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Sample records for prostate specific nuclear

  1. Image Reconstruction for Prostate Specific Nuclear Medicine imagers

    SciTech Connect

    Mark Smith

    2007-01-11

    There is increasing interest in the design and construction of nuclear medicine detectors for dedicated prostate imaging. These include detectors designed for imaging the biodistribution of radiopharmaceuticals labeled with single gamma as well as positron-emitting radionuclides. New detectors and acquisition geometries present challenges and opportunities for image reconstruction. In this contribution various strategies for image reconstruction for these special purpose imagers are reviewed. Iterative statistical algorithms provide a framework for reconstructing prostate images from a wide variety of detectors and acquisition geometries for PET and SPECT. The key to their success is modeling the physics of photon transport and data acquisition and the Poisson statistics of nuclear decay. Analytic image reconstruction methods can be fast and are useful for favorable acquisition geometries. Future perspectives on algorithm development and data analysis for prostate imaging are presented.

  2. Eosinophilic prostatitis and prostatic specific antigen.

    PubMed

    Liu, S; Miller, P D; Holmes, S A; Christmas, T J; Kirby, R S

    1992-01-01

    Eosinophilic prostatitis is a rare form of abacterial prostatitis with uncertain aetiology. Its clinical presentation, like other types of abacterial prostatitis, commonly mimics carcinoma of the prostate. Transrectal ultrasound may be helpful in the diagnosis of prostatitis but histological confirmation is necessary. Prostatic specific antigen has been widely used in the diagnosis and follow-up of patients with prostatic carcinoma. High levels of this antigen (greater than 30 micrograms/l) have been claimed to be highly specific for prostate cancer, although lesser elevations may also occur in patients with large benign prostate glands and in bacterial prostatitis. We report 3 patients with histologically proven eosinophilic prostatitis and high levels of prostatic specific antigen. This diagnosis may closely mimic carcinoma of the prostate and must be excluded by histological examination of biopsy material before treatment for presumed prostate carcinoma is initiated.

  3. Prediction of biochemical recurrence and prostate cancer specific death in men after radical retropublic prostatectomy: Use of pathology and computer-assisted quantitative nuclear grading information

    NASA Astrophysics Data System (ADS)

    Khan, Masood Ahmed

    Prostate cancer is the most common solid tumour in man. Accordingly, it is expected that 1 in 6 men will experience prostate cancer during their lifetime. Over the past 20 years there have been tremendous advancements in both diagnostic as well as surgical approach to prostate cancer. This has led not only to earlier detection of the disease in its natural history, but also the availability of effective surgical management. Furthermore, the discovery of serum prostate specific antigen as a marker for prostate cancer along with greater acceptance of prostate cancer screening has resulted in an increase in the incidence of prostate cancer in men younger than 50 years of age. This is an age group that has traditionally been associated with a poor prognosis after radical prostatectomy. In addition, despite being able to effectively remove the whole of the gland with limited morbidity, approximately 25% of men after radical prostatectomy will experience biochemical recurrence with time. Moreover, the majority will progress to distant metastases and/or die from prostate cancer. We firstly investigated whether radical prostatectomy is a viable option for men younger than 50 years of age diagnosed with clinically localised prostate cancer. We also determined factors that predict disease recurrence after radical prostatectomy. As many men demonstrate evidence of biochemical recurrence with some showing further progression after radical prostatectomy, we, therefore, investigated whether pathological variables as well as nuclear morphometry could be used to predict those that are at an increased risk for disease recurrence after radical prostatectomy. Our results demonstrated that 1) radical prostatectomy can be safely performed in younger men as it can provide excellent long-term disease-free survival; 2) We determined that there are a number of factors that are associated with an increased risk for disease recurrence after radical prostatectomy; 3) We have constructed a new

  4. Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnostics and Therapy for Prostate Cancer.

    PubMed

    Kratochwil, Clemens; Afshar-Oromieh, Ali; Kopka, Klaus; Haberkorn, Uwe; Giesel, Frederik L

    2016-09-01

    The prostate-specific membrane antigen (PSMA) is expressed by approximately 90% of prostate carcinomas. The expression correlates with unfavorable prognostic factors, such as a high Gleason score, infiltrative growth, metastasis, and hormone-independence. The high specificity, especially in the undifferentiated stage, makes it an excellent target for diagnosis and therapy. Therefore, antibodies and small molecule inhibitors have been developed for imaging and therapy. In 2011 PSMA-11, a ligand that consists of the Glu-urea-motif and the chelator HBED-CC, which can be exclusively radiolabeled with (68)Ga for PET imaging, presented the clinical breakthrough for prostate cancer diagnostics. In two large diagnostic studies (n = 319 and n = 248) PET/CT with PSMA-11 successfully localized the recurrent tumor in approximately 90% of patients with biochemical relapse. Integrating PSMA-PET/CT into the planning phase of radiotherapy, the treatment concept is changed in 30%-50% of the patients. The combination of the Glu-urea-motif with DOTA, which can be labeled with several diagnostic and therapeutic radionuclides, opened new avenues for therapeutic usage of the small-molecule PSMA ligands. In the beginning of 2016, there are four confirmative reports (n = 19, n = 24, n = 30, and n = 56) from four different centers reporting a PSA response in approximately 70% of patients treated with (177)Lu-labeled PSMA ligands. In conclusion, the data available up to now indicate a widespread use of PSMA ligands for diagnostic applications with respect to staging, detection of recurrence, or metastases in patients with rising tumor markers and for therapy in case of failure of guideline-compliant treatment. PMID:27553466

  5. Prostate-specific antigen (PSA) blood test

    MedlinePlus

    Prostate-specific antigen; Prostate cancer screening test; PSA ... special steps are needed to prepare for this test. ... Reasons for a PSA test: This test may be done to screen for prostate cancer. It is also used to follow people after prostate cancer ...

  6. Locus-specific gene repositioning in prostate cancer

    PubMed Central

    Leshner, Marc; Devine, Michelle; Roloff, Gregory W.; True, Lawrence D.; Misteli, Tom; Meaburn, Karen J.

    2016-01-01

    Genes occupy preferred spatial positions within interphase cell nuclei. However, positioning patterns are not an innate feature of a locus, and genes can alter their localization in response to physiological and pathological changes. Here we screen the radial positioning patterns of 40 genes in normal, hyperplasic, and malignant human prostate tissues. We find that the overall spatial organization of the genome in prostate tissue is largely conserved among individuals. We identify three genes whose nuclear positions are robustly altered in neoplastic prostate tissues. FLI1 and MMP9 position differently in prostate cancer than in normal tissue and prostate hyperplasia, whereas MMP2 is repositioned in both prostate cancer and hyperplasia. Our data point to locus-specific reorganization of the genome during prostate disease. PMID:26564800

  7. Experience with prostate-specific antigen in prostatic carcinoma.

    PubMed

    Romics, I; Bach, D

    1991-01-01

    A total of 71 prostatic tumour patients and 45 prostatic adenoma patients were tested for prostate-specific antigen (PSA), immunological prostatic acid phosphatase (PAP) concentration as well as serum prostatic phosphatase (SPP) and enzymic serum phosphatase. It was found among untreated patients that PSA showed the highest percentage of pathologic affection in each stage. PSA, on the evidence of clearance test in the initial days of therapy and after a follow-up period of several months, gave a good picture of the course that the disease had taken.

  8. Prostate specific antigen gene expression in androgen insensitive prostate carcinoma subculture cell line.

    PubMed

    Tsui, Ke-Hung; Feng, Tsui-Hsia; Chung, Li-Chuan; Chao, Chun-Hsiang; Chang, Phei-Lang; Juang, Horng-Heng

    2008-01-01

    A novel prostate cancer cell line (PC-J) was isolated from an androgen independent non-prostate specific antigen (non-PSA) producing carcinoma cell line. The homologous correlation between PC-J and PC-3 was determined by short tandem repeat analysis. The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. The RT-PCR assays revealed that the expression of several tumor markers, including interleukin-6, prostate stem cell antigen (PSCA), prostate epithelium-specific Ets transcription factor (PDEF) and matriptase, was lower in the PC-J cells than in the PC-3 cells. This cell model elucidated the regulation of PSA expression and enabled comparison of the gene profile at different stages of metastasis in prostatic carcinoma.

  9. Non-Prostate-Specific Membrane Antigen-Avid Metastatic Lung Nodule From Primary Prostatic Adenocarcinoma.

    PubMed

    Shetty, Deepa; Loh, Han; Bui, Chuong; Mansberg, Robert; Hadjashrafi, Amirazin; Do, Viet

    2016-10-01

    Ga-prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 56-year-old man with previous history of treated prostate cancer 4 years earlier presented with rising prostate-specific antigen level and underwent Ga-PSMA PET/CT, which demonstrated an enlarging pulmonary nodule without PSMA avidity. The pulmonary nodule, however, showed moderate uptake on a corresponding FDG PET/CT study, suspicious of primary lung malignancy. Cytological and histopathological examination of the pulmonary nodule confirmed a metastatic deposit from ductal prostatic adenocarcinoma, an uncommon variant of prostatic malignancy.

  10. The relationship between prostate-specific antigen and prostate cancer risk: the Prostate Biopsy Collaborative Group

    PubMed Central

    Vickers, Andrew J.; Cronin, Angel M.; Roobol, Monique J.; Hugosson, Jonas; Jones, J. Stephen; Kattan, Michael W.; Klein, Eric; Hamdy, Freddie; Neal, David; Donovan, Jenny; Parekh, Dipen J.; Ankerst, Donna; Bartsch, George; Klocker, Helmut; Horninger, Wolfgang; Benchikh, Amine; Salama, Gilles; Villers, Arnauld; Freedland, Steve J.; Moreira, Daniel M.; Schröder, Fritz H.; Lilja, Hans

    2010-01-01

    PURPOSE The relationship between prostate specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesize that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study. EXPERIMENTAL DESIGN We used data from 5 European and 3 US cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally-weighted scatterplot smoothing. RESULTS The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased risk of cancer (odds ratio for >6 vs. 6 core biopsy 1.35; 95% C.I. 1.18, 1.54; p<0.0005); recent screening led to a smaller increase in risk per unit change in PSA (p=0.001 for interaction term) and US cohorts had higher risk than the European cohorts (2.14; 95% C.I. 1.99, 2.30; p<0.0005). CONCLUSIONS Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated. PMID:20736330

  11. African Americans' Perceptions of Prostate-Specific Antigen Prostate Cancer Screening

    ERIC Educational Resources Information Center

    Hunter, Jaimie C.; Vines, Anissa I.; Carlisle, Veronica

    2015-01-01

    Background: In 2012, the U.S. Preventive Services Task Force released a hotly debated recommendation against prostate-specific antigen testing for all men. The present research examines African Americans' beliefs about their susceptibility to prostate cancer (PCa) and the effectiveness of prostate-specific antigen testing in the context of the…

  12. Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

    SciTech Connect

    Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D.; Marples, Brian

    2010-03-01

    Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing gammaH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2mug/mL], Trinovin [10mug/mL], and Prostate Rx [50 mug/mL]). However, both Trinovin (10mug/mL) and Prostate Rx (6mug/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

  13. Prostate-Specific Antigen (PSA) Test

    MedlinePlus

    ... What are some of the limitations and potential harms of the PSA test for prostate cancer screening? ... has been learned about both the benefits and harms of prostate cancer screening, a number of organizations ...

  14. PROSTATE SPECIFIC MEMBRANE ANTIGEN-BASED IMAGING

    PubMed Central

    Osborne, Joseph R.; Akhtar, Naveed H.; Vallabhajosula, Shankar; Anand, Alok; Deh, Kofi; Tagawa, Scott T.

    2012-01-01

    SUMMARY Prostate cancer (PC) is the most common non-cutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of PC does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for PC specific antigenic targets and generate agents able to specifically bind. Prostate specific membrane antigen (PSMA) is over-expressed in PC tissue, with low levels of expression in the small intestine, renal tubular cells and salivary gland. The first clinical agent for targeting PSMA was 111In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab pendetide i.e. inability to bind to live PC cells. One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics including the identification of bone metastases in PC. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate timeframe for diagnostic imaging. Urea-based compounds such as small molecule inhibitors may also present promising agents for PC imaging with SPECT and PET. Two such small-molecule inhibitors targeting PSMA, MIP-1072 and MIP-1095, have exhibited high affinity for PSMA. The uptake of 123I-MIP-1072 and 123I-MIP-1095 in PC xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity. PMID:22658884

  15. The current state of prostate-specific antigen testing.

    PubMed

    Lewis, Ryan; Hornberger, Brad

    2016-09-01

    Since prostate-specific antigen (PSA) testing was approved in 1994, the incidence of metastasis and mortality from prostate cancer have significantly decreased. However, PSA screening for prostate cancer has limitations and few large randomized controlled trials have been conducted to determine the mortality benefit of PSA screening. Two studies that have been conducted are the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). These were the two main studies the US Preventive Services Task Force (USPSTF) used in its recommendation against prostate cancer screening in 2012. However, new evidence has demonstrated that the PLCO trial had significant limitations and the results of the ERSPC trial were more significant than previously thought. This article describes the strengths and weaknesses of the USPSTF's recommendation, along with current guidelines for prostate cancer screening. PMID:27575906

  16. New concepts in tissue specificity for prostate cancer and benign prostatic hyperplasia.

    PubMed

    De Marzo, A M; Coffey, D S; Nelson, W G

    1999-03-01

    Of the hundreds of species of mammals, all of which have prostate glands, only humans and dogs are known to suffer from benign prostatic hyperplasia (BPH) and prostate carcinoma. In humans, prostate carcinoma is common, yet carcinomas of other sex accessory tissues are rare. In addition, different anatomic regions within the prostate gland have very different rates of BPH and carcinoma. In this article, we explore ideas and potential mechanisms relating to these paradoxical findings that may help explain the species, organ, and zone specificity of BPH and prostate cancer. We present an evolutionary argument that attempts to relate a high-fat diet, with its potential for generating oxidative DNA damage, to the species selectivity of prostate cancer. In addition, we outline an argument based on our preliminary studies indicating that chronic inflammation and the associated increase in cell turnover in the setting of increased oxidative stress may help to account for the organ selectivity of genitourinary carcinomas.

  17. Nuclear iASPP may facilitate prostate cancer progression

    PubMed Central

    Morris, E V; Cerundolo, L; Lu, M; Verrill, C; Fritzsche, F; White, M J; Thalmann, G N; ten Donkelaar, C S; Ratnayaka, I; Salter, V; Hamdy, F C; Lu, X; Bryant, R J

    2014-01-01

    One of the major challenges in prostate cancer (PCa) research is the identification of key players that control the progression of primary cancers to invasive and metastatic disease. The majority of metastatic PCa express wild-type p53, whereas loss of p63 expression, a p53 family member, is a common event. Here we identify inhibitor of apoptosis-stimulating protein of p53 (iASPP), a common cellular regulator of p53 and p63, as an important player of PCa progression. Detailed analysis of the prostate epithelium of iASPP transgenic mice, iASPPΔ8/Δ8 mice, revealed that iASPP deficiency resulted in a reduction in the number of p63 expressing basal epithelial cells compared with that seen in wild-type mice. Nuclear and cytoplasmic iASPP expression was greater in PCa samples compared with benign epithelium. Importantly nuclear iASPP associated with p53 accumulation in vitro and in vivo. A pair of isogenic primary and metastatic PCa cell lines revealed that nuclear iASPP is enriched in the highly metastatic PCa cells. Nuclear iASPP is often detected in PCa cells located at the invasive leading edge in vivo. Increased iASPP expression associated with metastatic disease and PCa-specific death in a clinical cohort with long-term follow-up. These results suggest that iASPP function is required to maintain the expression of p63 in normal basal prostate epithelium, and nuclear iASPP may inactivate p53 function and facilitate PCa progression. Thus iASPP expression may act as a predictive marker of PCa progression. PMID:25341046

  18. Dietary Lycopene, Angiogenesis, and Prostate Cancer: A Prospective Study in the Prostate-Specific Antigen Era

    PubMed Central

    2014-01-01

    Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ2 tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; P trend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening. PMID:24463248

  19. Cellular prostatic acid phosphatase, a PTEN-functional homologue in prostate epithelia, functions as a prostate-specific tumor suppressor

    PubMed Central

    Muniyan, Sakthivel; Ingersoll, Matthew A.; Batra, Surinder K.; Lin, Ming-Fong

    2014-01-01

    The inactivation of tumor suppressor genes (TSGs) plays a vital role in the progression of human cancers. Nevertheless, those ubiquitous TSGs have been shown with limited roles in various stages of diverse carcinogenesis. Investigation on identifying unique TSG, especially for early stage of carcinogenesis, is imperative. As such, the search for organ-specific TSGs has emerged as a major strategy in cancer research. Prostate cancer (PCa) has the highest incidence in solid tumors in US males. Cellular prostatic acid phosphatase (cPAcP) is a prostate-specific differentiation antigen. Despite intensive studies over the past several decades on PAcP as a PCa biomarker, the role of cPAcP as a PCa-specific tumor suppressor has only recently been emerged and validated. The mechanism underlying the pivotal role of cPAcP as a prostate-specific TSG is, in part, due to its function as a protein tyrosine phosphatase (PTP) as well as a phosphoinositide phosphatase (PIP), an apparent functional homologue to Phosphatase and tensin homolog (PTEN) in PCa cells. This review is focused on discussing the function of this authentic prostate-specific tumor suppressor and the mechanism behind the loss of cPAcP expression leading to prostate carcinogenesis. We review other phosphatases’ roles as TSGs which regulate oncogenic PI3K signaling in PCa and discuss the functional similarity between cPAcP and PTEN in prostate carcinogenesis. PMID:24747769

  20. Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor.

    PubMed

    Vamadevan, Shankar; Shetty, Deepa; Le, Ken; Bui, Chuong; Mansberg, Robert; Loh, Han

    2016-10-01

    Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor.

  1. Prostate-Specific Antigen: Any Successor in Sight?

    PubMed Central

    Obort, Aniebietabasi S; Ajadi, Mary B; Akinloye, Oluyemi

    2013-01-01

    Abstract Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men in the United States and other parts of the world. The lifetime risk of being diagnosed with PCa is approximately 16%. At present, the only widely accepted screening tools for PCa are prostate-specific antigen (PSA) and digital rectal examination. PSA is known to be prostate specific, but not PCa specific, and hence lacks the sensitivity to detect a large number of tumors, especially during the early stages. The PSA level is also known to be affected by many factors, such as medication, inflammation (benign prostatic hyperplasia and prostatitis), and urologic manipulation; hence, the controversy regarding the appropriate level of serum PSA that should trigger a biopsy or have clinical relevance to prostate metastases. Attempts to determine the level of prostate cells in peripheral blood by reverse transcriptase polymerase chain reaction did not significantly improve cancer diagnosis or predict postoperative failure. Therefore, the search continues for a novel biomarker or a panel of markers as well as other possible interventions to improve the use of PSA. This article reviews several possibilities. PMID:24223021

  2. Prostate-specific extracellular vesicles as a novel biomarker in human prostate cancer

    PubMed Central

    Park, Yong Hyun; Shin, Hyun Woo; Jung, Ae Ryang; Kwon, Oh Sung; Choi, Yeong-Jin; Park, Jaesung; Lee, Ji Youl

    2016-01-01

    Extracellular vesicles (EVs) may play an important role in cancer development and progression. We aimed to investigate the prognostic potential of prostate-specific EVs in prostate cancer (PCa) patients. Plasma and prostate tissue were collected from patients who underwent surgery for PCa (n = 82) or benign prostatic hyperplasia (BPH, n = 28). To analyze the quantity of EVs in prostate, we performed transmission electron microscopy (TEM), immuno-TEM with CD63 and prostate-specific membrane antigen (PSMA), and immunofluorescence staining. After EV isolation from plasma, CD63 and PSMA concentration was measured using ELISA kits. PSMA-positive areas in prostate differed in patients with BPH, and low-, intermediate-, and high-risk PCa (2.4, 8.2, 17.5, 26.5%, p < 0.001). Plasma PSMA-positive EV concentration differed in patients with BPH, and low-, intermediate-, and high-risk PCa (21.9, 43.4, 49.2, 59.9 ng/mL, p < 0.001), and ROC curve analysis indicated that plasma PSMA-positive EV concentration differentiated PCa from BPH (AUC 0.943). Patients with lower plasma PSMA-positive EV concentration had greater prostate volume (50.2 vs. 33.4 cc, p < 0.001) and lower pathologic Gleason score (p = 0.025). During the median follow-up of 18 months, patients with lower plasma PSMA-positive EV concentration tended to have a lower risk of biochemical failure than those with higher levels of prostate-specific EVs (p = 0.085). PMID:27503267

  3. Prostate-specific extracellular vesicles as a novel biomarker in human prostate cancer.

    PubMed

    Park, Yong Hyun; Shin, Hyun Woo; Jung, Ae Ryang; Kwon, Oh Sung; Choi, Yeong-Jin; Park, Jaesung; Lee, Ji Youl

    2016-01-01

    Extracellular vesicles (EVs) may play an important role in cancer development and progression. We aimed to investigate the prognostic potential of prostate-specific EVs in prostate cancer (PCa) patients. Plasma and prostate tissue were collected from patients who underwent surgery for PCa (n = 82) or benign prostatic hyperplasia (BPH, n = 28). To analyze the quantity of EVs in prostate, we performed transmission electron microscopy (TEM), immuno-TEM with CD63 and prostate-specific membrane antigen (PSMA), and immunofluorescence staining. After EV isolation from plasma, CD63 and PSMA concentration was measured using ELISA kits. PSMA-positive areas in prostate differed in patients with BPH, and low-, intermediate-, and high-risk PCa (2.4, 8.2, 17.5, 26.5%, p < 0.001). Plasma PSMA-positive EV concentration differed in patients with BPH, and low-, intermediate-, and high-risk PCa (21.9, 43.4, 49.2, 59.9 ng/mL, p < 0.001), and ROC curve analysis indicated that plasma PSMA-positive EV concentration differentiated PCa from BPH (AUC 0.943). Patients with lower plasma PSMA-positive EV concentration had greater prostate volume (50.2 vs. 33.4 cc, p < 0.001) and lower pathologic Gleason score (p = 0.025). During the median follow-up of 18 months, patients with lower plasma PSMA-positive EV concentration tended to have a lower risk of biochemical failure than those with higher levels of prostate-specific EVs (p = 0.085). PMID:27503267

  4. Prostate specific antigen through the years.

    PubMed

    Kouriefs, Chryssanthos; Sahoyl, Mukhtar; Grange, Philippe; Muir, Gordon

    2009-12-01

    PSA was first identified in the 1960s. Some controversy exist as to who should be credited with its discovery as different groups, simultaneously, isolated the same protein but gave it a different name. PSA was firstly approved by FDA in 1986 as a test to aid the management of patients diagnosed with prostate cancer. In 1994, it was approved by the FDA as a diagnostic tool and up to date its beneficial role as a screening test is largely unknown. The results of the PLCO and ERSPC trials are awaited. Increasing interest is also emerging on the use of PSA as a tool in the management of BPH. Recently some embryonic data on the use of other novel markers such as EPCA and prostasomes is emerging and the data on PCA3 as a diagnostic tool for prostate cancer is maturing.

