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Biomedical subjects

J Brantley Thrasher

Publications and source records attributed to J Brantley Thrasher.

At least 19 recordsLinked to original sources
PubMed2007

Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers.

BACKGROUND: Brahma gene (BRM) and Brahma-related gene 1 (BRG1) are major components with ATPase enzymatic activities in the nucleosome remodeling SWI/SNF complex, and their expression pattern in human prostate cancers is unknown. METHOD: We analyzed a published cDNA microarray data set of prostate cancers for the expression of SWI/SNF genes, and then we evaluated the expression levels of BRG1 and BRM proteins with a semi-quantitative immunohistochemistry (IHC) approach in a pairwise manner of malignant versus benign tissues from individual prostate cancers. The correlation of BRG1/BRM expression with clinical parameters was analyzed. RESULTS: Microarray data showed an aberrant expression of BRG1 and BRM but not SNF5/INI1 genes in different stages of the disease course. In immunochemistry studies, BRG1 expression was significantly higher in malignant tissues compared to their benign compartments, and this difference was more profound in high-grade cancers. Although BRM expression showed a heterogeneous pattern, the average level of BRM expression was lower in malignant tissues than that in benign tissues. More interestingly, BRG1 and BRM expression showed a reciprocal pattern in both benign and malignant tissues of individual cases. In malignant tissues, higher BRG1 but not BRM expression levels were associated with larger volume of tumor mass. Increased expression of BRG1 but not BRM protein was observed in invasive cancer cells. Consistently, overexpression of exogenous wild-type BRG1 and BRM but not mutant BRG1 enhanced cancer cell invasion in an in vitro cell invasion assay. CONCLUSIONS: We provide the first evidence that aberrant expression of BRG1 and BRM genes is associated with disease development and progression in prostate cancers and increased BRG1 expression may promote tumor growth and invasion.

Adenocarcinoma↗
PubMed2007

Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes.

PURPOSE: The American Urological Association Prostate Guideline Update Panel was charged with updating the Guidelines for Clinically Localized Prostate Cancer. In assessing outcomes with treatment, it became apparent that a highly variable number of definitions exist with respect to biochemical recurrence. Herein, we review the variability in published definitions of biochemical recurrence and make recommendations directed toward improving this terminology by recommending a standard definition in patients treated with radical prostatectomy. MATERIALS AND METHODS: Four PubMed literature searches were performed between May 2001 and April, 2004 and covered articles published from 1991 through early 2004. The search terms included the MeSH major headings of prostate cancer and prostatic neoplasm. All potentially relevant articles were retrieved and a more detailed screen for relevance was performed. An article was considered relevant if it reported treatment outcomes of patients with clinical T1 or T2N0M0 prostate cancer. Data extractors recorded the definition of biochemical recurrence and definitions were then collapsed into categories representing the same criteria. The results of biochemical failure were subcategorized by initial treatment. RESULTS: Of 13,800 citations, a total of 436 articles were selected. Among these, a total of 145 articles contained 53 different definitions of biochemical recurrence for those treated with radical prostatectomy. Of these, the most common definition (35) was a prostate specific antigen of >0.2 ng/mL or a slight variation thereof. In addition, a total of 208 articles reported 99 different definitions of biochemical failure among those treated with radiation therapy. Of these, the American Society for Therapeutic Radiology and Oncology definition (70) and/or a variation thereof was the most commonly reported. In total, 166 different definitions of biochemical failure were identified. Following radical prostatectomy, the Panel recommends defining biochemical recurrence as an initial serum prostate specific antigen of > or =0.2 ng/mL, with a second confirmatory level of prostate specific antigen of >0.2 ng/mL. The Panel recommends the use of the American Society for Therapeutic Radiology and Oncology criteria for patients treated with radiation therapy and acknowledges that these criteria will soon be updated although not yet published. CONCLUSIONS: A high degree of variability in the definition of biochemical recurrence exists following treatment for localized prostate cancer. Strict definitions for biochemical recurrence are necessary to identify men at risk for disease progression and to allow meaningful comparisons among patients treated similarly. The Panel acknowledges the American Society for Therapeutic Radiology and Oncology criteria and future modifications thereof for those receiving radiation therapy and recommends the newly developed American Urological Association criteria for those treated with radical prostatectomy. The purpose for the establishment of this standard is for data reporting purposes and for comparison of similarly treated patients. It is not intended to represent a threshold value for which to initiate treatment. The Panel acknowledges that the clinical decision to initiate treatment will be dependent on multiple factors including patient and physician interaction rather than a specific prostate specific antigen threshold value.

