instillation in one, 10, two and one patient, respectively. RESULTS: Crude and cause-specific 5 year-survival rates were 91.7 and 100%, respectively. Of 14 patients, five had bladder recurrences, but ipsilateral local recurrence developed in only one patient. Two patients died from metastasis of transitional cell carcinoma 61 and 89 months after initial treatment. The lesions of carcinoma in situ were well controlled with topical bacillus Calmette-Guerin therapy. CONCLUSION: The results of conservative treatment for upper urinary tract tumor were satisfactory and local excision can be indicated for low grade, solitary tumors located in the distal ureter.

Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate.

Androgen receptor (AR) is a hormone-activated transcriptional factor that can bind to androgen response elements and that regulates the transcription of target genes via a mechanism that presumably involves cofactors. We report here the cloning of a novel AR coactivator ARA55 using a yeast two-hybrid system. ARA55 consists of 444 amino acids with the predicted molecular mass of 55 kDa and its sequence shows very high homology to mouse hic5, a TGF-beta1-inducible gene. Yeast and mammalian two-hybrid systems and co-immunoprecipitation assays all prove ARA55 can bind to AR in a ligand-dependent manner. Transient transfection assay in prostate cancer DU145 cells further demonstrates that ARA55 can enhance AR transcriptional activity in the presence of 1 nM dihydrotestosterone or its antagonists such as 100 nM 17beta-estradiol or 1 microM hydroxyflutamide. Our data also suggest the C-terminal half of ARA55, which includes three LIM motifs, is sufficient to interact with AR. Northern blot and polymerase chain reaction quantitation showed ARA55 can be expressed differently in normal prostate and prostate tumor cells. Together, our data suggests that ARA55 may play very important roles in the progression of prostate cancer by the modulation of AR transactivation.