  5. EDB Fibronectin Specific Peptide for Prostate Cancer Targeting.

    PubMed

    Han, Zheng; Zhou, Zhuxian; Shi, Xiaoyue; Wang, Junpeng; Wu, Xiaohui; Sun, Da; Chen, Yinghua; Zhu, Hui; Magi-Galluzzi, Cristina; Lu, Zheng-Rong

    2015-05-20

    Extradomain-B fibronectin (EDB-FN), one of the oncofetal fibronectin (onfFN) isoforms, is a high-molecular-weight glycoprotein that mediates cell adhesion and migration. The expression of EDB-FN is associated with a number of cancer-related biological processes such as tumorigenesis, angiogenesis, and epithelial-to-mesenchymal transition (EMT). Here, we report the development of a small peptide specific to EDB-FN for targeting prostate cancer. A cyclic nonapeptide, CTVRTSADC (ZD2), was identified using peptide phage display. A ZD2-Cy5 conjugate was synthesized to accomplish molecular imaging of prostate cancer in vitro and in vivo. ZD2-Cy5 demonstrated effective binding to up-regulated EDB-FN secreted by TGF-β-induced PC3 cancer cells following EMT. Following intravenous injections, the targeted fluorescent probe specifically bound to and delineated PC3-GFP prostate tumors in nude mice bearing the tumor xenografts. ZD2-Cy5 also showed stronger binding to human prostate tumor specimens with a higher Gleason score (GS9) compared to those with a lower score (GS 7), with no binding in benign prostatic hyperplasia (BPH). Thus, the ZD2 peptide is a promising strategy for molecular imaging and targeted therapy of prostate cancer.

  6. Efficacy of lower cut off value of serum prostate specific antigen in diagnosis of prostate cancer.

    PubMed

    Rashid, M M; Alam, A K M K; Habib, A K M K; Rahman, H; Hossain, A K M S; Salam, M A; Rahman, S

    2012-12-01

    Indications of prostate biopsy are high serum prostate specific antigen (PSA) value and or abnormal digital rectal examination (DRE) findings. Although serum PSA value of 4 ng/ml is the most commonly used threshold for recommending prostate biopsy, significant proportion of men harbor prostate cancer even when their serum PSA values are less than 4.0 ng/ml. Therefore present study was designed to determine the performance status of serum PSA in lower cut-off values. This hospital based prospective study was conducted in the Department of Urology of Bangabandhu Sheikh Mujib Medical University (BSMMU) and Comfort Nursing Home Pvt. Ltd, Dhaka from July 2009 to October 2010. Two hundred six male patients aged over 50 years having lower urinary tract symptoms (LUTS) and serum PSA more than 2.5 ng/ml were prepared for prostate biopsy. Trans rectal ultrasound (TRUS) guided biopsy was done. The test statistics used to analyze the data were descriptive statistics, sensitivity, specificity, positive and negative predictive value, ROC curve. For all analytical tests, the level of significance was set at 0.05 and p < 0.05 was considered significant. In 2.5-4 serum PSA range, 28.26% (13 out of 46) of all malignancy were found, which would be missed if we take cut off value 4. At 2.5 PSA cut-off, Sensitivity 91.3%, Specificity 14.37%, PPV 23.46%, NPV 85.18%, Efficacy 31.55%. At 4 PSA cut-off value, Sensitivity 71.73%, Specificity 46.25%, PPV 27.73%, NPV 85.05%, Efficacy 51.94%. So it can be concluded that, for early diagnosis of prostate cancer cut-off value of serum PSA of 2.5 ng/ml can be recommended as an indication for prostate biopsy.

  7. Body mass index in relation to serum prostate-specific antigen levels and prostate cancer risk.

    PubMed

    Bonn, Stephanie E; Sjölander, Arvid; Tillander, Annika; Wiklund, Fredrik; Grönberg, Henrik; Bälter, Katarina

    2016-07-01

    High Body mass index (BMI) has been directly associated with risk of aggressive or fatal prostate cancer. One possible explanation may be an effect of BMI on serum levels of prostate-specific antigen (PSA). To study the association between BMI and serum PSA as well as prostate cancer risk, a large cohort of men without prostate cancer at baseline was followed prospectively for prostate cancer diagnoses until 2015. Serum PSA and BMI were assessed among 15,827 men at baseline in 2010-2012. During follow-up, 735 men were diagnosed with prostate cancer with 282 (38.4%) classified as high-grade cancers. Multivariable linear regression models and natural cubic linear regression splines were fitted for analyses of BMI and log-PSA. For risk analysis, Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) and natural cubic Cox regression splines producing standardized cancer-free probabilities were fitted. Results showed that baseline Serum PSA decreased by 1.6% (95% CI: -2.1 to -1.1) with every one unit increase in BMI. Statistically significant decreases of 3.7, 11.7 and 32.3% were seen for increasing BMI-categories of 25 < 30, 30 < 35 and ≥35 kg/m(2), respectively, compared to the reference (18.5 < 25 kg/m(2)). No statistically significant associations were seen between BMI and prostate cancer risk although results were indicative of a positive association to incidence rates of high-grade disease and an inverse association to incidence of low-grade disease. However, findings regarding risk are limited by the short follow-up time. In conclusion, BMI was inversely associated to PSA-levels. BMI should be taken into consideration when referring men to a prostate biopsy based on serum PSA-levels.

  8. Prostate Specific Membrane Antigen-Targeted Photodynamic Therapy Induces Rapid Cytoskeletal Disruption

    PubMed Central

    Liu, Tiancheng; Wu, Lisa Y.; Berkman, Clifford E.

    2010-01-01

    Prostate-specific membrane antigen (PSMA), an established enzyme-biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications. We aimed to determine the effects of PSMA-targeted photodynamic therapy (PDT) on cytoskeletal networks in prostate cancer cells. PSMA-targeted PDT resulted in rapid disruption of microtubules (α-/β-tubulin), microfilaments (actin), and intermediate filaments (cytokeratin 8/18) in the cytoplasm of LNCaP cells. The collapse of cytoplasmic microtubules and the later nuclear translocation of α-/β-tubulin were the most dramatic alternation. It is likely that these early changes of cytoskeletal networks are partly involved in the initiation of cell death. PMID:20452720

  9. Anti-prostate-specific membrane antigen-based radioimmunotherapy for prostate cancer.

    PubMed

    Tagawa, Scott T; Beltran, Himisha; Vallabhajosula, Shankar; Goldsmith, Stanley J; Osborne, Joseph; Matulich, Dan; Petrillo, Kristen; Parmar, Sarojben; Nanus, David M; Bander, Neil H

    2010-02-15

    Despite recent advances, advanced prostate cancer is suboptimally responsive to current chemotherapeutic agents. Radiolabeled monoclonal antibody therapy that targets prostate-specific membrane antigen (PSMA) shows promise and is an area of active investigation. J591 is a deimmunized IgG monoclonal antibody developed to target the extracellular domain of PSMA. Preclinical and early phase clinical studies using radiolabeled J591 have demonstrated efficacy in targeting tumor cells and decreasing levels of prostate-specific antigen. Radiolabeled J591 is well-tolerated, nonimmunogenic, and can be administered in multiple doses. The dose-limiting toxicity is reversible myelosuppression with little nonhematologic toxicity. Future studies will include approaches to optimize patient selection and incorporate novel strategies to improve the success of anti-PSMA radioimmunotherapy.

  10. The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence

    PubMed Central

    2013-01-01

    Background Although a previous meta-analysis reported no association between metabolic syndrome (MetS) and prostate cancer risk, a number of studies suggest that MetS may be associated with the aggressiveness and progression of prostate cancer. However, these results have been inconsistent. This systematic review and meta-analysis investigated the nature of this association. Methods We systematically searched MEDLINE, EMBASE and bibliographies of retrieved studies up to January 2013 using the keywords “metabolic syndrome” and “prostate cancer”. We assessed relative risks (RRs) of the prostate cancer, several parameters of prostate cancer aggressiveness and progression associated with MetS using 95% confidence intervals (95% CIs). Results The literature search produced 547 hits from which 19 papers were extracted for the meta-analysis. In cancer-free population with and without MetS, the combined adjusted RR (95% CI) of prostate cancer risk and prostate cancer-specific mortality in longitudinal cohort studies is 0.96 (0.85 ~ 1.09) and 1.12 (1.02 ~ 1.23) respectively. In the prostate cancer patients with and without MetS, the combined unadjusted OR (95% CI) of high grade Gleason prostate cancer is 1.44 (1.20 ~ 1.72), the OR of advanced prostate cancer is 1.37 (1.12 ~ 1.68) and the OR of biochemical recurrence is 2.06 (1.43 ~ 2.96). Conclusions The overall analyses revealed no association between MetS and prostate cancer risk, although men with MetS appear more likely to have high-grade prostate cancer and more advanced disease, were at greater risk of progression after radical prostatectomy and were more likely to suffer prostate cancer-specific death. Further primary studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required. PMID:23406686

  11. Reduction of prostate cancer mortality in Tyrol, Austria, after introduction of prostate-specific antigen testing.

    PubMed

    Oberaigner, Willi; Horninger, Wolfgang; Klocker, Helmut; Schönitzer, Dieter; Stühlinger, Wolf; Bartsch, Georg

    2006-08-15

    The objective of this study was to analyze in detail the time trend in prostate cancer mortality in the population of Tyrol, Austria. In Tyrol, prostate-specific antigen tests were introduced in 1988-1989 and, since 1993, have been offered to all men aged 45-74 years free of charge. More than three quarters of all men in this age group had at least one such test in the last decade. The authors applied the age-period-cohort model by Poisson regression to mortality data covering more than three decades, from 1970 to 2003. For Tyrol, the full model with age and period and cohort terms fit fairly well. Period terms showed a significant reduction in prostate cancer mortality in the last 5 years, with a risk ratio of 0.81 (95% confidence interval: 0.68, 0.98) for Tyrol; for Austria without Tyrol, no effect was seen, with a risk ratio of 1.00 (95% confidence interval: 0.95, 1.05). Each was compared with the mortality rate in the period 1989-1993. Although the results of randomized screening trials are not expected until 2008-2010, these findings support the evidence that prostate-specific antigen testing offered to a population free of charge can reduce prostate cancer mortality.

  12. Value of nuclear bone imaging in advanced prostatic cancer

    SciTech Connect

    Pollen, J.J.; Gerber, K.; Ashburn, W.L.; Schmidt, J.D.

    1981-02-01

    The nuclear bone scan is a highly sensitive means of detecting skeletal metastasis in patients with prostatic cancer. Serial bone imaging provides an accurate method to follow the response of osseous metastases to treatment and to detect relapsing disease in the skeleton. In selected instances the nuclear bone scan can provide information about vertebral metastases that can be important for planning palliative treatment of pain.

  13. Preclinical evaluation of a monoclonal antibody (3C6) specific for prostate-specific membrane antigen

    PubMed Central

    Regino, C.A.S.; Wong, K.J.; Milenic, D.E.; Holmes, E.H.; Garmestani, K.; Choyke, P.L.; Brechbiel, M.W.

    2008-01-01

    Better tumor markers are needed for early diagnosis and staging of prostate cancer, and for monitoring therapeutic response than the currently used prostate specific antigen (PSA). Prostate specific membrane antigen (PSMA) is highly expressed on the surface of prostatic epithelial cells making it a good target for prostate cancer. In this study, mAb 3C6, specific for the extracellular epitope of PSMA, was evaluated both in vitro and in vivo for PSMA-targeting. Immunoreactivity and specificity of mAb 3C6 was evaluated by flow cytometry using prostate cell lines expressing PSMA such as LNCaP and 22Rv1 and a cell line, DU145, that expresses very little PSMA. 3C6 was conjugated with the acyclic CHX-A” DTPA chelate, radiolabeled with 111In, and its in vitro and in vivo properties were assessed. The biodistribution of the radioimmunoconjugate evaluated in athymic mice bearing xenografts of three human prostate carcinoma cell lines shows high uptake after 72 hr in LNCaP tumors (%ID/g 22.93 ± 6.32) and 22Rv1 (%ID/g 10.44 ± 2.32) in contrast to low uptake by the DU145 tumors (%ID/g 4.27 ± 0.37). Planar γ-scintigraphic images obtained for xenografted tumor bearing mice demonstrated targeting for PSMA positive tumors suggesting possible applications in imaging and for targeted radiation therapy. PMID:20047017

  14. Salivary duct carcinoma secreting prostate-specific antigen.

    PubMed

    James, G K; Pudek, M; Berean, K W; Diamandis, E P; Archibald, B L

    1996-08-01

    Prostate-specific antigen (PSA) is a 30 kDa glycoprotein serine protease that shows high tissue specificity for prostatic tissue, both benign and malignant. However, recent reports have shown that a variety of normal and neoplastic tissue types express PSA immunohistochemically. In addition, rare instances of the secretion of PSA by nonprostatic cancers have been reported in the literature. The authors present a case of salivary duct carcinoma associated with elevated serum levels of PSA. Both the primary tumor and metastases stained positively with anti-PSA monoclonal antibodies, but were negative with antibodies directed against prostate-specific acid phosphatase. Elevated serum PSA levels were confirmed with three different immunoassay methods. A peak serum level of 140 micrograms/L was measured and this correlates with levels of PSA associated with metastatic prostatic carcinoma. High performance liquid chromatography with a molecular sieve column characterized the serum PSA into both free protein (approximately 20%) and protein bound to alpha-1-antichymotrypsin (PSA-ACT)(approximately 80%). Molecular weights of the free PSA and PSA-ACT subfractions were 27-31 kDa and 100-110 kDa, respectively.

  15. Prostate-specific acid phosphatase versus acid phosphatase in monitoring patients with prostate cancer.

    PubMed

    Killian, C S; Vargas, F P; Slack, N H; Murphy, G P; Chu, T M

    1982-01-01

    Serial levels of PAP and AcP activity were compared for their relative values in monitoring 57 early and 33 advanced prostate cancer patients. Several findings regarding the patients' disease status and the enzyme levels have been observed that may be beneficial to therapeutic management of these patients. They are: [1] an elevated PAP activity in disease recurrence and disease progression generally precedes an elevated AcP activity, and thus represents a more sensitive index for patients with early and advanced disease; [2] serial mean levels of PAP activity greater than the mean + 3 SD are more predictive for disease recurrence and progression than are those of AcP activity in both groups of patients; [3] PAP activity is a more sensitive monitor for changes in objective treatment response than is AcP activity; and [4] PAP is more specific than AcP for prostate, thus offering a more reliable marker to identify metastasis of unknown origin, or to confirm metastasis derived from a primary prostate tumor that may have been suggested by other non-prostate-specific marker[s]. In addition, data suggest a favorable prognosis for patients receiving therapy as inferred by a serial mean of PAP activity that is less than mean + 3 SD. PMID:6953924

  16. Prostate-Specific Antigen: Nonspecific in Deceased Organ Donors.

    PubMed

    Pabisiak, K; Ostrowski, M; Kram, A; Safranow, K; Myślak, M; Sieńko, J; Sulikowski, T; Ciechanowski, K

    2016-06-01

    Currently, there is no clear position regarding the donation of organs from donors with prostate carcinoma (CaP) in European countries, except Italy. The lengthening of life expectancy increases the probability of prostate cancer among potential organ donors. The concentration of prostate-specific antigen (PSA) >2 ng/mL at 60 years of age is related to the increasing possibility of identifying an advanced form of CaP. In recent years in Poland, the recommendation has been to determine tumor markers in potential donors. In the first year of the recommendation, 10% of potential male cadaveric donors were disqualified in West Pomerania, Poland, on the basis of elevated PSA levels (>10 ng/mL). To avoid reduction of the actual donor pool, each potential male donor reported to the center since January 2010 undergoes a routine histologic evaluation of the whole prostate, regardless of the PSA level, before organ implantation. In the study group (N = 52), histopathologic evaluation revealed 6 cases of CaP (12%). In CaP positive group Gleason score range from 2+2 to 3+4. In CaP donors PSA level have been noticed in range 1.79 ng/mL - 7.66 ng/mL. There was no correlation between histologically confirmed CaP and the PSA level. PMID:27496408

  17. Prostate-specific antigen doubling time and survival in patients with advanced metastatic prostate cancer.

    PubMed

    Loberg, Robert D; Fielhauer, Jeffery R; Pienta, Brian A; Dresden, Scott; Christmas, Patty; Kalikin, Linda M; Olson, Karin B; Pienta, Kenneth J

    2003-12-29

    The relation between tumor kinetics and disease progression in patients with hormone-refractory prostate cancer (HRPC) has not been well described. Biochemical recurrence of prostate cancer is characterized by detectable prostate-specific antigen (PSA) levels after treatment and occurs in approximately 30% of patients after therapy for apparent localized disease. An increase in PSA almost always occurs before clinical evidence of disease. The ability to identify early biochemical failure in patients to assess disease aggressiveness and guide changes in treatment needs to be examined. We examined serial PSA data from 249 patients with metastatic disease to assess PSA doubling time (PSADT) in hormone-naive prostate cancer (HNPC) and HRPC states. In a subset of patients, the relation of PSADT to Gleason score and survival was studied. PSADT decreased from 37.5 +/- 4.5 weeks to 15.6 +/- 1.6 weeks (mean +/- SEM) in patients with HNPC versus HRPC. In this small study, PSADT did not correlate with Gleason score, survival from start of hormonal treatment, length of time receiving hormone therapy, or survival in the HRPC state. The decrease in PSADT with disease state may help provide insight into understanding the biology of late-stage disease.

  18. Discoveries and application of prostate-specific antigen, and some proposals to optimize prostate cancer screening.

    PubMed

    Tokudome, Shinkan; Ando, Ryosuke; Koda, Yoshiro

    2016-01-01

    The discoveries and application of prostate-specific antigen (PSA) have been much appreciated because PSA-based screening has saved millions of lives of prostate cancer (PCa) patients. Historically speaking, Flocks et al first identified antigenic properties in prostate tissue in 1960. Then, Barnes et al detected immunologic characteristics in prostatic fluid in 1963. Hara et al characterized γ-semino-protein in semen in 1966, and it has been proven to be identical to PSA. Subsequently, Ablin et al independently reported the presence of precipitation antigens in the prostate in 1970. Wang et al purified the PSA in 1979, and Kuriyama et al first applied an enzyme-linked immunosorbent assay for PSA in 1980. However, the positive predictive value with a cutoff figure of 4.0 ng/mL appeared substantially low (∼30%). There are overdiagnoses and overtreatments for latent/low-risk PCa. Controversies exist in the PCa mortality-reducing effects of PSA screening between the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. For optimizing PCa screening, PSA-related items may require the following: 1) adjustment of the cutoff values according to age, as well as setting limits to age and screening intervals; 2) improving test performance using doubling time, density, and ratio of free: total PSA; and 3) fostering active surveillance for low-risk PCa with monitoring by PSA value. Other items needing consideration may include the following: 1) examinations of cell proliferation and cell cycle markers in biopsy specimens; 2) independent quantification of Gleason grading; 3) developing ethnicity-specific staging nomograms based on tumor stage, PSA value, and Gleason score; 4) delineation of the natural history; 5) revisiting the significance of the androgen/testosterone hypothesis; and 6) devoting special attention to individuals with a certain genetic predisposition. Finally

  19. Stereologically estimated mean nuclear volume of prostatic cancer is a reliable prognostic parameter.

    PubMed Central

    Arima, K.; Sugimura, Y.; Hioki, T.; Yamashita, A.; Kawamura, J.

    1997-01-01

    Although different histological grading systems of prostatic cancer refer to well-described characteristics, results are hard to reproduce. The aim of this study was to obtain morphometric data that would enable objective and reproducible grading of prostatic cancers by stereological estimation of mean nuclear volume (MNV). The clinical records and tissue specimens from 100 patients who were newly diagnosed as having prostatic cancer from 1973 to 1990 and who were followed up for 5 years or longer were retrospectively examined. We analysed the relationship between MNV and clinical stage, Gleason score and histological grading according to the World Health Organization (WHO) classification. To evaluate prognostic predictors, a multivariate analysis of factors associated with cause-specific survival was performed. We found a good correlation between the MNV and clinical stage and between the MNV and histological grading. There was no correlation between MNVs and Gleason scores. Multivariate analysis revealed that the MNV was the only predictor of survival time (coefficient 0.005; P < 0.0001; hazard ratio 1.005). We consider that the MNV is an excellent predictor of the prognosis in patients with prostatic cancer. Moreover, stereological estimation of MNV is a simple, quick, inexpensive and reliable morphometric procedure that enables the quantitative analysis of the histological and biological character of prostatic cancer. PMID:9231924

  20. Prostate-Specific Antigen Velocity for Early Detection of Prostate Cancer

    PubMed Central

    Vickers, Andrew J.; Wolters, Tineke; Savage, Caroline J.; Cronin, Angel M.; O’Brien, M. Frank; Pettersson, Kim; Roobol, Monique J.; Aus, Gunnar; Scardino, Peter T.; Hugosson, Jonas; Schröder, Fritz H.; Lilja, Hans

    2009-01-01

    Background It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy. Objective To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort. Design, setting, and participants There were 2742 screening-arm participants with PSA <3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Göteborg, Sweden, and who were subsequently biopsied during rounds 2[en]6 due to elevated PSA. Measurements Total, free, and intact PSA and human kallikrein 2 were measured for 1[en]6 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC). Results and limitations PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study. Conclusions In men with PSA of about ≥3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy. PMID:19682790

  1. [Specific prostatic antigen in prostatic carcinoma: its relationship with tumor differentiation and clinical course].