Humans↗
PubMed2006

Conditional Akt activation promotes androgen-independent progression of prostate cancer.

Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.

Androgens↗
PubMed2006

Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells.

AIM: To characterize the matrix metalloproteinases (MMP)-2 promoter and to identify androgen response elements (AREs) involved in androgen-induced MMP-2 expression. METHODS: MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction (RT-PCR). MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays (EMSA) were used to verify the identified AREs in the MMP-2 promoter. RESULTS: Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1591 to -1259 (relative to the start codon) of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5'-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor (AR) interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment. Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. CONCLUSION: Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

Androgens↗
PubMed2006

Buccal mucosal urethroplasty in patients who had multiple previous procedures.

OBJECTIVES: To review the success rate of ventral onlay buccal mucosal grafts for anterior bulbar urethroplasty in patients who had undergone multiple procedures before repair. METHODS: We performed a retrospective review of one surgeon's experience performing 58 consecutive buccal mucosal urethroplasties on 57 patients from September 1999 to September 2004. The cause of the anterior urethral stricture was unknown in 33, trauma in 20, and urethritis in 4. Most of these patients had undergone multiple procedures before urethroplasty. An American Urological Association symptom score questionnaire was sent to all patients. RESULTS: The average patient age was 40.7 years (range 17 to 72). The average follow-up was 29.6 months (range 6 to 66). Of the 57 patients, 48 responded to the American Urological Association questionnaire (84%), and the average symptom and bother score was 4.8 and 1.3, respectively. Three patients had treatment failure, for a 94% success rate. CONCLUSIONS: The results of this study confirm the efficacy of buccal mucosal urethroplasty for anterior urethral strictures, especially in a tertiary referral setting in which a number of our patients had undergone repeat endoscopic procedures and multiple urethral dilations.

Adolescent↗
PubMed2006

Evaluation of ureterointestinal anastomosis: Wallace vs Bricker.

PURPOSE: There are no published reports to our knowledge comparing the complication rates of the 2 most frequently used ureterointestinal anastomoses. We compared the Bricker method vs the Wallace method in terms of stricture rate. MATERIALS AND METHODS: A retrospective review of the cystectomy database at our institution covering 1997 to 2003 was conducted. Patients were reviewed in terms of type of anastomosis, stricture formation, intervention, radiation therapy, type of diversion, operating room time, sex and age. RESULTS: A total of 237 patients at our institution underwent cystectomy during the time evaluated. Of these patients, 33 had incomplete data, 2 were anephric and did not require diversion, and 4 patients underwent LeDuc anastomosis. These patients were excluded from analysis, leaving 198 patients, 86 (43%) undergoing Bricker and 112 (56%) undergoing Wallace. Bricker anastomoses were considered 2 anastomotic units while Wallace anastomoses were considered a single unit. Therefore, there were 162 (59%) total Bricker anastomoses compared to 112 (41%) Wallace anastomoses. There was no statistically significant difference between the 2 groups in terms of type of diversion, number of patients undergoing adjuvant or neoadjuvant radiation therapy, operating room time, and days of followup. There were 3 strictures (1.85%) in the Bricker group and 5 strictures (4.46%) in the Wallace group. There was no statistically significant difference between the stricture rate in these 2 groups (p = 0.21). Stricture rates for patients undergoing neoadjuvant or adjuvant radiation were not statistically significant from the patients with no adjuvant therapy. CONCLUSIONS: Overall the stricture rate for ureterointestinal anastomosis was 2.92%. There was no difference in stricture rate between the 2 types of ureterointestinal anastomosis.

Aged↗
PubMed2006

Dose effect of soy supplementation in prostate cancer: a pilot study.