    PubMed

    Sáenz de Chirife, A M; Bassi, A M; Celeste, F; Bergdolt, D

    1991-05-01

    Carcinoma of the prostate is a tumor with a variable clinical course and a high incidence of local progression and/or metastasis. This study was undertaken to evaluate tissue prostate specific antigen (PSA) in patients with carcinoma of the prostate, its correlation with Gleason's grading and its value in predicting the clinical course of these patients. We studied 28 transurethral biopsies of patients with prostatic carcinoma utilizing HE and peroxidase-antiperoxidase staining techniques. These were given a score of 2 to 10 using Gleason's grading. PSA was determined according to percent positivity. The clinical course was considered favourable (F) when the lesion remained stable and unfavourable (U) when peri-prostatic spread was evidenced, metastasis and/or death from the disease. Statistical analysis was performed with the linear discriminatory test. PSA percentages ranged from 0 to 95 and the Gleason score from 3 to 11. There was an indirect correlation between these methods (r = 0.74): high Gleason scores corresponded to low PSA values and viceversa. PSA was highly positive in patients with F and U clinical courses whereas low positive values (less than 40%) were observed only in patients with U clinical course. High Gleason (8 to 10) and low (less than 5) scores were observed only in patients with a clinical course of U or F, respectively, while intermediate values (5 to 8) were not predictive of the clinical course. Discriminatory analysis gave Z values of -2.446 (P = 0.014) for PSA, -2.90 (P = 0.004) for the Gleason score in predicting prognosis, conferring a greater value overall to the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer.

    PubMed

    Soydal, Cigdem; Ozkan, Elgin; Akyurek, Serap; Kucuk, Nuriye Ozlem

    2016-02-01

    We present pretreatment Ga prostate-specific membrane antigen (PSMA) PET/CT and posttreatment Lu-PSMA whole-body scintigraphy images of a 60-year-old patient with metastatic prostate cancer who is dramatically responding to Lu-PSMA treatment. PMID:26505861

  3. Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer.

    PubMed

    Soydal, Cigdem; Ozkan, Elgin; Akyurek, Serap; Kucuk, Nuriye Ozlem

    2016-02-01

    We present pretreatment Ga prostate-specific membrane antigen (PSMA) PET/CT and posttreatment Lu-PSMA whole-body scintigraphy images of a 60-year-old patient with metastatic prostate cancer who is dramatically responding to Lu-PSMA treatment.

  4. Free Prostate-Specific Antigen Provides More Precise Data on Benign Prostate Volume Than Total Prostate-Specific Antigen in Korean Population

    PubMed Central

    Choi, Hoon; Park, Jae Young; Shim, Ji Sung; Kim, Jae Heon

    2013-01-01

    Purpose To investigate the efficacy of total prostate-specific antigen (tPSA) and free prostate-specific antigen (fPSA) for the estimation of prostate volume (PV) in pathologically-proven benign prostatic hyperplasia (BPH) patients. Methods From January 2010 to March 2013, 165 Korean men with a PSA less than 10 ng/mL who were diagnosed without prostate cancer by prostate biopsy were enrolled. Patients were classified into three age groups: ≤60, 61-70, and >70 years old. The results were organized to estimate and compare the ability of serum tPSA and fPSA to assess the PV. Results Enrolled patients had a median age of 63.5 years (44 to 80), a median tPSA of 5.72 ng/mL, a median fPSA of 0.98 ng/mL and a median PV of 53.68 mL, respectively. Among the associations between tPSA, fPSA, age, and PV, the highest correlation was verified between fPSA and PV (r=0.377, P<0.0001); the correlation coefficient between tPSA and PV was much lower (r=0.262, P<0.001). All stratified age cohorts showed the same findings. The ROC curves (for PV greater than 30, 40, and 50 mL) showed that fPSA (area under the curve [AUC]=0.781, 0.718, and 0.700) outperformed tPSA (AUC=0.657, 0.583, and 0.67) in its ability to predict clinically significant PV enlargement. Conclusion Both tPSA and fPSA significantly correlated with PV in Korean men, while the correlation efficiency between fPSA and PV was more powerful. fPSA may be a useful tool in making therapeutic decisions and follow-up management in BPH patients. PMID:23869271

  5. Anti-Prostate Specific Membrane Antigen-based Radioimmunotherapy for Prostate Cancer

    PubMed Central

    Tagawa, Scott T.; Beltran, Himisha; Vallabhajosula, Shankar; Goldsmith, Stanley J.; Osborne, Joseph; Matulich, Dan; Petrillo, Kristen; Parmar, Sarojben; Nanus, David M.; Bander, Neil H.

    2009-01-01

    Despite recent advances, advanced prostate cancer is suboptimally responsive to current chemotherapeutic agents. Radiolabeled monoclonal antibody therapy that targets prostate specific membrane antigen (PSMA) shows promise and is an area of active investigation. J591 is a deimmunized IgG monoclonal antibody developed to target the extracellular domain of PSMA. Preclinical and early phase clinical studies utilizing radiolabeled J591 have demonstrated efficacy in targeting tumor cells and decreasing levels of PSA. Radiolabeled J591 is well-tolerated, non-immunogenic, and can be administered in multiple doses. The dose limiting toxicity is reversible myelosuppression with little non-hematologic toxicity. Future studies will include approaches to optimize patient selection and incorporate novel strategies to improve the success of anti-PSMA radioimmunotherapy. PMID:20127956

  6. Age and Prostate-Specific Antigen Level Prior to Diagnosis Predict Risk of Death from Prostate Cancer

    PubMed Central

    MacKintosh, F. Roy; Sprenkle, Preston C.; Walter, Louise C.; Rawson, Lori; Karnes, R. Jeffrey; Morrell, Christopher H.; Kattan, Michael W.; Nawaf, Cayce B.; Neville, Thomas B.

    2016-01-01

    A single early prostate-specific antigen (PSA) level has been correlated with a higher likelihood of prostate cancer diagnosis and death in younger men. PSA testing in older men has been considered of limited utility. We evaluated prostate cancer death in relation to age and PSA level immediately prior to prostate cancer diagnosis. Using the Veterans Affairs database, we identified 230,081 men aged 50–89 years diagnosed with prostate cancer and at least one prior PSA test between 1999 and 2009. Prostate cancer-specific death over time was calculated for patients stratified by age group (e.g., 50–59 years, through 80–89 years) and PSA range at diagnosis (10 ranges) using Kaplan–Meier methods. Risk of 10-year prostate cancer mortality across age and PSA was compared using log-rank tests with a Bonferroni adjustment for multiple testing. 10.5% of men diagnosed with prostate cancer died of cancer during the 10-year study period (mean follow-up = 3.7 years). Higher PSA values prior to diagnosis predict a higher risk of death in all age groups (p < 0.0001). Within the same PSA range, older age groups are at increased risk for death from prostate cancer (p < 0.0001). For PSA of 7–10 ng/mL, cancer-specific death, 10 years after diagnosis, increased from 7% for age 50–59 years to 51% for age 80–89 years. Men older than 70 years are more likely to die of prostate cancer at any PSA level than younger men, suggesting prostate cancer remains a significant problem among older men (even those aged 80+) and deserves additional study. PMID:27446803

  7. Local prostate cancer radiotherapy after prostate-specific antigen progression during primary hormonal therapy

    PubMed Central

    2012-01-01

    Background The outcome of patients after radiotherapy (RT) for localized prostate cancer in case of prostate-specific antigen (PSA) progression during primary hormonal therapy (HT) is not well known. Methods A group of 27 patients presenting with PSA progression during primary HT for local prostate cancer RT was identified among patients who were treated in the years 2000–2004 either using external-beam RT (EBRT; 70.2Gy; n=261) or Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18Gy + 50.4Gy; n=71). The median follow-up period after RT was 68 months. Results Median biochemical recurrence free (BRFS), disease specific (DSS) and overall survival (OS) for patients with PSA progression during primary HT was found to be only 21, 54 and 53 months, respectively, with a 6-year BRFS, DSS and OS of 19%, 41% and 26%. There were no significant differences between different RT concepts (6-year OS of 27% after EBRT and 20% after EBRT with HDR-BT). Considering all 332 patients in multivariate Cox regression analysis, PSA progression during initial HT, Gleason score>6 and patient age were found to be predictive for lower OS (p<0.001). The highest hazard ratio resulted for PSA progression during initial HT (7.2 in comparison to patients without PSA progression during primary HT). PSA progression and a nadir >0.5 ng/ml during initial HT were both significant risk factors for biochemical recurrence. Conclusions An unfavourable prognosis after PSA progression during initial HT needs to be considered in the decision process before local prostate radiotherapy. Results from other centres are needed to validate our findings. PMID:23227960

  8. Predictors of mortality after prostate-specific antigen failure

    SciTech Connect

    D'Amico, Anthony V. . E-mail: adamico@lroc.harvard.edu; Kantoff, Phillip; Loffredo, Marian; Renshaw, Andrew A.; Loffredo, Brittany; Chen Minghui

    2006-07-01

    Purpose: We identified factors associated with the length of survival after prostate-specific antigen (PSA) failure. Methods and Materials: The study cohort comprised 81 of 206 men enrolled on a randomized trial evaluating external-beam radiation therapy (RT) with or without androgen suppression therapy (AST) and who experienced PSA failure. Salvage AST was administered at a PSA level of {approx}10 ng/mL as per protocol. Cox regression was used to determine factors associated with length of survival after PSA failure. Results: A PSA DT (doubling time) <6 months (p = 0.04) and age at the time of PSA failure (p = 0.009) were significantly associated with length of survival. By 5 years, 35% and 65% of all-cause mortality was from prostate cancer in men whose age at PSA failure was 75 or higher vs. <75, respectively. Across all ages, 0%, 4%, as compared with 63% of men, were estimated to die of prostate cancer within 5 years after PSA failure if their PSA DT was >12, 6-12, or <6 months, respectively. Conclusions: Advanced age and a PSA DT <6 months at the time of PSA failure are associated with a significantly shorter survival.

  9. A specific molecular beacon probe for the detection of human prostate cancer cells.

    PubMed

    Jiang, Yu Lin; McGoldrick, Christopher A; Yin, Deling; Zhao, Jing; Patel, Vini; Brannon, Marianne F; Lightner, Janet W; Krishnan, Koyamangalath; Stone, William L

    2012-06-01

    The small-molecule, water-soluble molecular beacon probe 1 is hydrolyzed by the lysate and living cells of human prostate cancer cell lines (LNCaP), resulting in strong green fluorescence. In contrast, probe 1 does not undergo significant hydrolysis in either the lysate or living cells of human nontumorigenic prostate cells (RWPE-1). These results, corroborated by UV-Vis spectroscopy and fluorescent microscopy, reveal that probe 1 is a sensitive and specific fluorogenic and chromogenic sensor for the detection of human prostate cancer cells among nontumorigenic prostate cells and that carboxylesterase activity is a specific biomarker for human prostate cancer cells.

  10. Early prostate-specific antigen changes and the diagnosis and prognosis of prostate cancer

    PubMed Central

    Botchorishvili, George; Matikainen, Mika P.; Lilja, Hans

    2009-01-01

    Purpose of review To delineate how recent findings on prostate-specific antigen (PSA) can improve prediction of risk, detection, and prediction of clinical endpoints of prostate cancer (PCa). Recent findings The widely used PSA cut-point of 4.0 ng/ml increasingly appears arbitrary, but no cut-point achieves both high sensitivity and high specificity. The accuracy of detecting PCa can be increased by additional predictive factors and combinations of markers. Evidence implies that a panel of kallikrein markers improves the specificity and reduces costs by eliminating unnecessary biopsies. Large, population-based studies have provided evidence that PSA can be used to predict PCa risk many years in advance, improve treatment selection and patient care, and predict the risk of complications and disease recurrence. However, definitive evidence is currently lacking as to whether PSA screening lowers PCa -specific mortality. Summary PSA is still the main tool for early detection, risk stratification, and monitoring of PCa. However, PSA values are affected by many technical and biological factors. Instead of using a fixed PSA cut-point, using statistical prediction models and considering the integration additional markers may be able to improve and individualize PCa diagnostics. A single PSA measurement at early middle age can predict risk of advanced PCa decades in advance and stratify patients for intensity of subsequent screening. PMID:19318948

  11. Body Mass Index and Prostate-Specific Antigen Failure Following Brachytherapy for Localized Prostate Cancer

    SciTech Connect

    Efstathiou, Jason A. Skowronski, Rafi Y.; Coen, John J.; Grocela, Joseph A.; Hirsch, Ariel E.; Zietman, Anthony L.

    2008-08-01

    Purpose: Increasing body mass index (BMI) is associated with prostate-specific antigen (PSA) failure after radical prostatectomy and external beam radiation therapy (EBRT). We investigated whether BMI is associated with PSA failure in men treated with brachytherapy for clinically localized prostate cancer. Patients and Methods: Retrospective analyses were conducted on 374 patients undergoing brachytherapy for stage T1c-T2cNXM0 prostate cancer from 1996-2001. Forty-nine patients (13%) received supplemental EBRT and 131 (35%) received androgen deprivation therapy (ADT). Height and weight data were available for 353 (94%). Cox regression analyses were performed to evaluate the relationship between BMI and PSA failure (nadir + 2 ng/ml definition). Covariates included age, race, preimplantation PSA, Gleason score, T category, percent of prescription dose to 90% of the prostate, use of supplemental EBRT, and ADT. Results: Median age, PSA, and BMI were 66 years (range, 42-80 years), 5.7 ng/ml (range, 0.4-22.6 ng/ml), and 27.1 kg/m{sup 2} (range, 18.2-53.6 kg/m{sup 2}), respectively. After a median follow-up of 6.0 years (range, 3.0-10.2 years), there were 76 PSA recurrences. The BMI was not associated with PSA failure. Six-year PSA failure rates were 30.2% for men with BMI less than 25 kg/m{sup 2}, 19.5% for BMI of 25 or greater to less than 30 kg/m{sup 2}, and 14.4% for BMI of 30 kg/m{sup 2} or greater (p = 0.19). Results were similar when BMI was analyzed as a continuous variable, using alternative definitions of PSA failure, and excluding patients treated with EBRT and/or ADT. In multivariate analyses, only baseline PSA was significantly associated with shorter time to PSA failure (adjusted hazard ratio, 1.12; 95% confidence interval, 1.05-1.20; p 0.0006). Conclusions: Unlike after surgery or EBRT, BMI is not associated with PSA failure in men treated with brachytherapy for prostate cancer. This raises the possibility that brachytherapy may be a preferred treatment

  12. Prostate-specific RNA aptamer: promising nucleic acid antibody-like cancer detection

    PubMed Central

    Marangoni, Karina; Neves, Adriana F.; Rocha, Rafael M.; Faria, Paulo R.; Alves, Patrícia T.; Souza, Aline G.; Fujimura, Patrícia T.; Santos, Fabiana A. A.; Araújo, Thaise G.; Ward, Laura S.; Goulart, Luiz R.

    2015-01-01

    We described the selection of a novel nucleic acid antibody-like prostate cancer (PCa) that specifically binds to the single-stranded DNA molecule from a 277-nt fragment that may have been partially paired and bound to the PCA3 RNA conformational structure. PCA3-277 aptamer ligands were obtained, and the best binding molecule, named CG3, was synthesized for validation. Aiming to prove its diagnostic utility, we used an apta-qPCR assay with CG3-aptamer conjugated to magnetic beads to capture PCA3 transcripts, which were amplified 97-fold and 7-fold higher than conventional qPCR in blood and tissue, respectively. Histopathologic analysis of 161 prostate biopsies arranged in a TMA and marked with biotin-labeled CG3-aptamer showed moderate staining in both cytoplasm and nucleus of PCa samples; in contrast, benign prostatic hyperplasia (BPH) samples presented strong nuclear staining (78% of the cases). No staining was observed in stromal cells. In addition, using an apta-qPCR, we demonstrated that CG3-aptamer specifically recognizes the conformational PCA3-277 molecule and at least three other transcript variants, indicating that long non-coding RNA (lncRNA) is processed after transcription. We suggest that CG3-aptamer may be a useful PCa diagnostic tool. In addition, this molecule may be used in drug design and drug delivery for PCa therapy. PMID:26174796

  13. Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen

    PubMed Central

    Kiess, Ana P.; Hobbs, Robert; Sgouros, George; Mease, Ronnie C.; Pullambhatla, Mrudula; Shen, Colette J.; Foss, Catherine A.; Pomper, Martin G.

    2015-01-01

    Auger electron emitters such as 125I have a high linear energy transfer and short range of emission (<10 μm), making them suitable for treating micrometastases while sparing normal tissues. We used a highly specific small molecule targeting the prostate-specific membrane antigen (PSMA) to deliver 125I to prostate cancer cells. Methods The PSMA-targeting Auger emitter 2-[3-[1-carboxy-5-(4-125I-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid (125I-DCIBzL) was synthesized. DNA damage (via phosphorylated H2A histone family member X staining) and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human prostate cancer cells after treatment with 125I-DCIBzL. Subcellular drug distribution was assessed with confocal microscopy using a related fluorescent PSMA-targeting compound YC-36. In vivo antitumor efficacy was tested in nude mice bearing PSMA+ PC3 PIP or PSMA− PC3 flu flank xenografts. Animals were administered (intravenously) 111 MBq (3 mCi) of 125I-DCIBzL, 111 MBq (3 mCi) of 125I-NaI, an equivalent amount of nonradiolabeled DCIBzL, or saline. Results After treatment with 125I-DCIBzL, PSMA+ PC3 PIP cells exhibited increased DNA damage and decreased clonogenic survival when compared with PSMA− PC3 flu cells. Confocal microscopy of YC-36 showed drug distribution in the perinuclear area and plasma membrane. Animals bearing PSMA+ PC3 PIP tumors had significant tumor growth delay after treatment with 125I-DCIBzL, with only 1 mouse reaching 5 times the initial tumor volume by 60 d after treatment, compared with a median time to 5 times volume of less than 15 d for PSMA− PC3 flu tumors and all other treatment groups (P = 0.002 by log-rank test). Conclusion PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125I-DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of prostate cancer micrometastases. PMID:26182968

  14. Is there any association between National Institute of Health category IV prostatitis and prostate-specific antigen levels in patients with low-risk localized prostate cancer?

    PubMed Central

    Doluoglu, Omer Gokhan; Ceylan, Cavit; Kilinc, Fatih; Gazel, Eymen; Resorlu, Berkan; Odabas, Oner

    2016-01-01

    ABSTRACT Purpose We investigated the association between National Institute of Health category IV prostatitis and prostate-specific antigen levels in patients with low-risk localized prostate cancer. Materials and Methods The data of 440 patients who had undergone prostate biopsies due to high PSA levels and suspicious digital rectal examination findings were reviewed retrospectively. The patients were divided into two groups based on the presence of accompanying NIH IV prostatitis. The exclusion criteria were as follows: Gleason score>6, PSA level>20ng/mL, >2 positive cores, >50% cancerous tissue per biopsy, urinary tract infection, urological interventions at least 1 week previously (cystoscopy, urethral catheterization, or similar procedure), history of prostate biopsy, and history of androgen or 5-alpha reductase use. All patient's age, total PSA and free PSA levels, ratio of free to total PSA, PSA density and prostate volume were recorded. Results In total, 101 patients were included in the study. Histopathological examination revealed only PCa in 78 (77.2%) patients and PCa+NIH IV prostatitis in 23 (22.7%) patients. The median total PSA level was 7.4 (3.5–20.0) ng/mL in the PCa+NIH IV prostatitis group and 6.5 (0.6–20.0) ng/mL in the PCa group (p=0.67). The PSA level was≤10ng/mL in 60 (76.9%) patients in the PCa group and in 16 (69.6%) patients in the PCa+NIH IV prostatitis group (p=0.32). Conclusions Our study showed no statistically significant difference in PSA levels between patients with and without NIH IV prostatitis accompanying PCa. PMID:27256190

  15. Specific heat capacity of freshly excised prostate specimens.

    PubMed

    Patch, S K; Rao, N; Kelly, H; Jacobsohn, K; See, W A

    2011-11-01

    The specific heat capacity of tissue is a critical parameter for thermal therapies that act over a long period of time. It is also critical for thermoacoustic signal generation. We present ex vivo measurements of specific heat capacity performed by a dual-pin probe with tight temperature control of the specimen. One 30 mm × 1.28 mm probe heats steadily for 30 s, while another measurement probe measures temperatures 6 mm away from the center of the heater probe. Specific heat values ranging from 2.9 to 4 J cm(-3) °C(-1) were measured on 20 lobes from ten fresh prostate specimens with varying degrees of cancerous involvement as confirmed by histology.

  16. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen-era.

    PubMed

    Jahn, Jaquelyn L; Giovannucci, Edward L; Stampfer, Meir J

    2015-12-15

    Widespread prostate-specific antigen (PSA) screening detects many cancers that would have otherwise gone undiagnosed. To estimate the prevalence of unsuspected prostate cancer, we reviewed 19 studies of prostate cancer discovered at autopsy among 6,024 men. Among men aged 70-79, tumor was found in 36% of Caucasians and 51% of African-Americans. This enormous prevalence, coupled with the high sensitivity of PSA screening, has led to the marked increase in the apparent incidence of prostate cancer. The impact of PSA screening on clinical practice is well-recognized, but its effect on epidemiologic research is less appreciated. Before screening, a larger proportion of incident prostate cancers had lethal potential and were diagnosed at advanced stage. However, in the PSA era, overall incident prostate cancer mainly is indolent disease, and often reflects the propensity to be screened and biopsied. Studies must therefore focus on cancers with lethal potential, and include long follow-up to accommodate the lead time induced by screening. Moreover, risk factor patterns differ markedly for potentially lethal and indolent disease, suggesting separate etiologies and distinct disease entities. Studies of total incident or indolent prostate cancer are of limited clinical utility, and the main focus of research should be on prostate cancers of lethal potential.

  17. Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice

    PubMed Central

    Marks, Leonard S; Bostwick, David G

    2008-01-01

    A specific marker for early prostate cancer would fill an important void. In initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-à-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise. At the cellular level, PCA3 specificity for cancer is nearly perfect because of the gross overexpression of the gene by cancer cells. As a clinical test for early prostate cancer, heightened specificity is also seen in urine containing prostate cells from men with the disease. PCA3 gene testing holds valuable potential in PSA quandary situations: (1) men with elevated PSA levels but no cancer on initial biopsy; (2) men found to have cancer despite normal levels of PSA; (3) men with PSA elevations associated with varying degrees of prostatitis; and (4) men undergoing active surveillance for presumed microfocal disease. PMID:18836536

  18. Prostate-specific membrane antigen-based imaging.

    PubMed

    Osborne, Joseph R; Akhtar, Naveed H; Vallabhajosula, Shankar; Anand, Alok; Deh, Kofi; Tagawa, Scott T

    2013-02-01

    Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for CaP-specific antigenic targets and generate agents able to specifically bind. Prostate-specific membrane antigen (PSMA) is overexpressed in CaP tissue, with low levels of expression in the small intestine, renal tubular cells, and salivary gland. The first clinical agent for targeting PSMA was (111)In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab penditide (i.e., inability to bind to live CaP cells). One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics, including the identification of bone metastases in CaP. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate time frame for diagnostic imaging. Urea-based compounds, such as small molecule inhibitors may also present promising agents for CaP imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Two such small-molecule inhibitors targeting PSMA, MIP-1072, and MIP-1095 have exhibited high affinity for PSMA. The uptake of (123)I-MIP-1072 and (123)I-MIP-1095 in CaP xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity.

  19. Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.

    PubMed

    Roshan-Moniri, Mani; Hsing, Michael; Butler, Miriam S; Cherkasov, Artem; Rennie, Paul S

    2014-12-01

    Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and ‘‘dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1’’ (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers. PMID:25455729

  20. Prostate-specific antigen testing in Ontario: reasons for testing patients without diagnosed prostate cancer

    PubMed Central

    Bunting, P S; Goel, V; Williams, J I; Iscoe, N A

    1999-01-01

    BACKGROUND: The use of the prostate-specific antigen (PSA) test has been increasing rapidly in Canada since its introduction in 1988. The reasons for using the PSA test in patients without known prostate cancer are unclear. This paper reports on the first study in Canada to use physician records to assess the use of PSA testing. METHODS: A questionnaire was mailed to physicians attending 475 patients without diagnosed prostate cancer. The patients were randomly selected from 2 laboratory databases of PSA test records in the greater Toronto area during 1995. The physicians were asked to consult their patient records to avoid recall bias. Information obtained included physician's specialty, patient's age at time of PSA test and reason(s) for the test. RESULTS: There were 264 responses (56%), of which 240 (91%) were usable. Of these 240, 63% (95% confidence interval [Cl] 58%-70%) indicated that the test was conducted to screen for prostate cancer, 40% (95% Cl 34%-47%) said it was to investigate urinary symptoms, and 33% (95% Cl 27%-40%) responded that it was a follow-up to a medical procedure or drug therapy. More than one reason was permitted. Of 151 responses indicating screening as one reason for testing, 64% (95% Cl 56%-72%) stated that it was initiated by the patient, and 73% (95% Cl 65%-80%) stated that it was part of a routine examination. For 19%, both investigation of symptoms and screening asymptomatic patients were given as reasons for testing, and for another 19% both follow-up of a medical procedure and screening were given as reasons. Screening was recorded as a reason for testing far more commonly for patients seen by family physicians and general practitioners than for patients seen by urologists (67% v. 29%, p < 0.001). In contrast, the use of PSA testing to diagnose urinary symptoms was more common for patients seen by urologists than for those seen by family physicians and general practitioners (52% v. 37%, p = 0.044). No significant difference was

  1. PET Imaging in Prostate Cancer: Focus on Prostate-Specific Membrane Antigen

    PubMed Central

    Mease, Ronnie C.; Foss, Catherine A.; Pomper, Martin G.

    2014-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclinical data for new PSMA-based radiotracers are discussed and include new 89Zr- and 64Cu-labeled anti-PSMA antibodies and antibody fragments, 64Cu-labeled aptamers, and 11C-, 18F-, 68Ga-, 64Cu-, and 86Y-labeled low molecular weight inhibitors of PSMA. Several of these agents, namely 68Ga-HBED-CC conjugate 15, 18F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clinical studies. These early clinical results suggest that PET/CT using PSMA-targeted agents, especially with compounds of low molecular weight, will make valuable contributions to the management of PCa. PMID:23590171

  2. Highly specific transgene expression mediated by a complex adenovirus vector incorporating a prostate-specific amplification feedback loop

    PubMed Central

    Woraratanadharm, Jan; Rubinchik, Semyon; Yu, Hong; Fan, Fan; Morrow, Scotty M.; Dong., John Y.

    2007-01-01

    Summary Development of novel therapeutic agents is needed to address the problems of locally recurrent, metastatic, and advanced hormone-refractory prostate cancer. We have constructed a novel complex adenovirus (Ad) vector regulation system that incorporates both the prostate-specific ARR2PB promoter and a positive feedback loop using the TRE promoter to enhance gene expression. This regulation strategy involves the incorporation of the TRE upstream of the prostate-specific ARR2PB promoter to enhance its activity with Tet-regulation. The expressions of both GFP and tTA were placed under the control of these TRE-ARR2PB promoters, so that in the cells of prostate origin, a positive feedback loop would be generated. This design greatly enhanced GFP reporter expression in prostate cancer cells, while retaining tight control of expression in non-prostate cancer cells, even at MOI as high as 1000. This novel positive feedback loop with prostate specificity (PFLPS) regulation system we have developed may have broad applications for expressing not only high levels of toxic proteins in cancer cells but alternatively could be manipulated to regulate essential genes in a highly efficient conditionally replicative adenovirus (CRAd) vector specifically directed to prostate cancer cells. The PFLPS regulation system, therefore, serves as a promising new approach in the development of both a specific and effective vector for cancer gene therapy. PMID:15229631

  3. Prostate-Specific Antigen Bounce After High-Dose-Rate Monotherapy for Prostate Cancer

    SciTech Connect

    Mehta, Niraj H.; Kamrava, Mitchell; Wang, Pin-Chieh; Steinberg, Michael; Demanes, Jeffrey

    2013-07-15

    Purpose: To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. Methods and Materials: Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). Results: A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). Conclusions: A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way.

  4. Prostate-Specific Antigen (PSA) Screening and New Biomarkers for Prostate Cancer (PCa)

    PubMed Central

    Rittenhouse, Harry; Hu, Xinhai; Cammann, Henning; Jung, Klaus

    2014-01-01

    Abstract PSA screening reduces PCa-mortality but the disadvantages overdiagnosis and overtreatment require multivariable risk-prediction tools to select appropriate treatment or active surveillance. This review explains the differences between the two largest screening trials and discusses the drawbacks of screening and its meta-analysisxs. The current American and European screening strategies are described. Nonetheless, PSA is one of the most widely used tumor markers and strongly correlates with the risk of harboring PCa. However, while PSA has limitations for PCa detection with its low specificity there are several potential biomarkers presented in this review with utility for PCa currently being studied. There is an urgent need for new biomarkers especially to detect clinically significant and aggressive PCa. From all PSA-based markers, the FDA-approved prostate health index (phi) shows improved specificity over percent free and total PSA. Another kallikrein panel, 4K, which includes KLK2 has recently shown promise in clinical research studies but has not yet undergone formal validation studies. In urine, prostate cancer gene 3 (PCA3) has also been validated and approved by the FDA for its utility to detect PCa. The potential correlation of PCA3 with cancer aggressiveness requires more clinical studies. The detection of the fusion of androgen-regulated genes with genes of the regulatory transcription factors in tissue of ~50% of all PCa-patients is a milestone in PCa research. A combination of the urinary assays for TMPRSS2:ERG gene fusion and PCA3 shows an improved accuracy for PCa detection. Overall, the field of PCa biomarker discovery is very exciting and prospective.

  5. Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: implications for paracrine growth.

    PubMed

    Doherty, A; Smith, G; Banks, L; Christmas, T; Epstein, R J

    1999-07-01

    The characteristic sclerotic appearance of bone metastases from prostate cancer is unexplained but could involve excess peritumoural activity of osteoblast mitogens such as the insulin-like growth factors (IGFs). Since prostatic metastases are distinguished by androgen-dependent secretion of prostate-specific antigen (PSA), a serine protease which cleaves extracellular IGF-binding proteins and thereby enhances the bioavailability of IGFs, the relationship was examined between tumour PSA expression and the osteoblastic phenotype. To this end, a cohort of 27 prostate cancer patients was evaluated to determine the relationship between serum PSA and radiographic bone lesion density at first presentation with metastatic disease. No linear correlation between absolute PSA levels and metastatic osteosclerosis was apparent. However, non-parametric statistical analysis revealed a highly significant link between low-PSA (<20 ng/ml) metastatic prostate cancer and osteolytic bone lesions (p<0.0001, chi(2)=21.5). This finding raises the possibility that the osteoblastic phenotype of prostate cancer derives in part from PSA-dependent proteolysis of IGF-binding proteins within bone matrix.

  6. Risk of All-Cause and Prostate Cancer-Specific Mortality After Brachytherapy in Men With Small Prostate Size

    SciTech Connect

    Nguyen, Paul L.; Chen, Ming H.; Choueiri, Toni K.; Hoffman, Karen E.; Hu, Jim C.; Martin, Neil E.; Beard, Clair J.; Dosoretz, Daniel E.; Moran, Brian J.; Katin, Michael J.; Braccioforte, Michelle H.; Ross, Rudi; Salenius, Sharon A.; Kantoff, Philip W.; D'Amico, Anthony V.

    2011-04-01

    Background: Brachytherapy for prostate cancer can be technically challenging in men with small prostates ({<=}20 cc), but it is unknown whether their outcomes are different than those of men with larger prostates. Methods and Materials: We studied 6,416 men treated with brachytherapy in one of 21 community-based practices. Cox regression and Fine and Gray's regression were used to determine whether volume {<=}20 cc was associated with a higher risk of all-cause mortality (ACM) or prostate cancer-specific mortality (PCSM), respectively, after adjustment for other known prognostic factors. Results: 443 patients (6.9%) had a prostate volume {<=}20 cc. After a median follow-up of 2.91 years (interquartile range, 1.06-4.79), volume {<=}20 cc was associated with a significantly higher risk of ACM (adjusted hazard ratio = 1.33 [95% CI 1.08-1.65], p = 0.0085) with 3-year estimates of ACM for {<=}20 cc vs. >20 cc of 13.0% vs. 6.9% (p = 0.028). Only 23 men (0.36%) have died of prostate cancer, and no difference was seen in PCSM by volume (p = 0.4). Conclusion: Men with small prostates at the time of implant had a 33% higher risk of ACM, and the underlying cause of this remains uncertain. No increase in PCSM was observed in men with volume {<=}20cc, suggesting that a small prostate should not in itself be a contraindication for brachytherapy, but inasmuch as absolute rates of PCSM were small, further follow-up will be needed to confirm this finding.

  7. Infectious mononucleosis, other infections and prostate-specific antigen concentration as a marker of prostate involvement during infection.

    PubMed

    Sutcliffe, Siobhan; Nevin, Remington L; Pakpahan, Ratna; Elliott, Debra J; Langston, Marvin E; De Marzo, Angelo M; Gaydos, Charlotte A; Isaacs, William B; Nelson, William G; Sokoll, Lori J; Walsh, Patrick C; Zenilman, Jonathan M; Cersovsky, Steven B; Platz, Elizabeth A

    2016-05-01

    Although Epstein-Barr virus has been detected in prostate tissue, no associations have been observed with prostate cancer in the few studies conducted to date. One possible reason for these null findings may be use of cumulative exposure measures that do not inform the timing of infection, i.e., childhood versus adolescence/early adulthood when infection is more likely to manifest as infectious mononucleosis (IM). We sought to determine the influence of young adult-onset IM on the prostate by measuring prostate-specific antigen (PSA) as a marker of prostate inflammation/damage among U.S. military members. We defined IM cases as men diagnosed with IM from 1998 to 2003 (n = 55) and controls as men without an IM diagnosis (n = 255). We selected two archived serum specimens for each participant, the first collected after diagnosis for cases and one randomly selected from 1998 to 2003 for controls (index), as well as the preceding specimen (preindex). PSA was measured in each specimen. To explore the specificity of our findings for prostate as opposed to systemic inflammation, we performed a post hoc comparison of other infectious disease cases without genitourinary involvement (n = 90) and controls (n = 220). We found that IM cases were more likely to have a large PSA rise than controls (≥ 20 ng/mL: 19.7% versus 8.8%, p = 0.027; ≥ 40% rise: 25.7% versus 9.4%, p = 0.0021), as were other infectious disease cases (25.7% versus 14.0%, p = 0.020; 27.7% versus 18.0%, p = 0.092). These findings suggest that, in addition to rising because of prostate infection, PSA may also rise because of systemic inflammation, which could have implications for PSA interpretation in older men.

  8. Dairy intake after prostate cancer diagnosis in relation to disease-specific and total mortality.

    PubMed

    Yang, Meng; Kenfield, Stacey A; Van Blarigan, Erin L; Wilson, Kathryn M; Batista, Julie L; Sesso, Howard D; Ma, Jing; Stampfer, Meir J; Chavarro, Jorge E

    2015-11-15

    Information regarding postdiagnostic dairy intake and prostate cancer survival is limited. We evaluated intake of total, high-fat and low-fat dairy after prostate cancer diagnosis in relation to disease-specific and total mortality. We included 926 men from the Physicians' Health Study diagnosed with non-metastatic prostate cancer between 1982 and 2000 who completed a diet questionnaire a median of 5 years after diagnosis and were followed thereafter for a median of 10 years to assess mortality. Cox proportional hazards regression was used to estimate associations between dairy intake and prostate cancer specific and all-cause mortality. During 8,903 person-years of follow-up, 333 men died, 56 due to prostate cancer. Men consuming ≥3 servings/day of total dairy products had a 76% higher risk of total mortality and a 141% higher risk of prostate cancer-specific mortality compared to men who consumed less than 1 dairy product/day (hazard ratio (HR) = 1.76, 95% confidence interval (CI): 1.21, 2.55, ptrend  < 0.001 for total mortality; HR = 2.41, 95% CI: 0.96, 6.02, ptrend  = 0.04 for prostate cancer-specific mortality). The association between high-fat dairy and mortality risk appeared to be stronger than that of low-fat dairy, but the difference between them was not statistically significant (p for difference = 0.57 for prostate cancer-specific mortality and 0.56 for total mortality). Among men without metastases when diagnosed, higher intake of dairy foods after prostate cancer diagnosis may be associated with increased prostate cancer-specific and all-cause mortality.

  9. Velocity and doubling time of prostate-specific antigen: mathematics can matter.

    PubMed

    Uchio, Edward; Aslan, Mihaela; Ko, John; Wells, Carolyn K; Radhakrishnan, Krishnan; Concato, John

    2016-02-01

    Changes in prostate-specific antigen (PSA) values are often reported as velocity or doubling time. We compared the association of these two calculations-at the time of PSA failure after primary treatment for prostate cancer-with prostate cancer mortality. From a source population of 1313 US Veterans with prostate cancer, including 623 treated with curative intent, the study population included 242 men experiencing biochemical failure, 81 after surgery and 161 after radiation therapy. Clinically relevant calculations of PSA velocity (linear slope) and PSA doubling time (logarithmic slope) were assessed for their association with 11-16 years of mortality from prostate cancer. Death due to prostate cancer occurred in 52/242 (21.5%) men. Among men receiving surgery, PSA velocity ≥1.0 ng/mL/year was associated with increased prostate cancer mortality (HR=4.2, p value=0.037), whereas doubling time ≤12 months did not confer risk (HR=1.0, p value=0.95). Conversely, among patients receiving radiation therapy, doubling time ≤12 months was associated with increased prostate cancer mortality (HR=2.4, p value=0.049), but velocity did not confer a statistically significant risk (HR=3.8, p value=0.19). When assessing risk of prostate cancer mortality, PSA velocity can be more predictive after surgery and PSA doubling time can be more predictive after radiation therapy. PMID:26767890

  10. Velocity and doubling time of prostate-specific antigen: mathematics can matter.

    PubMed

    Uchio, Edward; Aslan, Mihaela; Ko, John; Wells, Carolyn K; Radhakrishnan, Krishnan; Concato, John

    2016-02-01

    Changes in prostate-specific antigen (PSA) values are often reported as velocity or doubling time. We compared the association of these two calculations-at the time of PSA failure after primary treatment for prostate cancer-with prostate cancer mortality. From a source population of 1313 US Veterans with prostate cancer, including 623 treated with curative intent, the study population included 242 men experiencing biochemical failure, 81 after surgery and 161 after radiation therapy. Clinically relevant calculations of PSA velocity (linear slope) and PSA doubling time (logarithmic slope) were assessed for their association with 11-16 years of mortality from prostate cancer. Death due to prostate cancer occurred in 52/242 (21.5%) men. Among men receiving surgery, PSA velocity ≥1.0 ng/mL/year was associated with increased prostate cancer mortality (HR=4.2, p value=0.037), whereas doubling time ≤12 months did not confer risk (HR=1.0, p value=0.95). Conversely, among patients receiving radiation therapy, doubling time ≤12 months was associated with increased prostate cancer mortality (HR=2.4, p value=0.049), but velocity did not confer a statistically significant risk (HR=3.8, p value=0.19). When assessing risk of prostate cancer mortality, PSA velocity can be more predictive after surgery and PSA doubling time can be more predictive after radiation therapy.

  11. Metastatic superscan in prostate carcinoma on gallium-68-prostate-specific membrane antigen positron emission tomography/computed tomography scan

    PubMed Central

    Agarwal, Krishan Kant; Tripathi, Madhavi; Kumar, Rajeev; Bal, Chandrasekhar

    2016-01-01

    We describe the imaging features of a metastatic superscan on gallium-68 Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)], abbreviated as gallium-68-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging. 68Ga-PSMA is novel radiotracer undergoing evaluation for PET/CT imaging of prostate carcinoma. This patient had a superscan of metastases on conventional bone scintigraphy and was referred for 68Ga-PSMA PET/CT to evaluate the feasibility of 177Lu-PSMA therapy. PMID:27095868

  12. Patient-specific Deformation Modelling via Elastography: Application to Image-guided Prostate Interventions.

    PubMed

    Wang, Yi; Ni, Dong; Qin, Jing; Xu, Ming; Xie, Xiaoyan; Heng, Pheng-Ann

    2016-01-01

    Image-guided prostate interventions often require the registration of preoperative magnetic resonance (MR) images to real-time transrectal ultrasound (TRUS) images to provide high-quality guidance. One of the main challenges for registering MR images to TRUS images is how to estimate the TRUS-probe-induced prostate deformation that occurs during TRUS imaging. The combined statistical and biomechanical modeling approach shows promise for the adequate estimation of prostate deformation. However, the right setting of the biomechanical parameters is very crucial for realistic deformation modeling. We propose a patient-specific deformation model equipped with personalized biomechanical parameters obtained from shear wave elastography to reliably predict the prostate deformation during image-guided interventions. Using data acquired from a prostate phantom and twelve patients with suspected prostate cancer, we compared the prostate deformation model with and without patient-specific biomechanical parameters in terms of deformation estimation accuracy. The results show that the patient-specific deformation model possesses favorable model ability, and outperforms the model without patient-specific biomechanical parameters. The employment of the patient-specific biomechanical parameters obtained from elastography for deformation modeling shows promise for providing more precise deformation estimation in applications that use computer-assisted image-guided intervention systems. PMID:27272239

  13. An overview of prostate diseases and their characteristics specific to Asian men

    PubMed Central

    Xia, Shu-Jie; Cui, Di; Jiang, Qi

    2012-01-01

    In this paper, we reviewed the features of common prostate diseases, such as benign prostatic hyperplasia (BPH), prostate cancer (PCa) and chronic prostatitis (CP) that are specific to Asian men. Compared to the Westerners, Asians exhibit particular characteristics of prostate diseases. Through summarizing the epidemiology, symptomatology, diagnostics and therapeutics of these diseases, we find that Asians have a lower incidence of PCa than whites, but the incidences of BPH and CP are similar. Asian men with CP often suffer from fewer disease sites, but have a higher frequency of pain during urination rather than after sexual climax. Prostate-specific antigen (PSA) is a widely used marker for the diagnosis of PCa in both Asian and Western countries. Although the PSA level may be lower in Asians, the threshold used is based on whites. After reviewing the treatments available for these diseases, we did not find a fundamental difference between Asians and whites. Furthermore, the selection for the most appropriate treatment based on the individual needs of patients remains a challenge to urologists in Asia. After considering the traits of prostate diseases that are specific to Asian men, we hope to pave the way for the development of specific diagnostic and therapeutic strategies targeted specifically to Asian men. PMID:22306914

  14. Patient-specific Deformation Modelling via Elastography: Application to Image-guided Prostate Interventions

    PubMed Central

    Wang, Yi; Ni, Dong; Qin, Jing; Xu, Ming; Xie, Xiaoyan; Heng, Pheng-Ann

    2016-01-01

    Image-guided prostate interventions often require the registration of preoperative magnetic resonance (MR) images to real-time transrectal ultrasound (TRUS) images to provide high-quality guidance. One of the main challenges for registering MR images to TRUS images is how to estimate the TRUS-probe-induced prostate deformation that occurs during TRUS imaging. The combined statistical and biomechanical modeling approach shows promise for the adequate estimation of prostate deformation. However, the right setting of the biomechanical parameters is very crucial for realistic deformation modeling. We propose a patient-specific deformation model equipped with personalized biomechanical parameters obtained from shear wave elastography to reliably predict the prostate deformation during image-guided interventions. Using data acquired from a prostate phantom and twelve patients with suspected prostate cancer, we compared the prostate deformation model with and without patient-specific biomechanical parameters in terms of deformation estimation accuracy. The results show that the patient-specific deformation model possesses favorable model ability, and outperforms the model without patient-specific biomechanical parameters. The employment of the patient-specific biomechanical parameters obtained from elastography for deformation modeling shows promise for providing more precise deformation estimation in applications that use computer-assisted image-guided intervention systems. PMID:27272239

  15. Combining population and patient-specific characteristics for prostate segmentation on 3D CT images

    NASA Astrophysics Data System (ADS)

    Ma, Ling; Guo, Rongrong; Tian, Zhiqiang; Venkataraman, Rajesh; Sarkar, Saradwata; Liu, Xiabi; Tade, Funmilayo; Schuster, David M.; Fei, Baowei

    2016-03-01

    Prostate segmentation on CT images is a challenging task. In this paper, we explore the population and patient-specific characteristics for the segmentation of the prostate on CT images. Because population learning does not consider the inter-patient variations and because patient-specific learning may not perform well for different patients, we are combining the population and patient-specific information to improve segmentation performance. Specifically, we train a population model based on the population data and train a patient-specific model based on the manual segmentation on three slice of the new patient. We compute the similarity between the two models to explore the influence of applicable population knowledge on the specific patient. By combining the patient-specific knowledge with the influence, we can capture the population and patient-specific characteristics to calculate the probability of a pixel belonging to the prostate. Finally, we smooth the prostate surface according to the prostate-density value of the pixels in the distance transform image. We conducted the leave-one-out validation experiments on a set of CT volumes from 15 patients. Manual segmentation results from a radiologist serve as the gold standard for the evaluation. Experimental results show that our method achieved an average DSC of 85.1% as compared to the manual segmentation gold standard. This method outperformed the population learning method and the patient-specific learning approach alone. The CT segmentation method can have various applications in prostate cancer diagnosis and therapy.