We performed a pilot study to determine the dose effect of soy supplement on serum hormonal levels, estrogen receptor alpha (ERalpha) and androgen receptor (AR) expression in patients scheduled to undergo prostatectomy. Cohorts of 3-4 eligible patients received escalating doses of a commercial soy supplement, Flav-ein, from the time of study enrollment until prostatectomy. Serum levels of prostate specific antigen (PSA), testosterone, and estrogen were measured at study enrollment and prior to prostatectomy. AR and ERalpha expression was evaluated in the pretreatment biopsy specimen and post-treatment prostatectomy specimen using immunohistochemical analysis. A total of 13 patients were enrolled in this pilot study and 11 patients were assessable for response. With soy supplementation, serum testosterone levels decreased in 9 of 11 patients and estrogen levels decreased in 8 of 10 patients in a dose-dependent manner. There was a variable effect on ERalpha expression with downregulation of receptor expression seen at the highest dose level. There was no effect on AR expression. In conclusion, supplementation with this commercial soy product produced a consistent decrease in serum sex hormone levels. Additional studies are needed to evaluate a potential dose effect on ERalpha expression.

Dehydroepiandrosterone↗
PubMed2005

The role of soy phytoestrogens in prostate cancer.

PURPOSE OF REVIEW: As alternative medicine gains popularity in the US, a greater understanding of the proven benefits and detriments of the supplements commonly used is needed by physicians. Chemoprevention through the use of supplements or dietary means is one example. Through epidemiological studies, it is clear that there is variation in the geographic incidence of certain cancers. One such variation is in prostate cancer, for which Asian men have a decreased death rate as compared with their Western counterparts. One hypothesis for this reduction in prostate cancer deaths is due to the difference in soy consumption. The purpose of this paper is to review the effects of soy at the molecular level as well as to review the in-vivo effects. RECENT FINDINGS: The mechanism by which soy or, more accurately, the isoflavones act is described in this review. Multiple studies attempting to clarify the effects of the isoflavones on molecular pathways will be discussed. Furthermore, recent studies demonstrating the effect of isoflavones on prostate-specific antigen, testosterone, estrogen, and hormone receptor expression in human subjects will be reviewed. SUMMARY: After reading this review, we expect that the reader will understand the background of the isoflavones, the effect they exert at the molecular level, and their proposed benefits and limitations in human patients. However, what will be evident at the conclusion of this manuscript is the need for future studies of the effects of soy in prostate cancer patients.

Anticarcinogenic Agents↗
PubMed2005

Clinical and pathological characteristics of unstageable prostate cancer: analysis of the CaPSURE database.

PURPOSE: The new and older clinical staging systems for prostate cancer overlook a group of patients in whom abnormal digital rectal examinations (DREs) do not correlate with prostate biopsy findings. These cases are clinically unstageable. We evaluated the prevalence and pathological characteristics of these patients and stratified them into the 1997 American Joint Committee on Cancer clinical staging categories. MATERIALS AND METHODS: Using the CaPSURE database, a longitudinal disease registry of patients with various stages of prostate cancer, the unstageable cohort was identified. The postoperative pathological stage distribution of the unstageable cohort was used to assign the appropriate preoperative clinical stages in retrograde fashion. Pearson product moment correlation was used to establish the best clinical stage for this unstageable group. RESULTS: A total of 5,543 patients with recorded DREs were evaluated, of whom 2,610 (47%) had an isolated unilateral abnormality on DRE. A total of 235 patients (9%) had prostate needle biopsies positive only on the contralateral side, yielding an unstageable prevalence of 4.2%. Of the cohort 102 patients (44%) underwent radical prostatectomy and 96 had adequate pathological staging data available for review and correlation. Pathological staging revealed pT2a cancers in 26%, pT2b in 53%, pT3a in 19%, pT3b and pT0 in 1% of patients. This distribution indicated that the unstageable cohort correlated most precisely with clinical stage T1c (r = 0.99). CONCLUSIONS: Thus, the prevalence of unstageable prostate cancer is low but significant and it can be accurately classified into clinical stage T1c.

Databases, Factual↗
PubMed2005

Parenteral medroxyprogesterone for the management of luteinizing hormone releasing hormone induced hot flashes in men with advanced prostate cancer.