  16. Combining Population and Patient-Specific Characteristics for Prostate Segmentation on 3D CT Images

    PubMed Central

    Ma, Ling; Guo, Rongrong; Tian, Zhiqiang; Venkataraman, Rajesh; Sarkar, Saradwata; Liu, Xiabi; Tade, Funmilayo; Schuster, David M.; Fei, Baowei

    2016-01-01

    Prostate segmentation on CT images is a challenging task. In this paper, we explore the population and patient-specific characteristics for the segmentation of the prostate on CT images. Because population learning does not consider the inter-patient variations and because patient-specific learning may not perform well for different patients, we are combining the population and patient-specific information to improve segmentation performance. Specifically, we train a population model based on the population data and train a patient-specific model based on the manual segmentation on three slice of the new patient. We compute the similarity between the two models to explore the influence of applicable population knowledge on the specific patient. By combining the patient-specific knowledge with the influence, we can capture the population and patient-specific characteristics to calculate the probability of a pixel belonging to the prostate. Finally, we smooth the prostate surface according to the prostate-density value of the pixels in the distance transform image. We conducted the leave-one-out validation experiments on a set of CT volumes from 15 patients. Manual segmentation results from a radiologist serve as the gold standard for the evaluation. Experimental results show that our method achieved an average DSC of 85.1% as compared to the manual segmentation gold standard. This method outperformed the population learning method and the patient-specific learning approach alone. The CT segmentation method can have various applications in prostate cancer diagnosis and therapy. PMID:27660382

  17. Septa design for a prostate specific PET camera

    SciTech Connect

    Qi, Jinyi; Huber, Jennifer S.; Huesman, Ronald H.; Moses, William W.; Derenzo, Stephen E.; Budinger, Thomas F.

    2003-11-15

    The recent development of new prostate tracers has motivated us to build a low cost PET camera optimized to image the prostate. Coincidence imaging of positron emitters is achieved using a pair of external curved detector banks. The bottom bank is fixed below the patient bed, and the top bank moves upward for patient access and downward for maximum sensitivity. In this paper, we study the design of septa for the prostate camera using Monte Carlo simulations. The system performance is measured by the detectability of a prostate lesion. We have studied 17 septa configurations. The results show that the design of septa has a large impact on the lesion detection at a given activity concentration. Significant differences are also observed between the lesion detectability and the conventional noise equivalent count (NEC) performance, indicating that the NEC is not appropriate for the detection task.

  18. Prostate-Specific Antigen Bounce After Permanent Iodine-125 Prostate Brachytherapy-An Australian Analysis

    SciTech Connect

    Zwahlen, Daniel R.; Smith, Ryan; Andrianopoulos, Nick; Matheson, Bronwyn; Royce, Peter; Millar, Jeremy L.

    2011-01-01

    Purpose: To report on prostate-specific antigen (PSA) 'bounces' after {sup 125}I prostate brachytherapy to review the relationship to biochemical control and correlate both clinical and dosimetric variables. Methods and Materials: We analyzed 194 hormone-naive patients with a follow-up of {>=}3 years. Four bounce definitions were applied: an increase of {>=}0.2 ng/mL (definition I), {>=}0.4 ng/mL (definition II), {>=}15% (definition III), and {>=}35% (definition IV) of a previous value with spontaneous return to the prebounce level or lower. Results: Using definition I, II, III, and IV, a bounce was detected in 50%, 34%, 11%, and 9% of patients, respectively. The median time to onset was 14-16 months, the duration was 12-21.5 months, and the magnitude of the increase was 0.5-2 ng/mL. A magnitude of >2 ng/mL, fulfilling the criteria for biochemical failure (BF) according to the American Society for Therapeutic Radiology and Oncology Phoenix definition, was detected in 11.3%, 16.9%, 47.6%, and 50% using definitions I, II, III, and IV, respectively; 11 patients (5.7%) had true BF. The PSA bounces occurred earlier than BF (p < 0.001). The prediction of BF remains controversial and is probably unrelated to biochemical control. The only statistically significant factor predictive of a PSA bounce was younger age (definitions I and II). Conclusion: PSA bounces are common after brachytherapy. All definitions resulted in a high number of false-positive calls for BF during the first 2 years. The definition of an increase of {>=}0.2 ng/mL should be preferred because of the lowest number of false-positive results for BF. Patients experiencing a PSA bounce during the first 2 years after brachytherapy should undergo surveillance every 3-6 months. Additional investigations are recommended for elevated postimplant PSA levels that have not corrected by 3 years of follow-up.

  19. Prostate-specific Antigen Density Variation Rate as a Potential Guideline Parameter for Second Prostate Cancer Detection Biopsy

    PubMed Central

    Xie, Gan-Sheng; Lyv, Jin-Xing; Li, Gang; Yan, Chun-Yin; Hou, Jian-Quan; Pu, Jin-Xian; Ding, Xiang; Huang, Yu-Hua

    2016-01-01

    Background: The diagnostic value of current prostate-specific antigen (PSA) tests is challenged by the poor detection rate of prostate cancer (PCa) in repeat prostate biopsy. In this study, we proposed a novel PSA-related parameter named PSA density variation rate (PSADVR) and designed a clinical trial to evaluate its potential diagnostic value for detecting PCa on a second prostate biopsy. Methods: Data from 184 males who underwent second ultrasound-guided prostate biopsy 6 months after the first biopsy were included in the study. The subjects were divided into PCa and non-PCa groups according to the second biopsy pathological results. Prostate volume, PSA density (PSAD), free-total PSA ratio, and PSADVR were calculated according to corresponding formulas at the second biopsy. These parameters were compared using t-test or Mann-Whitney U-test between PCa and non-PCa groups, and receiver operating characteristic analysis were used to evaluate their predictability on PCa detection. Results: PCa was detected in 24 patients on the second biopsy. Mean values of PSA, PSAD, and PSADVR were greater in the PCa group than in the non-PCa group (8.39 μg/L vs. 7.16 μg/L, 0.20 vs. 0.16, 14.15% vs. −1.36%, respectively). PSADVR had the largest area under the curve, with 0.667 sensitivity and 0.824 specificity when the cutoff was 10%. The PCa detection rate was significantly greater in subjects with PSADVR >10% than PSADVR ≤10% (28.6% vs. 6.5%, P < 0.001). In addition, PSADVR was the only parameter in this study that showed a significant correlation with mid-to-high-risk PCa (r = 0.63, P = 0.03). Conclusions: Our results demonstrated that PSADVR improved the PCa detection rate on second biopsies, especially for mid-to-high-risk cancers requiring prompt treatment. PMID:27453228

  20. Semiconductor nanocrystal-aptamer bioconjugate probes for specific prostate carcinoma cell targeting

    NASA Astrophysics Data System (ADS)

    Shieh, Felice; Lavery, Laura; Chu, Chitai T.; Richards-Kortum, Rebecca; Ellington, Andrew D.; Korgel, Brian A.

    2005-04-01

    Cancer of the prostate affects approximately 1 in 11 men. Current early screening for prostate cancer utilizes digital rectal examinations to detect anomalies in the prostate gland and blood test screenings for upregulated levels of prostate specific antigen (PSA). Many of these tests are invasive and can often be inconclusive as PSA levels may be heightened due to benign factors. Prostate specific membrane antigen (PSMA), a well-characterized integral membrane protein, is expressed in virtually all prostate cancers and often correlates with cancer aggressiveness. Therefore, it may be used as an indicator of cancer growth and metastases. PSMA-specific antibodies have been identified and conjugated to fluorescent markers for cancer cell targeting; however, both the antibodies and markers possess significant limitations in their pharmaceutical and diagnostic value. Here we report the use of semiconductor nanocrystals bioconjugated to PSMA-specific aptamer recognition molecules for prostate carcinoma cell targeting. The nanocrystal/aptamer bioconjugates are small biocompatible probes with the potential for color-tunability for multicolor imaging. Ongoing in vitro and in vivo research seeks to introduce these nanoparticle bioconjugates into medical diagnostics.

  1. Proteasome inhibitors induce apoptosis of prostate cancer cells by inducing nuclear translocation of IkappaBalpha.

    PubMed

    Vu, Hai-Yen; Juvekar, Ashish; Ghosh, Chandra; Ramaswami, Sitharam; Le, Dung Hong; Vancurova, Ivana

    2008-07-15

    Proteasome inhibitors are known to suppress the proteasome-mediated degradation of IkappaBalpha in stimulated cells. This results in the cytoplasmic retention of NFkappaB and its reduced nuclear transcriptional activity. In this study, we show that in the metastatic prostate cancer cells, the proteasome inhibitors exhibit a novel, previously unrecognized effect: they increase the cellular levels of IkappaBalpha, which then translocates to the nucleus, associates with the nuclear p65 NFkappaB, thus inhibiting the constitutive NFkappaB DNA binding activity and inducing apoptosis. The proteasome inhibition-induced nuclear translocation of IkappaBalpha is dependent on de novo protein synthesis, occurs also in other cell types, and does not require IkappaBalpha phosphorylation on Ser-32. Since NFkappaB activity is constitutively increased in many human cancers as well as in inflammatory disorders, the proteasome inhibition-induced nuclear translocation of IkappaBalpha could thus provide a new therapeutic strategy aimed at the specific inhibition of NFkappaB activity by the nuclear IkappaBalpha.

  2. Increasing level of prostate-specific antigen and prostate cancer risk factors among 193 men examined in screening procedure.

    PubMed

    Opalińska, Edyta; Michalak, Anna; Stoma, Filip; Latalski, Maciej; Goniewicz, Mariusz

    2003-01-01

    Prostate cancer is one of the most common cancers in men, therefore has become recently an essential problem of public health. The factors influencing cancer include: androgens metabolism disorders, diabetes mellitus, overweight and obesity, smoking, alcohol and black coffee intake, diet rich in saturated fats and poor in unsaturated, lack of physical activity, geographical zone, race, such carcinogenic substances as: cadmium, materials used in rubber, painting, printing, ship industry etc., contagious factors and also older age and a positive family history of the disease. To diagnose prostate cancer in its early stage such screening procedures as physical examination--digital rectal exam (DRE) and determination of prostate-specific antigen (PSA) level in blood serum are used. The aim of the study was to assess prostate cancer risk factors occurrence in the examined 193 men, aged 50-70 years, who reported to urology outpatient department at Clinical Hospital in Lublin, measure the PSA level in blood serum and examine the correlation between them. Respondents filled in a questionnaire about the presence of prostate cancer risk factors and urogenital symptoms. The questionnaire was completed with DRE and PSA measurement. The results led us to the following conclusions: 1/ in the studied population elevated PSA level is determined in 3.1% of 193 examined men, 2/ increased PSA occurs mainly in men from rural areas, with elementary education, divorced, older (>60 years), using fat-rich diet, smokers, black coffee drinkers, with overweight or obesity and non diabetic, 3/ a combination of PSA test with DRE seems to be useful and rather cheap for the detection of prostate cancer in the early stage of its development.

  3. Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer.

    PubMed

    Mendonca, Janet; Sharma, Anup; Kim, Hae-Soo; Hammers, Hans; Meeker, Alan; De Marzo, Angelo; Carducci, Michael; Kauffman, Michael; Shacham, Sharon; Kachhap, Sushant

    2014-08-15

    Mislocalization of proteins is a common feature of cancer cells. Since localization of proteins is tightly linked to its function, cancer cells can inactivate function of a tumor suppressor protein through mislocalization. The nuclear exportin CRM1/XPO 1 is upregulated in many cancers. Targeting XPO 1 can lead to nuclear retention of cargo proteins such as p53, Foxo, and BRCA1 leading to cell cycle arrest and apoptosis. We demonstrate that selective inhibitors of nuclear export (SINE) can functionally inactivate XPO 1 in prostate cancer cells. Unlike the potent, but toxic, XPO 1 inhibitor leptomycin B, SINE inhibitors (KPT-185, KPT-330, and KPT-251) cause a decrease in XPO 1 protein level through the proteasomal pathway. Treatment of prostate cancer cells with SINE inhibitors lead to XPO 1 inhibition, as evaluated by RevGFP export assay, leading to nuclear retention of p53 and Foxo proteins, consequently, triggering apoptosis. Our data reveal that treatment with SINE inhibitors at nanomolar concentrations results in decrease in proliferation and colonogenic capacity of prostate cancer cells by triggering apoptosis without causing any cell cycle arrest. We further demonstrate that SINE inhibitors can be combined with other chemotherapeutics like doxorubicin to achieve enhanced growth inhibition of prostate cancer cells. Since SINE inhibitors offer increased bioavailability, reduced toxicity to normal cells, and are orally available they can serve as effective therapeutics against prostate cancer. In conclusion, our data reveals that nucleocytoplasmic transport in prostate cancer can be effectively targeted by SINE inhibitors.

  4. Fluorescence of prostate-specific antigen as measured with a portable 1D scanner

    NASA Astrophysics Data System (ADS)

    Kim, Byeong C.; Jeong, Jin H.; Jeong, Dong S.; Kim, Young M.; Oh, Sang W.; Choi, Eui Y.; Kim, Jae H.; Nahm, Kie B.

    2005-01-01

    Prostate-specific antigen (PSA) is an androgen-dependent glycoprotein protease (M.W. 33 kDa) and a member of kallikrein super-family of serine protease, and has chymotrypsin-like enzymatic activity. It is synthesized by the prostate epithelial cells and found in the prostate gland and seminal plasma as a major protein. It is widely used as a clinical marker for diagnosis, screening, monitoring and prognosis of prostate cancer. In normal male adults, the concentration of PSA in the blood is below 4 ng/ml and this value increases in patients with the prostate cancer or the benign prostatic hyperplasia (BPH) due to its leakage into the circulatory system. As such, systematic monitoring of the PSA level in the blood can provide critical information about the progress of the prostatic disease. We have developed a compact integral system that can quantitatively measure the concentration of total PSA in human blood. This system utilizes the fluorescence emitted from the dye molecules attached to PSA molecules after appropriate immunoassay-based processing. Developed for the purpose of providing an affordable means of fast point-of-care testing of the prostate cancer, this system proved to be able to detect the presence of the PSA at the level of 0.18 ng/ml in less than 12 minutes, with the actual measurement taking less than 2 minutes. The design concept for this system is presented together with the result for a few representative samples.

  5. Tissue specificity of the hormonal response in sex accessory tissues is associated with nuclear matrix protein patterns.

    PubMed

    Getzenberg, R H; Coffey, D S

    1990-09-01

    The DNA of interphase nuclei have very specific three-dimensional organizations that are different in different cell types, and it is possible that this varying DNA organization is responsible for the tissue specificity of gene expression. The nuclear matrix organizes the three-dimensional structure of the DNA and is believed to be involved in the control of gene expression. This study compares the nuclear structural proteins between two sex accessory tissues in the same animal responding to the same androgen stimulation by the differential expression of major tissue-specific secretory proteins. We demonstrate here that the nuclear matrix is tissue specific in the rat ventral prostate and seminal vesicle, and undergoes characteristic alterations in its protein composition upon androgen withdrawal. Three types of nuclear matrix proteins were observed: 1) nuclear matrix proteins that are different and tissue specific in the rat ventral prostate and seminal vesicle, 2) a set of nuclear matrix proteins that either appear or disappear upon androgen withdrawal, and 3) a set of proteins that are common to both the ventral prostate and seminal vesicle and do not change with the hormonal state of the animal. Since the nuclear matrix is known to bind androgen receptors in a tissue- and steroid-specific manner, we propose that the tissue specificity of the nuclear matrix arranges the DNA in a unique conformation, which may be involved in the specific interaction of transcription factors with DNA sequences, resulting in tissue-specific patterns of secretory protein expression.

  6. Nuclear Structure as a Source of Cancer Specific Biomarkers

    PubMed Central

    Leman, Eddy S.; Getzenberg, Robert H.

    2012-01-01

    There are few biomarkers that have been developed which have proven clinical utility for the detection and prognosis of cancer. Cancer is diagnosed today, in large part, by examining cells under the microscope and determining the shape and texture of the nucleus. The molecular underpinnings of this hallmark of cancer are the components of the nuclear matrix. Utilizing proteomics focused on this subset of proteins, biomarkers have been identified that are specific for cancer types including prostate, colon and bladder cancer. These cancer biomarkers now serve as the basis of assays which can specifically identify individuals with cancer by sampling their blood and/or urine. In addition, these may serve as potential therapeutic targeting or imaging approaches. PMID:17455233

  7. Relationship between prostate-specific antigen levels and ambient temperature

    NASA Astrophysics Data System (ADS)

    Ohwaki, Kazuhiro; Endo, Fumiyasu; Hattori, Kazunori; Muraishi, Osamu

    2014-07-01

    We examined the association between prostate-specific antigen (PSA) and daily mean ambient temperature on the day of the test in healthy men who had three annual checkups. We investigated 9,694 men who visited a hospital for routine health checkups in 2007, 2008, and 2009. Although the means and medians of ambient temperature for the three years were similar, the mode in 2008 (15.8 °C) was very different from those in 2007 and 2009 (22.4 °C and 23.2 °C). After controlling for age, body mass index, and hematocrit, a multiple regression analysis revealed a U-shaped relationship between ambient temperature and PSA in 2007 and 2009 ( P < 0.001 and P = 0.004, respectively), but not in 2008 ( P = 0.779). In 2007, PSA was 13.5 % higher at 5 °C and 10.0 % higher at 30 °C than that at 18.4 °C (nadir). In 2009, PSA was 7.3 % higher at 5 °C and 6.8 % at 30 °C compared with the level at 17.7 °C (nadir). In logistic regression analysis, a U-shaped relationship was found for the prevalence of a higher PSA (> 2.5 ng/mL) by ambient temperature, with the lowest likelihood of having a high PSA at 17.8 °C in 2007 ( P = 0.038) and 15.5 °C in 2009 ( P = 0.033). When tested at 30 °C, there was a 57 % excess risk of having a high PSA in 2007 and a 61 % higher risk in 2009 compared with those at each nadir temperature. We found a U-shaped relationship between PSA and ambient temperature with the lowest level of PSA at 15-20 °C.

  8. High Performance Organ-Specific Nuclear Medicine Imagers.

    NASA Astrophysics Data System (ADS)

    Majewski, Stan

    2006-04-01

    One of the exciting applications of nuclear science is nuclear medicine. Well-known diagnostic imaging tools such as PET and SPECT (as well as MRI) were developed as spin-offs of basic scientific research in atomic and nuclear physics. Development of modern instrumentation for applications in particle physics experiments offers an opportunity to contribute to development of improved nuclear medicine (gamma and positron) imagers, complementing the present set of standard imaging tools (PET, SPECT, MRI, ultrasound, fMRI, MEG, etc). Several examples of new high performance imagers developed in national laboratories in collaboration with academia will be given to demonstrate this spin-off activity. These imagers are designed to specifically image organs such as breast, heart, head (brain), or prostate. The remaining and potentially most important challenging application field for dedicated nuclear medicine imagers is to assist with cancer radiation treatments. Better control of radiation dose delivery requires development of new compact in-situ imagers becoming integral parts of the radiation delivery systems using either external beams or based on radiation delivery by inserting or injecting radioactive sources (gamma, beta or alpha emitters) into tumors.

  9. Prostate-Specific Antigen Velocity Before and After Elimination of Factors That Can Confound the Prostate-Specific Antigen Level

    SciTech Connect

    Park, Jessica J.; Chen, Ming-Hui; Loffredo, Marian; D'Amico, Anthony V.

    2012-03-01

    Purpose: Prostate-specific antigen (PSA) velocity, like PSA level, can be confounded. In this study, we estimated the impact that confounding factors could have on correctly identifying a patient with a PSA velocity >2 ng/ml/y. Methods and Materials: Between 2006 and 2010, a total of 50 men with newly diagnosed PC comprised the study cohort. We calculated and compared the false-positive and false-negative PSA velocity >2 ng/ml/y rates for all men and those with low-risk disease using two approaches to calculate PSA velocity. First, we used PSA values obtained within 18 months of diagnosis; second, we used values within 18 months of diagnosis, substituting the prebiopsy PSA for a repeat, nonconfounded PSA that was obtained using the same assay and without confounders. Results: Using PSA levels pre-biopsy, 46% of all men had a PSA velocity >2 ng/ml/y; whereas this value declined to 32% when substituting the last prebiopsy PSA for a repeat, nonconfounded PSA using the same assay and without confounders. The false-positive rate for PSA velocity >2 ng/ml/y was 43% as compared with a false-negative rate of PSA velocity >2 ng/ml/y of 11% (p = 0.0008) in the overall cohort. These respective values in the low-risk subgroup were 60% and 16.7% (p = 0.09). Conclusion: This study provides evidence to explain the discordance in cancer-specific outcomes among groups investigating the prognostic significance of PSA velocity >2 ng/ml/y, and highlights the importance of patient education on potential confounders of the PSA test before obtaining PSA levels.

  10. Expression of CXCR3 on specific T cells is essential for homing to the prostate gland in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

    PubMed

    Breser, Maria L; Motrich, Ruben D; Sanchez, Leonardo R; Mackern-Oberti, Juan P; Rivero, Virginia E

    2013-04-01

    Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-γ(-/-), exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD-IFN-γ(-/-) mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after "in vitro" or "in vivo" treatment with rIFN-γ, T cells from NOD-IFN-γ(-/-) mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3(+)CD3(+) T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome.

  11. Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality.

    PubMed

    Yang, Meng; Kenfield, Stacey A; Van Blarigan, Erin L; Batista, Julie L; Sesso, Howard D; Ma, Jing; Stampfer, Meir J; Chavarro, Jorge E

    2015-06-01

    Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer-specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00-6.42; Ptrend = 0.02) for prostate cancer-specific mortality and 1.67 (95% CI, 1.16-2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44-0.93; Ptrend = 0.02); the relationship with prostate cancer-specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis.

  12. Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality

    PubMed Central

    Yang, Meng; Kenfield, Stacey A.; Van Blarigan, Erin L.; Batista, Julie L.; Sesso, Howard D.; Ma, Jing; Stampfer, Meir J.; Chavarro, Jorge E.

    2015-01-01

    Men diagnosed with non-metastatic prostate cancer have a long life expectancy and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may impact disease-specific and overall mortality. 926 men participating in the Physicians' Health Study diagnosed with non-metastatic prostate cancer completed diet questionnaires a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer-specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95%CI: 1.00-6.42; Ptrend=0.02) for prostate cancer-specific mortality and 1.67 (95%CI: 1.16-2.42; Ptrend=0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs Quartile 1: 0.64; 95% CI: 0.44-0.93; Ptrend=0.02); the relationship with prostate cancer-specific mortality was inverse but not statistically significant. Post-diagnostic Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis. PMID:26031631

  13. Identification of Threshold Prostate Specific Antigen Levels to Optimize the Detection of Clinically Significant Prostate Cancer by Magnetic Resonance Imaging/Ultrasound Fusion Guided Biopsy

    PubMed Central

    Shakir, Nabeel A.; George, Arvin K.; Siddiqui, M. Minhaj; Rothwax, Jason T.; Rais-Bahrami, Soroush; Stamatakis, Lambros; Su, Daniel; Okoro, Chinonyerem; Raskolnikov, Dima; Walton-Diaz, Annerleim; Simon, Richard; Turkbey, Baris; Choyke, Peter L.; Merino, Maria J.; Wood, Bradford J.; Pinto, Peter A.

    2015-01-01

    Purpose Prostate specific antigen sensitivity increases with lower threshold values but with a corresponding decrease in specificity. Magnetic resonance imaging/ultrasound targeted biopsy detects prostate cancer more efficiently and of higher grade than standard 12-core transrectal ultrasound biopsy but the optimal population for its use is not well defined. We evaluated the performance of magnetic resonance imaging/ultrasound targeted biopsy vs 12-core biopsy across a prostate specific antigen continuum. Materials and Methods We reviewed the records of all patients enrolled in a prospective trial who underwent 12-core transrectal ultrasound and magnetic resonance imaging/ultrasound targeted biopsies from August 2007 through February 2014. Patients were stratified by each of 4 prostate specific antigen cutoffs. The greatest Gleason score using either biopsy method was compared in and across groups as well as across the population prostate specific antigen range. Clinically significant prostate cancer was defined as Gleason 7 (4 + 3) or greater. Univariate and multivariate analyses were performed. Results A total of 1,003 targeted and 12-core transrectal ultrasound biopsies were performed, of which 564 diagnosed prostate cancer for a 56.2% detection rate. Targeted biopsy led to significantly more upgrading to clinically significant disease compared to 12-core biopsy. This trend increased more with increasing prostate specific antigen, specifically in patients with prostate specific antigen 4 to 10 and greater than 10 ng/ml. Prostate specific antigen 5.2 ng/ml or greater captured 90% of upgrading by targeted biopsy, corresponding to 64% of patients who underwent multiparametric magnetic resonance imaging and subsequent fusion biopsy. Conversely a greater proportion of clinically insignificant disease was detected by 12-core vs targeted biopsy overall. These differences persisted when controlling for potential confounders on multivariate analysis. Conclusions Prostate

  14. Body composition and serum prostate-specific antigen: review and findings from Flint Men's Health Study.

    PubMed

    Beebe-Dimmer, Jennifer L; Faerber, Gary J; Morgenstern, Hal; Werny, David; Wojno, Kirk; Halstead-Nussloch, Bronwen; Cooney, Kathleen A

    2008-04-01

    Recent studies have suggested that obesity is associated with lower serum prostate-specific antigen levels, perhaps influencing the recommendation for prostate biopsy and potentially explaining part of the observed poorer prognosis among obese men. African-American men have the greatest rates of prostate cancer and are more likely to die of the disease, making early detection a priority in this group. We present findings from the Flint Men's Health Study, a study of African-American men, that are consistent with most studies suggesting that overweight men have prostate-specific antigen levels that are 0.15 to 0.30 ng/mL lower than those who are not overweight. We have coupled our results with a systematic review of publications in this area.

  15. Effect of ejaculation on Serum Prostate-Specific Antigen concentration

    PubMed Central

    Tarhan, Fatih; Demir, Kadir; Orçun, Asuman; Madenci, Ozlem Cakır

    2016-01-01

    ABSTRACT Abstract Purpose:To evaluate the effect of ejaculation on serum prostate-specific antigen (PSA) concentrations in patients with lower urinary tract symptom (LUTS). Materials and Methods Our study includes 98 men (62 study and 36 control). After three days of sexual abstinence, blood samples were drawn for the measurement of baseline PSA levels. Then the patients were told to ejaculate. One, 5, 24 and 72 hours after ejaculation, serum total (tPSA), free (fPSA) and complexed PSA (cPSA) levels were measured. Serum PSA sampling was performed at the same intervals in the control group without ejaculation. Results The mean age in study and control groups patients were 59.03±0.99 years, 61.14±1.30 years, respectively. In the study group, changes in tPSA and fPSA levels after ejaculation were found statistically significant while changes in cPSA levels and f/tPSA ratios were not significant (p=0.016, p=0.0003, p=0.176, and p=0.173, respectively). Baseline values showed significant differences with 1st and 5th hours. No significant changes in tPSA, fPSA, cPSA levels and f/tPSA values were found in control group (p=0.223, p=0.224, p=0.444, and p=0.718, respectively). The changes in the number of patients exceeding the cutoff values after ejaculation were not statistically significant for tPSA, cPSA, and f/tPSA ratio. Conclusions In this study, ejaculation increased tPSA and fPSA concentrations but it didn’t have a significant effect on serum cPSA levels and f/tPSA ratios. However, recent ejaculation may affect the biopsy indication at least near cut off PSA values. Further studies are needed to explain the mechanisms of alterations in the concentration of PSA. PMID:27286109

  16. The utility of STAT6 and ALDH1 expression in the differential diagnosis of solitary fibrous tumor versus prostate-specific stromal neoplasms.

    PubMed

    Guner, Gunes; Bishop, Justin A; Bezerra, Stephania M; Taheri, Diana; Zahavi, David J; Mendoza Rodriguez, Maria Angelica; Sharma, Rajni; Epstein, Jonathan I; Netto, George J

    2016-08-01

    Solitary fibrous tumor (SFT) diagnosis in prostate can be challenging on small biopsies. Prostatic stromal tumors of unknown malignant potential (STUMP) and SFT have overlapping features. NAB2-STAT6 gene fusions that were recently identified in various SFTs lead to nuclear translocalization of STAT6. Nuclear STAT6 immunostaining is now considered an adjunct for SFT diagnosis. We evaluated STAT6 and an emerging stemness marker, ALDH1, in the differential diagnosis of SFT versus prostatic stromal lesions. Sixteen STUMPs, 12 SFTs, and 4 prostatic stromal sarcomas (12 needle biopsies, 13 radical prostatectomies, 7 transurethral resections) were retrieved (1995-2015). Sections were stained with polyclonal STAT6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; S20, 1:100) and monoclonal ALDH1 antibody (BD Biosciences, San Jose, CA; clone 44, 1:250). In STAT6 cases, only unequivocal nuclear staining (with/without cytoplasmic staining) was considered positive. Cytoplasmic ALDH1 staining was counted positive. Ten of 11 evaluable SFTs demonstrated strong and diffuse nuclear STAT6 positivity; 4 of 16 STUMPs had nuclear staining that was weak (1/4) or focal (1/4). ALDH1 positivity was seen in 10 of 12 evaluable SFTs and 3 of 15 STUMPs. Prostatic stromal sarcomas were STAT6 negative (4/4); 2 of 4 were ALDH1 positive. The sensitivity and specificity for STAT6 for the diagnosis of SFT were 91% and 75%, respectively. Coexpression of STAT6 and ALDH1 yielded the same sensitivity but improved the specificity (100%) for the diagnosis of SFT. STAT6 is a useful marker in the differential diagnosis of SFT versus STUMP. Using STAT6 and ALDH1 together increases specificity. STUMPs can show STAT6 positivity, and when they do, it is likely to be weak or focal. PMID:27068523

  17. The utility of STAT6 and ALDH1 expression in the differential diagnosis of solitary fibrous tumor versus prostate-specific stromal neoplasms.

    PubMed

    Guner, Gunes; Bishop, Justin A; Bezerra, Stephania M; Taheri, Diana; Zahavi, David J; Mendoza Rodriguez, Maria Angelica; Sharma, Rajni; Epstein, Jonathan I; Netto, George J

    2016-08-01

    Solitary fibrous tumor (SFT) diagnosis in prostate can be challenging on small biopsies. Prostatic stromal tumors of unknown malignant potential (STUMP) and SFT have overlapping features. NAB2-STAT6 gene fusions that were recently identified in various SFTs lead to nuclear translocalization of STAT6. Nuclear STAT6 immunostaining is now considered an adjunct for SFT diagnosis. We evaluated STAT6 and an emerging stemness marker, ALDH1, in the differential diagnosis of SFT versus prostatic stromal lesions. Sixteen STUMPs, 12 SFTs, and 4 prostatic stromal sarcomas (12 needle biopsies, 13 radical prostatectomies, 7 transurethral resections) were retrieved (1995-2015). Sections were stained with polyclonal STAT6 antibody (Santa Cruz Biotechnology, Santa Cruz, CA; S20, 1:100) and monoclonal ALDH1 antibody (BD Biosciences, San Jose, CA; clone 44, 1:250). In STAT6 cases, only unequivocal nuclear staining (with/without cytoplasmic staining) was considered positive. Cytoplasmic ALDH1 staining was counted positive. Ten of 11 evaluable SFTs demonstrated strong and diffuse nuclear STAT6 positivity; 4 of 16 STUMPs had nuclear staining that was weak (1/4) or focal (1/4). ALDH1 positivity was seen in 10 of 12 evaluable SFTs and 3 of 15 STUMPs. Prostatic stromal sarcomas were STAT6 negative (4/4); 2 of 4 were ALDH1 positive. The sensitivity and specificity for STAT6 for the diagnosis of SFT were 91% and 75%, respectively. Coexpression of STAT6 and ALDH1 yielded the same sensitivity but improved the specificity (100%) for the diagnosis of SFT. STAT6 is a useful marker in the differential diagnosis of SFT versus STUMP. Using STAT6 and ALDH1 together increases specificity. STUMPs can show STAT6 positivity, and when they do, it is likely to be weak or focal.

  18. Highly specific expression of luciferase gene in lungs of naive nude mice directed by prostate-specific antigen promoter

    SciTech Connect

    Li Hongwei; Li Jinzhong; Helm, Gregory A.; Pan Dongfeng . E-mail: Dongfeng_pan@yahoo.com

    2005-09-09

    PSA promoter has been demonstrated the utility for tissue-specific toxic gene therapy in prostate cancer models. Characterization of foreign gene overexpression in normal animals elicited by PSA promoter should help evaluate therapy safety. Here we constructed an adenovirus vector (AdPSA-Luc), containing firefly luciferase gene under the control of the 5837 bp long prostate-specific antigen promoter. A charge coupled device video camera was used to non-invasively image expression of firefly luciferase in nude mice on days 3, 7, 11 after injection of 2 x 10{sup 9} PFU of AdPSA-Luc virus via tail vein. The result showed highly specific expression of the luciferase gene in lungs of mice from day 7. The finding indicates the potential limitations of the suicide gene therapy of prostate cancer based on selectivity of PSA promoter. By contrary, it has encouraging implications for further development of vectors via PSA promoter to enable gene therapy for pulmonary diseases.

  19. Race, genetic West African ancestry, and prostate cancer prediction by prostate-specific antigen in prospectively screened high-risk men.

    PubMed

    Giri, Veda N; Egleston, Brian; Ruth, Karen; Uzzo, Robert G; Chen, David Y T; Buyyounouski, Mark; Raysor, Susan; Hooker, Stanley; Torres, Jada Benn; Ramike, Teniel; Mastalski, Kathleen; Kim, Taylor Y; Kittles, Rick

    2009-03-01

    "Race-specific" prostate-specific antigen (PSA) needs evaluation in men at high risk for prostate cancer for optimizing early detection. Baseline PSA and longitudinal prediction for prostate cancer were examined by self-reported race and genetic West African (WA) ancestry in the Prostate Cancer Risk Assessment Program, a prospective high-risk cohort. Eligibility criteria were age 35 to 69 years, family history of prostate cancer, African American race, or BRCA1/2 mutations. Biopsies were done at low PSA values (<4.0 ng/mL). WA ancestry was discerned by genotyping 100 ancestry informative markers. Cox proportional hazards models evaluated baseline PSA, self-reported race, and genetic WA ancestry. Cox models were used for 3-year predictions for prostate cancer. Six hundred forty-six men (63% African American) were analyzed. Individual WA ancestry estimates varied widely among self-reported African American men. Race-specific differences in baseline PSA were not found by self-reported race or genetic WA ancestry. Among men with > or =1 follow-up visit (405 total, 54% African American), 3-year prediction for prostate cancer with a PSA of 1.5 to 4.0 ng/mL was higher in African American men with age in the model (P = 0.025) compared with European American men. Hazard ratios of PSA for prostate cancer were also higher by self-reported race (1.59 for African American versus 1.32 for European American, P = 0.04). There was a trend for increasing prediction for prostate cancer with increasing genetic WA ancestry. "Race-specific" PSA may need to be redefined as higher prediction for prostate cancer at any given PSA in African American men. Large-scale studies are needed to confirm if genetic WA ancestry explains these findings to make progress in personalizing prostate cancer early detection.

  20. [Expression of prostate stem cell antigen (PSCA) and selection of its specific binding peptide].

    PubMed

    Hou, Li-Hua; Du, Yong; Zhang, Xiao-Peng; An, Xiao-Ping; Chen, Wei

    2004-09-01

    Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigen, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. To obtain the specific peptide binding with PSCA for targeted immunotherapy, PSCA gene was obtained by RT-PCR from human prostate cancer cell line DU145 and the transcated PSCA (tPSCA) gene was cloned into vector pQE30 for soluble expression in E. coli. The identity of recombinant tPSCA was confirmed through ELISA and western blot by use of anti-PSCA monoclonal antibody. Then the 12-peptide phage display library was screened with the purified tPSCA protein for its specific binding peptide through 3 rounds panning. For identifying the peptide's specificity, the peptide was coupled with EGFP (enhanced green fluorecent protein) by recombinant DNA technology and the recombinant coupled protein was termed 11-EGFP. The binding specificity with tPSCA of 11-EGFP was further confirmed by ELISA and competitive inhibition experiment. Flow cytometry demonstrated its binding specificity with cell line DU145. In conclusion, a 12-amino-acid peptide which could bind with PSCA specifically was found and it may be a potential tool for targeted immunotherapy of prostate carcinoma. PMID:15973992

  1. Inverse relation between prostate-specific antigen and insulin-like growth factor-binding protein 3 in bone metastases and serum of patients with prostate cancer.

    PubMed

    Smith, G L; Doherty, A P; Mitchell, H; Hanham, I W; Christmas, T J; Epstein, R J

    1999-12-11

    The usual osteoblastic phenotype of metastatic prostate cancer is unexplained. Here we show that tissue and serum concentrations of prostate-specific antigen (PSA)-vary inversely with a substrate protein that binds a growth factor known to activate osteoblasts. These findings suggest that PSA may contribute to the osteoblastic phenotype, and could thus represent a new drug target devoid of antiandrogenic toxicity.

  2. Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

    PubMed

    Drake, Justin M; Paull, Evan O; Graham, Nicholas A; Lee, John K; Smith, Bryan A; Titz, Bjoern; Stoyanova, Tanya; Faltermeier, Claire M; Uzunangelov, Vladislav; Carlin, Daniel E; Fleming, Daniel Teo; Wong, Christopher K; Newton, Yulia; Sudha, Sud; Vashisht, Ajay A; Huang, Jiaoti; Wohlschlegel, James A; Graeber, Thomas G; Witte, Owen N; Stuart, Joshua M

    2016-08-11

    We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients. PMID:27499020

  3. Prostate Cancer Imaging with Novel PET Tracers.

    PubMed

    Lindenberg, Liza; Choyke, Peter; Dahut, William

    2016-03-01

    Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy.

  4. Posttreatment prostatic-specific antigen doubling time as a surrogate endpoint for prostate cancer-specific survival: An analysis of Radiation Therapy Oncology Group Protocol 92-02

    SciTech Connect

    Valicenti, Richard K. . E-mail: Richard.Valicenti@mail.tju.edu; DeSilvio, Michelle; Hanks, Gerald E.; Porter, Arthur; Brereton, Harmar; Rosenthal, Seth A.; Shipley, William U.; Sandler, Howard M.

    2006-11-15

    Purpose: We evaluated whether posttreatment prostatic-specific antigen doubling time (PSADT) was predictive of prostate cancer mortality by testing the Prentice requirements for a surrogate endpoint. Methods and Materials: We analyzed posttreatment PSA measurements in a cohort of 1,514 men with localized prostate cancer (T2c-4 and PSA level <150 ng/mL), treated and monitored prospectively on Radiation Therapy Oncology Group Protocol 92-02. From June 1992 to April 1995, men were randomized to neoadjuvant androgen deprivation and 65-70 Gy of radiation therapy (n = 761), or in combination with 24 months of adjuvant androgen deprivation (n = 753). Using an adjusted Cox proportional hazards model, we tested if PSADT was prognostic and independent of randomized treatment in this cohort. The endpoints were time to PSADT (assuming first-order kinetics for a minimum of 3 rising PSA measurements) and cancer-specific survival (CSS). Results: After a median follow-up time of 5.9 years, randomized treatment was a significant predictor for CSS (p{sub Cox} = 0.002), PSADT <6 months (p{sub Cox} < 0.001), PSADT <9 months (p{sub Cox} < 0.001), and PSADT <12 months (p{sub Cox} < 0.001) but not for PSADT <3 (p{sub Cox} = 0.4). The significant posttreatment PSADTs were also significant predictors of CSS (p{sub Cox}< 0.001). After adjusting for T stage, Gleason score and PSA, all of Prentice's requirements were not met, indicating that the effect of PSADT on CSS was not independent of the randomized treatment. Conclusions: Prostatic specific antigen doubling time is significantly associated with CSS, but did not meet all of Prentice's requirements for a surrogate endpoint of CSS. Thus, the risk of dying of prostate cancer is not fully explained by PSADT.

  5. Expression and purification of recombinant active prostate-specific antigen from Escherichia coli.

    PubMed

    Jeong, Sujin; Lee, Seong-Wook

    2007-05-01

    Human prostate-specific antigen (PSA), a 33 kDa serine protease with comprehensive homology to glandular kallikrein, is secreted from prostatic tissue into the seminal fluid and enters into the circulation. The level of PSA increases in the serum of patients with prostatic cancer and hence is widely employed as a marker of the disease status. In particular, an enzymatically active PSA that is a form cleaved at the N-terminal seven-amino-acids prosequence, APLILSR, of proPSA may play an important roll in the progression of prostate cancer. Thus, the presence of the active form would selectively discriminate the cancer from benign prostatic hyperplasia. In this study, we developed a convenient purification method for the acquisition of active PSA and proPSA. Recombinant proPSA and active PSA were expressed directly in Escherichia coli, easily and efficiently isolated from inclusion bodies, refolded, and purified. Moreover, the enzymatic activity of the recombinant active PSA was confirmed as serine protease using chromogenic chymotrypsin substrate. This purified active PSA could be further applied to scrutinize the biological or conformational characteristics of the protein and to develop specific diagnostic and/or therapeutic agents against prostate cancer.

  6. A prostate-specific antigen-dependent fusion polypeptide inhibits growth of prostate cancer cells in vitro and in vivo

    PubMed Central

    Zhang, Xiang; Ma, Yueyun; Wei, Hua; Li, Bin; Xiao, Fengjing; Yang, Jing; Yue, Qiaohong; Yang, Angang; Hao, Xiaoke

    2016-01-01

    Polypeptide APP8 is a prostate-specific antigen (PSA)-activated prodrug that was designed to synergize the effects of the Bcl-2 homology domain 3 (BH3) peptide, K237 and the DG2 peptide. The aim of this study is to evaluate its biodistribution and anticancer effect in vitro and in vivo. In this study, APP8 and each component peptide were synthesized. The biodistribution was identified using con-focal microscopyin both PSA+ cell line and PSA- cell line in vitro. Then cell cycle, MTT and in-cell western blot were accessed to analyze the effect mechanisms. Finally, xenografts were used to confirm the anticancer effect in vivo. Here, it was shown that APP8 was hydrolyzed and BH3 was released into the nucleus, while K237 and DG2 were located predominantly in the cytoplasm, only in LNCaP cells (PSA+), but not PC3 cells (PSA-). K237 and DG2 could induce cell apoptosis through decreasing the phosphorylation of ERK-2 and Flk-1. APP8 also caused the death of LNCaP cells, and was predominantly dependent on BH3 in vitro. In addition, It was noted that as the tumor grew in vivo, APP8 could inhibit the tumor volume to 77.3%, mainly depending on K237 and DG2 via inhibition of the growth of vascular endothelial cells. Our results suggested that APP8 could promote prostate cancer cell death and stop prostate cancer growth via synergizing apoptosis induction of tumor cell and inhibition of the growth of vascular endothelial cells. It provides a novel candidate prodrug for specific therapy of prostate cancer. PMID:27293998

  7. Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.