PURPOSE: Luteinizing hormone releasing hormone (LHRH) agonist therapy for advanced prostate cancer can manifest significant side effects affecting quality of life, most notably hot flashes. This study evaluated the effectiveness of parenteral medroxyprogesterone acetate (MPA) in reducing the frequency and severity of these hot flashes. MATERIALS AND METHODS: A multi-institutional retrospective review of hot flashes from LHRH therapy for prostate cancer was conducted. The hot flashes were quantified and the severity was graded (3-point analogue scale) before and after treatment with MPA. Two doses of MPA (400 or 150 mg intramuscularly) were administered. Statistical analysis (Student's t test) evaluated the quantity of hot flashes, the quality of hot flashes, and dose effectiveness. RESULTS: A total of 48 men (40 at 400 mg, 8 at 150 mg) with a mean age of 71.4 years (range 54 to 87) from 3 institutions were evaluated. There were 91% with symptomatic improvement with MPA, and half (46%) had a complete response defined as total elimination of hot flashes. The median number of the hot flashes per day decreased from 4 to 1 and the median severity score decreased from 2 to 1 (p <0.05). Significance was not achieved comparing the 2 doses. Complete responders were not noted with the 150 mg dose. Anticipated response to MPA did not correlate with the number or severity of the hot flashes. CONCLUSIONS: This study is the first multi-institutional evaluation of hot flashes demonstrating significant reduction in quantity and severity with MPA. Based on these data we now manage hot flashes associated with LHRH analogues with 400 mg of MPA.

Androgen Antagonists↗
PubMed2005

Small-interfering RNA-induced androgen receptor silencing leads to apoptotic cell death in prostate cancer.

Prostate cancer is the second leading cause of cancer death in the United States and, thus far, there has been no effective therapy for the treatment of hormone-refractory disease. Recently, the androgen receptor (AR) has been shown to play a critical role in the development and progression of the disease. In this report, we showed that knocking down the AR protein level by a small interfering RNA (siRNA) approach resulted in a significant apoptotic cell death as evidenced by an increased annexin V binding, reduced mitochondrial potential, caspase-3/6 activation, and DFF45 and poly(ADP-ribose) polymerase cleavage. The apoptotic response was specifically observed in those siRNA-transfected cells that harbor a native AR gene. No cell death was found in the AR-null prostate cancer cell PC-3 or its subline that has been reconstituted with an exogenous AR gene, as well as two breast cancer cell lines that are AR positive. Moreover, in parallel with the siRNA-induced AR silencing, the antiapoptotic protein Bcl-xL was significantly reduced, which might account for the apoptotic cell death because ectopic enforced expression of Bcl-xL protein partially inhibited apoptosis after AR silencing. Taken together, our data showed that knocking down the AR protein level in prostate cancer cells leads to apoptosis by disrupting the Bcl-xL-mediated survival signal downstream of AR-dependent survival pathway.

Annexin A5↗
PubMed2004

Adrenergic regulation of salt and fluid secretion in human medullary collecting duct cells.

Transepithelial salt and fluid secretion mediated by cAMP in initial inner medullary collecting ducts (IMCDi) may be important for making final adjustments to urine composition. We examined in primary cultures of human IMCDi cells the effects of adrenergic receptor (AR) agonists and antagonists on intracellular cAMP levels, short-circuit current (I(SC)), and fluid secretion. Epinephrine (1 microM), norepinephrine (1 microM), and isoproterenol (10 nM) individually increased intracellular cAMP levels 57-, 2-, and 25-fold, respectively, and stimulated I(SC) 3.3-, 2.9-, and 3.4-fold, respectively. beta-AR activation increased net fluid secretion by cultured human IMCDi cell monolayers from 0.09 +/- 0.04 to 0.26 +/- 0.05 microl x h(-1) x cm(-2) and freshly isolated rat IMCDi from 0.02 +/- 0.01 to 0.09 +/- 0.02 nl x h(-1) x mm(-1). In monolayers, these effects were eliminated by blocking beta2-AR, but not beta1-AR. Activation of alpha2-AR with guanabenz inhibited isoproterenol-induced I(SC) by 37% in human IMCDi monolayers and fluid secretion by 91% in rat IMCDi. Immunohistochemistry of human medullary tissue sections revealed greater expression of beta2-AR than beta1-AR; beta2-AR was localized to the basolateral membranes of human IMCDi. Immunoblots identified alpha2A-AR and alpha2B-AR in cultured human IMCDi cell monolayers. We conclude that 1) catecholamines stimulate cAMP-dependent anion and fluid secretion by IMCDi cells primarily through beta2-AR activation and 2) alpha2-AR activation attenuates cAMP-dependent anion secretion.