    PubMed

    Johnson, James K; Skoda, Erin M; Zhou, Jianhua; Parrinello, Erica; Wang, Dan; O'Malley, Katherine; Eyer, Benjamin R; Kazancioglu, Mustafa; Eisermann, Kurtis; Johnston, Paul A; Nelson, Joel B; Wang, Zhou; Wipf, Peter

    2016-08-11

    After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development. PMID:27563404

  8. On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer.

    PubMed

    Bangma, Chris H; van Schaik, Ron H; Blijenberg, Bert G; Roobol, Monique J; Lilja, Hans; Stenman, Ulf-Håkan

    2010-11-01

    Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC. PMID:21047594

  9. Evaluation of the Prostate Imaging Reporting and Data System for Magnetic Resonance Imaging Diagnosis of Prostate Cancer in Patients with Prostate-specific Antigen <20 ng/ml

    PubMed Central

    Wang, Xuan; Wang, Jian-Ye; Li, Chun-Mei; Zhang, Ya-Qun; Wang, Jian-Long; Wan, Ben; Zhang, Wei; Chen, Min; Li, Sa-Ying; Wan, Gang; Liu, Ming

    2016-01-01

    Background: The European Society of Urogenital Radiology has built the Prostate Imaging Reporting and Data System (PI-RADS) for standardizing the diagnosis of prostate cancer (PCa). This study evaluated the PI-RADS diagnosis method in patients with prostate-specific antigen (PSA) <20 ng/ml. Methods: A total of 133 patients with PSA <20 ng/ml were prospectively recruited. T2-weighted (T2WI) and diffusion-weighted (DWI) magnetic resonance images of the prostate were acquired before a 12-core transrectal prostate biopsy. Each patient's peripheral zone was divided into six regions on the images; each region corresponded to two of the 12 biopsy cores. T2WI, DWI, and T2WI + DWI scores were computed according to PI-RADS. The diagnostic accuracy of the PI-RADS score was evaluated using histopathology of prostate biopsies as the reference standard. Results: PCa was histologically diagnosed in 169 (21.2%) regions. Increased PI-RADS score correlated positively with increased cancer detection rate. The cancer detection rate for scores 1 to 5 was 2.8%, 15.0%, 34.6%, 52.6%, and 88.9%, respectively, using T2WI and 12.0%, 20.2%, 48.0%, 85.7%, and 93.3%, respectively, using DWI. For T2WI + DWI, the cancer detection rate was 1.5% (score 2), 13.5% (scores 3–4), 41.3% (scores 5–6), 75.9% (scores 7–8), and 92.3% (scores 9–10). The area under the curve for cancer detection was 0.700 (T2WI), 0.735 (DWI) and 0.749 (T2WI + DWI). The sensitivity and specificity were 53.8% and 89.2%, respectively, when using scores 5–6 as the cutoff value for T2WI + DWI. Conclusions: The PI-RADS score correlates with the PCa detection rate in patients with PSA <20 ng/ml. The summed score of T2WI + DWI has the highest accuracy in detection of PCa. However, the sensitivity should be further improved. PMID:27270538

  10. Integrated and Functional Genomics Analysis Validates the Relevance of the Nuclear Variant ErbB380kDa in Prostate Cancer Progression

    PubMed Central

    El Maassarani, Mahmoud; Barbarin, Alice; Fromont, Gaëlle; Kaissi, Ouafae; Lebbe, Margot; Vannier, Brigitte; Moussa, Ahmed; Séité, Paule

    2016-01-01

    The EGF-family of tyrosine-kinase receptors activates cytoplasmic pathways involved in cell proliferation, migration and differentiation in response to specific extracellular ligands. Beside these canonical pathways, the nuclear localization of the ErbB receptors in primary tumours and cancer cell lines led to investigate their role as transcriptional regulators of cancer genes. The nuclear localization of ErbB3 has been reported in various cancer tissues and cell lines but the nuclear functions and the putative correlation with tumour progression and resistance to therapy remain unclear. We first assessed ErbB3 expression in normal and tumour prostate tissues. The nuclear staining was mainly due to an isoform matching the C-terminus domain of the full length ErbB3185kDa receptor. Nuclear staining was also restricted to cancer cells and was increased in advanced castration-resistant prostate cancer when compared to localized tumours, suggesting it could be involved in the progression of prostate cancer up to the terminal castration-resistant stage. ChIP-on-chip experiments were performed on immortalized and tumour cell lines selected upon characterization of endogenous nuclear expression of an ErbB380kDa isoform. Among the 1840 target promoters identified, 26 were selected before ErbB380kDa-dependent gene expression was evaluated by real-time quantitative RT-PCR, providing evidence that ErbB380kDa exerted transcriptional control on those genes. Some targets are already known to be involved in prostate cancer progression even though no link was previously established with ErbB3 membrane and/or nuclear signalling. Many others, not yet associated with prostate cancer, could provide new therapeutic possibilities for patients expressing ErbB380kDa. Detecting ErbB380kDa could thus constitute a useful marker of prognosis and response to therapy. PMID:27191720

  11. DNA Ploidy Measured on Archived Pretreatment Biopsy Material May Correlate With Prostate-Specific Antigen Recurrence After Prostate Brachytherapy

    SciTech Connect

    Keyes, Mira; MacAulay, Calum; Hayes, Malcolm; Korbelik, Jagoda; Morris, W. James; Palcic, Branko

    2013-08-01

    Purpose: To explore whether DNA ploidy of prostate cancer cells determined from archived transrectal ultrasound-guided biopsy specimens correlates with disease-free survival. Methods and Materials: Forty-seven failures and 47 controls were selected from 1006 consecutive low- and intermediate-risk patients treated with prostate {sup 125}I brachytherapy (July 1998-October 2003). Median follow-up was 7.5 years. Ten-year actuarial disease-free survival was 94.1%. Controls were matched using age, initial prostate-specific antigen level, clinical stage, Gleason score, use of hormone therapy, and follow-up (all P nonsignificant). Seventy-eight specimens were successfully processed; 27 control and 20 failure specimens contained more than 100 tumor cells were used for the final analysis. The Feulgen-Thionin stained cytology samples from archived paraffin blocks were used to determine the DNA ploidy of each tumor by measuring integrated optical densities. Results: The samples were divided into diploid and aneuploid tumors. Aneuploid tumors were found in 16 of 20 of the failures (80%) and 8 of 27 controls (30%). Diploid DNA patients had a significantly lower rate of disease recurrence (P=.0086) (hazard ratio [HR] 0.256). On multivariable analysis, patients with aneuploid tumors had a higher prostate-specific antigen failure rate (HR 5.13). Additionally, those with “excellent” dosimetry (V100 >90%; D90 >144 Gy) had a significantly lower recurrence rate (HR 0.25). All patients with aneuploid tumors and dosimetry classified as “nonexcellent” (V100 <90%; D90 <144 Gy) (5 of 5) had disease recurrence, compared with 40% of patients with aneuploid tumors and “excellent” dosimetry (8 of 15). In contrast, dosimetry did not affect the outcome for diploid patients. Conclusions: Using core biopsy material from archived paraffin blocks, DNA ploidy correctly classified the majority of failures and nonfailures in this study. The results suggest that DNA ploidy can be used as a

  12. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy.

    PubMed

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  13. Metastasis in urothelial carcinoma mimicking prostate cancer metastasis in Ga-68 prostate-specific membrane antigen positron emission tomography-computed tomography in a case of synchronous malignancy

    PubMed Central

    Gupta, Manoj; Choudhury, Partha Sarathi; Gupta, Gurudutt; Gandhi, Jatin

    2016-01-01

    Prostate cancer is the second most common cancer in man. It commonly presents with urinary symptoms, bone pain, or diagnosed with elevated prostate-specific antigen.(PSA) levels. Correct staging and early diagnosis of recurrence by a precise imaging tool are the keys for optimum management. Molecular imaging of prostate cancer with Ga-68 prostate-specific membrane antigen.(PSMA), positron emission tomography-computed tomography.(PET-CT) has recently received significant attention and frequently used with a signature to prostate cancer-specific remark. However, this case will highlight the more cautious use of it. A-72-year-old male treated earlier for synchronous double malignancy.(invasive papillary urothelial carcinoma right ureter and carcinoma prostate) presented with rising PSA.(0.51.ng/ml) and referred for Ga-68 PSMA PET-CT, which showed a positive enlarged left supraclavicular lymph node. Lymph node biopsy microscopic and immunohistochemistry examination revealed metastatic carcinoma favoring urothelial origin. Specificity of PSMA scan to prostate cancer has been seen to be compromised in a certain situation mostly due to neoangiogenesis, and false positives emerged in renal cell cancer, differentiated thyroid cancer, glioblastoma, breast cancer brain metastasis, and paravertebral schwannomas. Understanding the causes of false positive will further enhance the confidence of interpretating PSMA scans. PMID:27385897

  14. Prostate-specific antigen and hormone receptor expression in male and female breast carcinoma

    PubMed Central

    2010-01-01

    Background Prostate carcinoma is among the most common solid tumors to secondarily involve the male breast. Prostate specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) are expressed in benign and malignant prostatic tissue, and immunohistochemical staining for these markers is often used to confirm the prostatic origin of metastatic carcinoma. PSA expression has been reported in male and female breast carcinoma and in gynecomastia, raising concerns about the utility of PSA for differentiating prostate carcinoma metastasis to the male breast from primary breast carcinoma. This study examined the frequency of PSA, PSAP, and hormone receptor expression in male breast carcinoma (MBC), female breast carcinoma (FBC), and gynecomastia. Methods Immunohistochemical staining for PSA, PSAP, AR, ER, and PR was performed on tissue microarrays representing six cases of gynecomastia, thirty MBC, and fifty-six FBC. Results PSA was positive in two of fifty-six FBC (3.7%), focally positive in one of thirty MBC (3.3%), and negative in the five examined cases of gynecomastia. PSAP expression was absent in MBC, FBC, and gynecomastia. Hormone receptor expression was similar in males and females (AR 74.1% in MBC vs. 67.9% in FBC, p = 0.62; ER 85.2% vs. 68.5%, p = 0.18; and PR 51.9% vs. 48.2%, p = 0.82). Conclusions PSA and PSAP are useful markers to distinguish primary breast carcinoma from prostate carcinoma metastatic to the male breast. Although PSA expression appeared to correlate with hormone receptor expression, the incidence of PSA expression in our population was too low to draw significant conclusions about an association between PSA expression and hormone receptor status in breast lesions. PMID:20863373

  15. Prostate-Specific Membrane Antigen PET/CT: False-Positive Results due to Sarcoidosis?

    PubMed Central

    Hermann, Robert M.; Djannatian, Manoutschehr; Czech, Norbert; Nitsche, Mirko

    2016-01-01

    We report on a 72-year-old male patient who developed sarcoidosis of the mediastinal lymph nodes, the liver, and the prostate 11 years ago. Seven years later, he underwent transurethral resection of the prostate by laser due to hematuria. Pathology of the resected chips showed a ‘granulomatous prostatitis with epitheloid cells’. Malignancy was histologically excluded at that time. Four years later, he was diagnosed with an undifferentiated prostate carcinoma, with a Gleason score of 5 + 4 = 9. After initiation of antihormonal therapy, he underwent radical prostatectomy and pelvic lymphadenectomy, which revealed a pT3b pN1 carcinoma with infiltrated resection margins. Three months later, the prostate-specific antigen level was 1.4 ng/ml, and a local recurrence was suspected by ultrasound; consequently, a 68Ga-prostate-specific membrane antigen (PSMA) PET/CT was performed. This examination seemed to confirm the local recurrence, a right pelvic lymph node metastasis, and a hepatic metastasis. However, ultrasound with contrast medium could not confirm the metastatic spread to the liver. In palliative intention, radiotherapy of the pelvis was done. After 50 Gy, the supposed recurrence had markedly shrunk, and an additional boost dose with 16.2 Gy was applied. Two years later, the patient is still free of disease. Due to this clinical development, we doubt the diagnosis of a fulminant progression of the prostate cancer as suspected by PSMA-PET/CT. Instead, we suspect a recurrence of the previously proven sarcoidosis leading to false-positive results. Our focus in this report is on the interaction between PSMA-PET/CT and sarcoidosis. Another report on a case of sarcoidosis of the spleen seems to confirm this possibility [Kobe et al: Clin Nucl Med 2015;40: 897–898]. PMID:27721768

  16. Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity.

    PubMed

    Krönig, Malte; Walter, Max; Drendel, Vanessa; Werner, Martin; Jilg, Cordula A; Richter, Andreas S; Backofen, Rolf; McGarry, David; Follo, Marie; Schultze-Seemann, Wolfgang; Schüle, Roland

    2015-01-20

    A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer.

  17. Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity

    PubMed Central

    Krönig, Malte; Walter, Max; Drendel, Vanessa; Werner, Martin; Jilg, Cordula A.; Richter, Andreas S.; Backofen, Rolf; McGarry, David; Follo, Marie; Schultze-Seemann, Wolfgang; Schüle, Roland

    2015-01-01

    A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer. PMID:25514598

  18. CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells

    PubMed Central

    Olson, Brian M.; McNeel, Douglas G.

    2012-01-01

    The androgen receptor (AR) is a hormone receptor that plays a critical role in prostate cancer, and depletion of its ligand has long been the cornerstone of treatment for metastatic disease. Here, we evaluate the AR ligand-binding domain (LBD) as an immunological target, seeking to identify HLA-A2-restricted epitopes recognized by T-cells in prostate cancer patients. Ten ARLBD-derived, HLA-A2-binding peptides were identified and ranked with respect to HLA-A2 affinity, and were used to culture peptide-specific T-cells from HLA-A2+ prostate cancer patients. These T-cell cultures identified peptide-specific T-cells specific for all ten peptides in at least one patient, and T-cells specific for peptides AR805 and AR811 were detected in over half of patients. Peptide-specific CD8+ T-cell clones were then isolated and characterized for prostate cancer cytotoxicity and cytokine expression, identifying that AR805 and AR811 CD8+ T-cell clones could lyse prostate cancer cells in an HLA-A2-restricted fashion, but only AR811 CTL had polyfunctional cytokine expression. Epitopes were confirmed using immunization studies in HLA-A2 transgenic mice, in which the AR LBD is an autologous antigen with an identical protein sequence, which showed that mice immunized with AR811 developed peptide-specific CTL that lyse HLA-A2+ prostate cancer cells. These data show that AR805 and AR811 are HLA-A2-restricted epitopes for which CTL can be commonly detected in prostate cancer patients. Moreover, CTL responses specific for AR811 can be elicited by direct immunization of A2/DR1 mice. These findings suggest that it may be possible to elicit an anti-prostate tumor immune response by augmenting CTL populations using ARLBD-based vaccines. PMID:21350948

  19. Extended use of Prostate Health Index and percentage of [-2]pro-prostate-specific antigen in Chinese men with prostate specific antigen 10–20 ng/mL and normal digital rectal examination

    PubMed Central

    Chiu, Peter Ka-Fung; Teoh, Jeremy Yuen-Chun; Lee, Wai-Man; Yee, Chi-Hang; Chan, Eddie Shu-Yin; Hou, See-Ming

    2016-01-01

    Purpose We investigated the extended use of Prostate Health Index (PHI) and percentage of [-2]pro-prostate-specific antigen (%p2PSA) in Chinese men with prostate-specific antigen (PSA) 10–20 ng/mL and normal digital rectal examination (DRE). Materials and Methods All consecutive Chinese men with PSA 10–20 ng/mL and normal DRE who agreed for transrectal ultrasound (TRUS)-guided 10-core prostate biopsy were recruited. Blood samples were taken immediately before TRUS-guided prostate biopsy. The performances of total PSA (tPSA), %free-to-total PSA (%fPSA), %p2PSA, and PHI were compared using logistic regression, receiver operating characteristic, and decision curve analyses (DCA). Results From 2008 to 2015, 312 consecutive Chinese men were included. Among them, 53 out of 312 (17.0%) men were diagnosed to have prostate cancer on biopsy. The proportions of men with positive biopsies were 6.7% in PHI<35, 22.8% in PHI 35–55, and 54.5% in PHI>55 (chi-square test, p<0.001). The area under curves (AUC) of the base model including age, tPSA and status of initial/repeated biopsy was 0.64. Adding %p2PSA and PHI to the base model improved the AUC to 0.79 (p<0.001) and 0.78 (p<0.001), respectively, and provided net clinical benefit in DCA. The positive biopsy rates of Gleason 7 or above prostate cancers were 2.2% for PHI<35, 7.9% for PHI 35–55, and 36.4% for PHI>55 (chi-square test, p<0.001). By utilizing the PHI cutoff of 35 to men with PSA 10–20 ng/mL and normal DRE, 57.1% (178 of 312) biopsies could be avoided. Conclusions Both PHI and %p2PSA performed well in predicting prostate cancer and high grade prostate cancer. The use of PHI and %p2PSA should be extended to Chinese men with PSA 10–20 ng/mL and normal DRE. PMID:27617315

  20. Extended use of Prostate Health Index and percentage of [-2]pro-prostate-specific antigen in Chinese men with prostate specific antigen 10–20 ng/mL and normal digital rectal examination

    PubMed Central

    Chiu, Peter Ka-Fung; Teoh, Jeremy Yuen-Chun; Lee, Wai-Man; Yee, Chi-Hang; Chan, Eddie Shu-Yin; Hou, See-Ming

    2016-01-01

    Purpose We investigated the extended use of Prostate Health Index (PHI) and percentage of [-2]pro-prostate-specific antigen (%p2PSA) in Chinese men with prostate-specific antigen (PSA) 10–20 ng/mL and normal digital rectal examination (DRE). Materials and Methods All consecutive Chinese men with PSA 10–20 ng/mL and normal DRE who agreed for transrectal ultrasound (TRUS)-guided 10-core prostate biopsy were recruited. Blood samples were taken immediately before TRUS-guided prostate biopsy. The performances of total PSA (tPSA), %free-to-total PSA (%fPSA), %p2PSA, and PHI were compared using logistic regression, receiver operating characteristic, and decision curve analyses (DCA). Results From 2008 to 2015, 312 consecutive Chinese men were included. Among them, 53 out of 312 (17.0%) men were diagnosed to have prostate cancer on biopsy. The proportions of men with positive biopsies were 6.7% in PHI<35, 22.8% in PHI 35–55, and 54.5% in PHI>55 (chi-square test, p<0.001). The area under curves (AUC) of the base model including age, tPSA and status of initial/repeated biopsy was 0.64. Adding %p2PSA and PHI to the base model improved the AUC to 0.79 (p<0.001) and 0.78 (p<0.001), respectively, and provided net clinical benefit in DCA. The positive biopsy rates of Gleason 7 or above prostate cancers were 2.2% for PHI<35, 7.9% for PHI 35–55, and 36.4% for PHI>55 (chi-square test, p<0.001). By utilizing the PHI cutoff of 35 to men with PSA 10–20 ng/mL and normal DRE, 57.1% (178 of 312) biopsies could be avoided. Conclusions Both PHI and %p2PSA performed well in predicting prostate cancer and high grade prostate cancer. The use of PHI and %p2PSA should be extended to Chinese men with PSA 10–20 ng/mL and normal DRE.

  1. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy

    SciTech Connect

    Beyer, David C. . E-mail: dbeyer@azoncology.com; McKeough, Timothy; Thomas, Theresa

    2005-04-01

    Purpose: To review the impact of prior hormonal therapy on 10-year overall and prostate cancer specific survival after primary brachytherapy. Methods and Materials: A retrospective review was performed on the Arizona Oncology Services tumor registry for 2,378 consecutive permanent prostate brachytherapy cases from 1988 through 2001. Hormonal therapy was administered before the implant in 464 patients for downsizing of the prostate or at the discretion of the referring physician. All deceased patients with known clinical recurrence were considered to have died of prostate cancer, irrespective of the immediate cause of death. Risk groups were defined, with 1,135 favorable (prostate-specific antigen [PSA] < 10, Gleason < 7, Stage T1-T2a), 787 intermediate (single adverse feature), and 456 unfavorable (two or more adverse features) patients. Kaplan-Meier actuarial survival curves were generated for both overall and cause-specific survival from the time of treatment. Multivariate analysis was performed to assess the impact of hormonal intervention in comparison with known risk factors of grade, PSA, and age. Results: With follow-up ranging up to 12.6 years and a median of 4.1 year, a total of 474 patients died, with 67 recorded as due to prostate cancer. Overall and cause-specific 10-year survival rates are 43% and 88%, respectively. Overall survival is 44% for the hormone naive patients, compared with 20% for the hormone-treated cohort (p = 0.02). The cancer-specific survival is 89% vs. 81% for the same groups (p = 0.133). Multivariate analysis confirms the significance of age > 70 years (p = 0.0013), Gleason score {>=} 7 (p = 0.0005), and prior hormone use (p = 0.0065) on overall survival. Conclusions: At 10 years, in prostate cancer patients receiving brachytherapy, overall survival is worse in men receiving neoadjuvant hormonal therapy, compared with hormone naive patients. This does not appear to be due to other known risk factors for survival (i.e., stage, grade

  2. Spent Nuclear Fuel (SNF) Project Product Specification

    SciTech Connect

    PAJUNEN, A.L.

    2000-01-20

    This document establishes the limits and controls for the significant parameters that could potentially affect the safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for processing, transport, and storage. The product specifications in this document cover the SNF packaged in Multi-Canister Overpacks to be transported throughout the SNF Project.

  3. Immunohistochemical characterization of 53 monoclonal antibodies to prostate-specific antigen.

    PubMed

    Nap, M; van der Kwast, T M

    1999-01-01

    Fifty-three antibodies submitted to the ISOBM TD-3 Workshop on the prostate specific antigen (PSA) were evaluated for their reactivity in frozen and formalin fixed tissue from benign hyperplastic prostate and salivary gland tissue. Only 13/53 antibodies showed clear reactivity in both frozen and paraffin sections, while some antibodies appeared to react only in formalin-fixed paraffin sections. Many antibodies showed extensive nonspecific reactivity in tissue sections. These results highlight the fact that the number of monoclonal antibodies suitable for immunohistochemical detection of PSA is still relatively limited.

  4. Evaluation of prostatic cancer prevalence in patients with prostatic-specific antigen between 4 and 10 and normal digital rectal examination

    PubMed Central

    Tadayon, Farhad; Arezegar, Hamid Reza; Khorrami, Mohammad Hatef; Hashemi Juzdani, Rasoul; Shahdoost, Amir Abbas; Mellat, Mehdi

    2016-01-01

    Background: Prostate cancer is one of the most common male cancers. The prevalence of prostate cancer is different due to genetic and environmental factors. Diagnosis of prostate cancer is by biopsy due to prostate-specific antigen (PSA) and Digital Rectal Examination (DRE). Controversy about decision making for prostate biopsy in PSA between 4 and 10 and normal DRE, is one of the problems in this time. In this study we evaluated the prevalence of prostate cancer in males with PSA between 4 and 10 and normal DRE. We also evaluated the PSA density and percent of free PSA in patients with prostate cancer. Materials and Methods: A total of 121 males with PSA between 4 and 10 and normal DRE, were evaluated. Then, transrectal ultrasonography (TRUS) andprostate biopsy from 12 points of peripheral zone, was done. These data were analyzed by Chi-square, t-test and ANOVA and Roc curve. Results: In this study, the prevalence of prostate cancer in PSA between 4 and 10 and normal DRE, was evaluated, 29.8%. With use of Roc curve, PSA density cutoff point was calculated 0.12 and percent of free PSA cutoff point, was calculated, 18%. Conclusion: In males with PSA between 4 and 10 and normal DRE, PSA density smaller than 0.12-0.15, and percent of free PSA greater than 18%, the prevalence of prostate cancer is very few and we can safely ignore the TRUS and prostate biopsy in these males and eliminate its costs and side effects. PMID:27403407

  5. Prostate-specific membrane antigen as a target for cancer imaging and therapy

    PubMed Central

    KIESS, A. P.; BANERJEE, S. R.; MEASE, R. C.; ROWE, S. P.; RAO, A.; FOSS, C. A.; CHEN, Y.; YANG, X.; CHO, S. Y.; NIMMAGADDA, S.; POMPER, M. G.