Adrenergic alpha-Agonists↗
PubMed2004

Hedgehog signaling promotes prostate xenograft tumor growth.

During fetal prostate development, Sonic hedgehog (Shh) expression by the urogenital sinus epithelium activates Gli-1 expression in the adjacent mesenchyme and promotes outgrowth of the nascent ducts. Shh signaling is down-regulated at the conclusion of prostate ductal development. However, a survey of adult human prostate tissues reveals substantial levels of Shh signaling in normal, hyperplasic, and malignant prostate tissue. In cancer specimens, the Shh expression is localized to the tumor epithelium, whereas Gli-1 expression is localized to the tumor stroma. Tight correlation between the levels of Shh and Gli-1 expression suggests active signaling between the tissue layers. To determine whether Shh-Gli-1 signaling could be functionally important for tumor growth and progression, we performed experiments with the LNCaP xenograft tumor model and demonstrated that: 1). Shh expressed by LNCaP tumor cells activates Gli-1 expression in the tumor stroma, 2). genetically engineered Shh overexpression in LNCaP cells leads to increased tumor stromal Gli-1 expression, and 3). Shh overexpression dramatically accelerates tumor growth. These data suggest that hedgehog signaling from prostate cancer cells to the stroma can elicit the expression of paracrine signals, which promote tumor growth.

Adult↗
PubMed2004

Glycogen synthase kinase-3beta activity is required for androgen-stimulated gene expression in prostate cancer.

Despite the specificity inferred by its name, glycogen synthase kinase (GSK)-3beta is an important kinase with a plethora of significant cellular targets, including cytoskeletal proteins and transcription factors, and its activity is regulated by phosphorylation on tyrosine/serine residues. As part of our efforts to dissect the molecular basis responsible for androgen-independent progression of prostate cancer, we investigated the role of GSK-3beta in androgen-stimulated gene expression in human prostate cancer cells. Pretreatment of prostate cancer cells harboring wild-type or mutant androgen receptor with the GSK-3beta inhibitors, lithium chloride (LiCl), RO318220, or GF109203X, inhibited R1881-stimulated androgen-responsive reporter activity in a dose- and time-dependent manner. In addition, the expression of two endogenous androgen-stimulated gene products, prostate-specific antigen and matrix metalloproteinase-2, was suppressed by the GSK-3beta inhibitors in those cells. Most importantly, knocking down GSK-3beta expression via a small interference RNA-mediated gene silencing approach also reduced R1881-stimulated gene expression, demonstrating the specificity of GSK-3beta involvement. Moreover, R1881 treatment of the cells increased phosphorylation status of GSK-3beta on tyrosine residue Y(216) but not on serine residue S(9). Pretreatment of the cells with phosphatidylinositol 3-kinase inhibitor LY294002 or wortmannin, which blocks androgen action in cells, abolished R1881-induced GSK-3beta Y(216) phosphorylation. However, the phosphatidylinositol 3kinase or GSK-3beta inhibitors did not block R1881-induced nuclear translocation of androgen receptor. Finally, knocking down the expression of Akt or beta-catenin, the two GSK-3beta-related signaling molecules, via siRNA-mediated gene silencing did not significant affect R1881-stimulated gene expression. These findings suggest that GSK-3beta activity is required for androgen-stimulated gene expression in prostate cancer cells.

Androgens↗
PubMed2004

The craft of urologic surgery: modern radical perineal prostatectomy.

Radical perineal prostatectomy (RPP) is the original approach used by urologists for removing the entire prostate for cancer treatment. From its original description approximately 100 years ago, it has gone through periods of increased and decreased popularity. RPP has not been performed as commonly in the United States since the late 1970s, with the introduction of the radical retropubic prostatectomy. With increased emphasis on reducing morbidity associated with radical prostatectomy by less-invasive techniques, however, more surgeons are revisiting RPP. As discussed in this article, RPP offers several advantages over the retropubic or laparoscopic approach for certain patients.

Blood Loss, Surgical↗