    2016-01-01

    The prostate-specific membrane antigen (PSMA) is a molecular target whose use has resulted in some of the most productive work toward imaging and treating prostate cancer over the past two decades. A wide variety of imaging agents extending from intact antibodies to low-molecular-weight compounds permeate the literature. In parallel there is a rapidly expanding pool of antibody-drug conjugates, radiopharmaceutical therapeutics, small-molecule drug conjugates, theranostics and nanomedicines targeting PSMA. Such productivity is motivated by the abundant expression of PSMA on the surface of prostate cancer cells and within the neovasculature of other solid tumors, with limited expression in most normal tissues. Animating the field is a variety of small-molecule scaffolds upon which the radionuclides, drugs, MR-detectable species and nanoparticles can be placed with relative ease. Among those, the urea-based agents have been most extensively leveraged, with expanding clinical use for detection and more recently for radiopharmaceutical therapy of prostate cancer, with surprisingly little toxicity. PSMA imaging of other cancers is also appearing in the clinical literature, and may overtake FDG for certain indications. Targeting PSMA may provide a viable alternative or first-line approach to managing prostate and other cancers. PMID:26213140

  6. Treatment Outcomes in Non-Metastatic Prostate Cancer Patients With Ultra-High Prostate-Specific Antigen

    SciTech Connect

    Tai, Patricia; Tonita, Jon; Woitas, Carla; Zhu Tong; Joseph, Kurian; Skarsgard, David

    2012-07-15

    Purpose: It is commonly believed that prostate cancer patients with very high prostate-specific antigen (PSA) levels are unlikely to benefit from definitive local treatment, and patients with very high PSA are often underrepresented in, or excluded from, randomized clinical trials. Consequently, little is known about their optimal treatment or prognosis. We performed a registry-based analysis of management and outcome in this population of patients. Methods and Materials: Our provincial Cancer Registry was used to identify all men who were diagnosed with prostate cancer from 1990 to 2001. A retrospective chart review provided information on stage, Gleason score, PSA at diagnosis, and treatment. In this study, ultra-high PSA was defined as PSA of {>=}50 ng/ml. For a more complete perspective, treatment outcomes of patients with PSA of 20 to 49.9 ng/ml were also studied. Results: Of the 8378 men diagnosed with prostate cancer during this period, 6,449 had no known nodal or distant metastatic disease. The median follow-up of this group was 67.2 months (range, 0-192 months). A total of 1534 patients had PSA of {>=}20 ng/ml. Among the 995 patients with PSA 20 to 49.9 ng/ml, 85 had radical prostatectomy (RP), and their 5- and 10-year cause-specific survivals (CSS) were 95% and 84%, respectively. The 497 patients treated with radiotherapy (RT) had 5- and 10-year CSS of 92% and 71%. For the 332 patients with PSA 50-99.9 ng/ml, RT was associated with 5- and 10-year CSS of 81% and 55%. For the 207 patients with PSA of {>=}100 ng/ml, RT was associated with 5- and 10-year CSS of 80% and 54%. Conclusions: This is the largest series in the world on non metastatic cancer patients with ultra-high PSA at diagnosis. Even in the setting of a very high presenting PSA level, prostatectomy and radiotherapy are often associated with prolonged survival.

  7. Prostate-specific Antigen (PSA) Density and Free to Total PSA Ratio in Diagnosing Prostate Cancer with Prostate-Specific Antigen Levels of 4.0 ng/ml or Less

    PubMed Central

    LIU, Xin; TANG, Jie; FEI, Xiang; LI, Qiu-Yang

    2015-01-01

    Background: We aimed to value the usefulness of free to total prostate-specific antigen and Prostate-specific antigen (PSA) density for prostate cancer in the patients with PSA levels of 4.0 ng/ml or less. Methods: A total of 343 subjects with PSA levels of 4.0 ng/ml or less were biopsied. All patients were divided into four groups according to the PSA levels: 0 to 1.0 ng/ml, 1.1 to 2.0 ng/ml, 2.1 to 3.0 ng/ml, and 3.1 to 4.0 ng/ml. The reliability of cancer detection in relation to the f/t PSA ratio and PSAD were estimated. Results: Overall, 65 people were diagnosed with prostate cancer. The detection rate was 16.28%、17.17%, 21.82%, 25.00% in subjects with PSA levels of 0 to 1.0 ng/ml, 1.1 to 2.0 ng/ml, 2.1 to 3.0 ng/ml, and 3.1 to 4.0 ng/ml, respectively. The f/t PSA ratio was significantly lower in patients with prostate cancer and PSA levels of 2.1 to 4.0 ng/ml (P<0.05). The PSAD had no statistical significance between the two groups. Conclusions: Routine prostate biopsy should be undertaken if the f/t PSA ratio less than 15% with /without abnormal DRE/TRUS findings. PMID:26744703

  8. Salvage Radiotherapy for Rising Prostate-Specific Antigen Levels After Radical Prostatectomy for Prostate Cancer: Dose-Response Analysis

    SciTech Connect

    Bernard, Johnny Ray; Buskirk, Steven J.; Heckman, Michael G.; Diehl, Nancy N.; Ko, Stephen J.; Macdonald, Orlan K.; Schild, Steven E.; Pisansky, Thomas M.

    2010-03-01

    Purpose: To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising prostate-specific antigen (PSA) level after radical prostatectomy. Methods and Materials: We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy). Results: A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). Conclusions: Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.

  9. Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody.

    PubMed

    Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Jhanwar, Yuliya S; Kaur, Gurveen; Tagawa, Scott T; Nanus, David M; Bander, Neil H; Goldsmith, Stanley J

    2016-01-01

    Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.

  10. Prostate cancer nodal oligometastasis accurately assessed using prostate-specific membrane antigen positron emission tomography-computed tomography and confirmed histologically following robotic-assisted lymph node dissection

    PubMed Central

    O’Kane, Dermot B.; Lawrentschuk, Nathan; Bolton, Damien M.

    2016-01-01

    We herein present a case of a 76-year-old gentleman, where prostate-specific membrane antigen positron emission tomography-computed tomography (PSMA PET-CT) was used to accurately detect prostate cancer (PCa), pelvic lymph node (LN) metastasis in the setting of biochemical recurrence following definitive treatment for PCa. The positive PSMA PET-CT result was confirmed with histological examination of the involved pelvic LNs following pelvic LN dissection. PMID:27141207

  11. Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

    PubMed Central

    Chatalic, Kristell L.S.; Heskamp, Sandra; Konijnenberg, Mark; Molkenboer-Kuenen, Janneke D.M.; Franssen, Gerben M.; Clahsen-van Groningen, Marian C.; Schottelius, Margret; Wester, Hans-Jürgen; van Weerden, Wytske M.; Boerman, Otto C.; de Jong, Marion

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics—they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA. PMID:27162555

  12. Prostate-Specific Antigen (PSA)–Based Population Screening for Prostate Cancer: An Evidence-Based Analysis

    PubMed Central

    Pron, G

    2015-01-01

    Background Prostate cancer (PC) is the most commonly diagnosed non-cutaneous cancer in men and their second or third leading cause of cancer death. Prostate-specific antigen (PSA) testing for PC has been in common practice for more than 20 years. Objectives A systematic review of the scientific literature was conducted to determine the effectiveness of PSA-based population screening programs for PC to inform policy decisions in a publicly funded health care system. Data Sources A systematic review of bibliographic databases was performed for systematic reviews or randomized controlled trials (RCT) of PSA-based population screening programs for PC. Review Methods A broad search strategy was employed to identify studies reporting on key outcomes of PC mortality and all-cause mortality. Results The search identified 5 systematic reviews and 6 RCTs. None of the systematic reviews found a statistically significant reduction in relative risk (RR) of PC mortality or overall mortality with PSA-based screening. PC mortality reductions were found to vary by country, by screening program, and by age of men at study entry. The European Randomized Study of Screening for Prostate Cancer found a statistically significant reduction in RR in PC mortality at 11-year follow-up (0.79; 95% CI, 0.67–0.92), although the absolute risk reduction was small (1.0/10,000 person-years). However, the primary treatment for PCs differed significantly between countries and between trial arms. The American Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) found a statistically non-significant increase in RR for PC mortality with 13-year follow-up (1.09; 95% CI, 0.87–1.36). The degree of opportunistic screening in the control arm of the PLCO trial, however, was high. None of the RCTs found a reduction in all-cause mortality and all found a statistically significant increase in the detection of mainly low-risk, organ-confined PCs in the screening arm. Conclusions There was no

  13. Specific Pomegranate Juice Components as Potential Inhibitors of Prostate Cancer Metastasis12

    PubMed Central

    Wang, Lei; Ho, Jeffrey; Glackin, Carlotta; Martins-Green, Manuela

    2012-01-01

    Pomegranate juice (PJ) is a natural product that inhibits prostate cancer progression. A clinical trial on patients with recurrent prostate cancer resulted in none of the patients progressing to a metastatic stage during the period of the trial. We have previously found that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also markedly increases adhesion and decreases migration of the cells that do not die. However, because PJ is a very complex mixture of components and is found in many different formulations, it is important to identify specific components that are effective in inhibiting growth and metastasis. Here, we show that the PJ components luteolin, ellagic acid, and punicic acid together inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and inhibit their migration and their chemotaxis toward stromal cell-derived factor 1α (SDF1α), a chemokine that is important in prostate cancer metastasis to the bone. These components also increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control and cell migration. Furthermore, they increase several well-known tumor-suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis. Our results suggest that these components may be more effective in inhibiting prostate cancer growth and metastasis than simply drinking the juice. Chemical modification of these components could further enhance their bioavailability and efficacy of treatment. Moreover, because the mechanisms of metastasis are similar for most cancers, these PJ components may also be effective in the treatment of metastasis of other cancers. PMID:23066443

  14. Screening and Characterization of a Novel RNA Aptamer That Specifically Binds to Human Prostatic Acid Phosphatase and Human Prostate Cancer Cells

    PubMed Central

    Kong, Hoon Young; Byun, Jonghoe

    2015-01-01

    Prostatic acid phosphatase (PAP) expression increases proportionally with prostate cancer progression, making it useful in prognosticating intermediate to high-risk prostate cancers. A novel ligand that can specifically bind to PAP would be very helpful for guiding prostate cancer therapy. RNA aptamers bind to target molecules with high specificity and have key advantages such as low immunogenicity and easy synthesis. Here, human PAP-specific aptamers were screened from a 2′-fluoropyrimidine (FY)-modified RNA library by SELEX. The candidate aptamer families were identified within six rounds followed by analysis of their sequences and PAP-specific binding. A gel shift assay was used to identify PAP binding aptamers and the 6N aptamer specifically bound to PAP with a Kd value of 118 nM. RT-PCR and fluorescence labeling analyses revealed that the 6N aptamer bound to PAP-positive mammalian cells, such as PC-3 and LNCaP. IMR-90 negative control cells did not bind the 6N aptamer. Systematic minimization analyses revealed that 50 nucleotide sequences and their two hairpin structures in the 6N 2′-FY RNA aptamer were equally important for PAP binding. Renewed interest in PAP combined with the versatility of RNA aptamers, including conjugation of anti-cancer drugs and nano-imaging probes, could open up a new route for early theragnosis of prostate cancer. PMID:25591398

  15. High expression of a specific T-cell receptor γ transcript in epithelial cells of the prostate

    PubMed Central

    Essand, Magnus; Vasmatzis, George; Brinkmann, Ulrich; Duray, Paul; Lee, Byungkook; Pastan, Ira

    1999-01-01

    We have identified expression of T-cell receptor γ chain (TCRγ) mRNA in human prostate and have shown that it originates from epithelial cells of the prostate and not from infiltrating T-lymphocytes. In contrast, the T-cell receptor δ chain (TCRδ) gene is silent in human prostate. The major TCRγ transcript in prostate has a different size than the transcript expressed in thymus, spleen, and blood leukocytes. It is expressed in normal prostate epithelium, adenocarcinoma of the prostate, and the prostatic adenocarcinoma cell line LNCaP. The RNA originates from an unrearranged TCRγ locus, and it is initiated within the intronic sequence directly upstream of the Jγ1.2 gene segment. The prostate-specific TCRγ transcript consists of the Jγ1.2 and Cγ1 gene segments, and it has an untranslated sequence including a polyadenylation signal and poly(A) sequence at the 3′end. The finding that prostate epithelial cells express a high level of a transcript from a gene that was thought to by exclusively expressed by T-lymphocytes is highly unexpected. PMID:10430935

  16. Ultrahigh Specific Impulse Nuclear Thermal Propulsion

    SciTech Connect

    Anne Charmeau; Brandon Cunningham; Samim Anghaie

    2009-02-09

    Research on nuclear thermal propulsion systems (NTP) have been in forefront of the space nuclear power and propulsion due to their design simplicity and their promise for providing very high thrust at reasonably high specific impulse. During NERVA-ROVER program in late 1950's till early 1970's, the United States developed and ground tested about 18 NTP systems without ever deploying them into space. The NERVA-ROVER program included development and testing of NTP systems with very high thrust (~250,000 lbf) and relatively high specific impulse (~850 s). High thrust to weight ratio in NTP systems is an indicator of high acceleration that could be achieved with these systems. The specific impulse in the lowest mass propellant, hydrogen, is a function of square root of absolute temperature in the NTP thrust chamber. Therefor optimizing design performance of NTP systems would require achieving the highest possible hydrogen temperature at reasonably high thrust to weight ratio. High hydrogen exit temperature produces high specific impulse that is a diret measure of propellant usage efficiency.

  17. Repeated spurious elevation of serum prostate-specific antigen values solved by chemiluminescence analysis: A possible interference by heterophilic antibodies

    PubMed Central

    Bayó, Miquel; Muñoz-Rodríguez, Jesús; Bellido, Jose Antonio; Abascal-Junquera, Jose María; Hannaoui, Naim; Banús, Josep Maria

    2015-01-01

    Heterophilic antibodies are human immunoglobulins directed against various animal antigens. They can produce false-positive results in the analysis of different tumor markers, including prostate-specific antigen. This interference can lead to misdiagnosis, unnecessary tests, and overtreatment in some cases. We present herein the case of a 52-year-old man with repeated spurious elevation of prostate-specific antigen, reaching levels of 108.7 ng/mL, that were suspected to be caused by heterophilic antibodies. The interference was solved by changing the analysis technique. Real values of prostate-specific antigen were less than 1 ng/mL. PMID:26568798

  18. SU-E-T-603: PBS Prostate Plan Robustness: A Tool for Patient Specific Setup Tolerance

    SciTech Connect

    Tang, S; Song, L; Chen, C; Chang, C; Chon, B; Tsai, H; Soffen, E; Cahlon, O; Mah, D

    2015-06-15

    Purpose: Fiducial markers are commonly used for setup of prostate patients using orthogonal radiographs. After aligned with the markers, the displacement of the bony anatomy relative to the planned DRR can be up to 10 mm. Such offset can potentially have significant dosimetric effects because it changes the radiological path length of protons in differing amounts of bone. It is imperative to develop a method to evaluate its impact on target coverage and hence establish patient specific setup tolerance for prostate proton PBS treatment. Methods: Prostate patients were planned in RayStation according to the PCG protocol with bi-lateral beams. The primary planning objectives are: (1) 100% of CTV receives full prescription dose; (2) 98% of the prescription dose covers at least 98% of the PTV; (3) OARs meet criteria per protocol. For each patient 108 dose perturbations were automatically generated using an in-house script, which considered the isocenter shifting in S-I and A-P directions (up to ±15 mm with an interval of 6mm) as well as the range uncertainty (±3.5%). The target coverage was evaluated on the contour shifted along with prostate to mimic the daily treatment. Results: The minimum CTV coverage as a function of offsets in S-I and A-P directions is presented in a 2D contour map. The offsets along A-P direction generally have greater impact than along S-I direction. Both the CTV D98%>98% or CTV V98%>98% are achievable for most patients if the offset is <10 mm in either direction despite of range uncertainties. Conclusion: We developed a method to evaluate the plan robustness for proton PBS prostate treatment. It can provide patient specific setup tolerance of bony structure offset. For our current planning approach, a 1 cm displacement is acceptable. This approach can be generalized to other target structures that move relative to bony anatomy.

  19. Prostate-specific targeting of the aqueous root extract of Croton membranaceus in experimental animals.

    PubMed

    Afriyie, D K; Asare, G A; Bugyei, K; Asiedu-Gyekye, I J; Tackie, R; Adjei, S

    2014-09-01

    Croton membranaceus Müll.Arg. (Euphorbiaceae) is used for benign prostate hyperplasia (BPH) treatment. The study aimed at investigating organs that the aqueous root extracts of C. membranaceus (CMARE) target, which is absent in literature. Twenty-four male Sprague-Dawley rats (100-140 g) were randomly divided into 4 groups. Group 1, the control group received distilled water. Groups 2, 3 and 4 received 30, 150 and 300 mg kg(-1) b.wt CMARE respectively (oral gavage). Rats fed 90 days the standard chow diet ad libitum. Upon sacrifice, major organs were histologically examined and serum prostate-specific antigen (PSA) biochemically determined. Only the prostate was abnormal. Histologically, H&E staining revealed thickness and infoldings of the epithelial cells shrinking with increasing dose. The 30 mg kg(-1) group showed low columnar or flattened epithelium cells, whereas the columnar epithelium infoldings of the 150 mg kg(-1) b.wt and 300 mg kg(-1) b.wt groups were virtually nonexistent. The acini of the control, 30 mg kg(-1) b.wt group and the 150 mg kg(-1) b.wt groups showed clear pinkish secretion. However, secretion of the high-dose group appeared light pink in colour and the stroma cells appeared much darker than all the treated and control group. C. membranaceus targets the prostate with significant PSA reduction (P < 0.01).

  20. Systematic meta-analyses of gene-specific genetic association studies in prostate cancer

    PubMed Central

    Hao, Qiang; Wei, Dong; Zhang, Yaoguang; Chen, Xin; Yang, Fan; Yang, Ze; Zhu, Xiaoquan; Wang, Jianye

    2016-01-01

    In the past twenty-five years, over 700 case-control association studies on the risk of prostate cancer have been published worldwide, but their results were largely inconsistent. To facilitate following and explaining these findings, we performed a systematic meta-analysis using allelic contrasts for gene-specific SNVs from at least three independent population-based case-control studies, which were published in the field of prostate cancer between August 1, 1990 and August 1, 2015. Across 66 meta-analyses, a total of 20 genetic variants involving 584,100 subjects in 19 different genes (KLK3, IGFBP3, ESR1, SOD2, CAT, CYP1B1, VDR, RFX6, HNF1B, SRD5A2, FGFR4, LEP, HOXB13, FAS, FOXP4, SLC22A3, LMTK2, EHBP1 and MSMB) exhibited significant association with prostate cancer. The average summary OR was 1.33 (ranging from: 1.016–3.788) for risk alleles and 0.838 (ranging from: 0.757–0.896) for protective alleles. Of these positive variants, FOXP4 rs1983891, LMTK2 rs6465657 and RFX6 rs339331 had not been previously meta-analyzed. Further analyses with sufficient power design and investigations of the potential biological roles of these genetic variants in prostate cancer should be conducted. PMID:26967244

  1. Spent nuclear fuel project product specification

    SciTech Connect

    Pajunen, A.L.

    1998-01-30

    Product specifications are limits and controls established for each significant parameter that potentially affects safety and/or quality of the Spent Nuclear Fuel (SNF) packaged for transport to dry storage. The product specifications in this document cover the spent fuel packaged in MultiCanister Overpacks (MCOs) to be transported throughout the SNF Project. The SNF includes N Reactor fuel and single-pass reactor fuel. The FRS removes the SNF from the storage canisters, cleans it, and places it into baskets. The MCO loading system places the baskets into MCO/Cask assembly packages. These packages are then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the MCO cask packages are transferred to the Canister Storage Building (CSB), where the MCOs are removed from the casks, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The key criteria necessary to achieve these goals are documented in this specification.

  2. Rapid and specific electrochemical detection of prostate cancer cells using an aperture sensor array.

    PubMed

    Moscovici, Mario; Bhimji, Alyajahan; Kelley, Shana O

    2013-03-01

    A rapid, simple and specific cancer cell counting sensor would allow for early detection and better disease management. We have developed a novel cell counting device that can specifically count 125 prostate cancer cells in both complex media with serum and a mixed cell population containing non-target cells within 15 min. The microfabricated glass chip with exposed gold apertures utilizes the anti-EpCAM antibody to selectively count prostate cancer cells via differential pulse voltammetry. The newly developed sensor exhibits excellent sensitivity and selectivity. The cells remain viable throughout the counting process and can be used for further analysis. This device could have utility for future applications in early stage cancer diagnosis.

  3. Predicting Gleason score using the initial serum total prostate-specific antigen in Black men with symptomatic prostate adenocarcinoma in Nigeria

    PubMed Central

    Nnabugwu, Ikenna I; Udeh, Emeka I; Ugwumba, Fredrick O; Ozoemena, Francis O

    2016-01-01

    Background Men of Black African descent are known to have the highest incidence of prostate cancer. The disease is also more aggressive in this group possibly due to biologically more aggressive tumor or late presentation. Currently, serum prostate-specific antigen (PSA) assay plays a significant role in making the diagnosis of prostate cancer. However, the obtained value of serum PSA may not directly relate with the Gleason score (GS), a measure of tumor aggression in prostate cancer. This study explores the relationship between serum total PSA at presentation (iPSA) and GS. Patients and methods The iPSA of patients with histologically confirmed prostate cancer was compared with the obtained GS of the prostate biopsy specimens. The age of the patients at presentation and the prostate volumes were also analyzed with respect to the iPSA and GS. The data were analyzed retrospectively using IBM SPSS Version 20. Pearson correlation was used for numeric variables, whereas Fisher’s exact test was used for categorical variables. Significance was set at P≤0.05. Results There were 205 patients from January 2010 to November 2013 who satisfied the inclusion criteria. iPSA as well as age at presentation and prostate volume were not found to significantly correlate with the primary Gleason grade, the secondary Gleason grade, or the GS. However, the presence of distant metastasis was identified to significantly correlate positively with GS. Conclusion GS may not be confidently predicted by the iPSA. Higher iPSA does not correlate with higher GS and vice versa. PMID:27486316

  4. CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

    PubMed

    Ishikura, Nobuyuki; Kawata, Hiromitsu; Nishimoto, Ayako; Nakamura, Ryo; Tsunenari, Toshiaki; Watanabe, Miho; Tachibana, Kazutaka; Shiraishi, Takuya; Yoshino, Hitoshi; Honma, Akie; Emura, Takashi; Ohta, Masateru; Nakagawa, Toshito; Houjo, Takao; Corey, Eva; Vessella, Robert L; Aoki, Yuko; Sato, Haruhiko

    2015-04-01

    Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH

  5. Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI

    NASA Astrophysics Data System (ADS)

    Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing; Yang, Jenny J.

    2016-06-01

    Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 × 10-22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM-1 s-1 and r2 of 37.9 mM-1 s-1 per Gd (55.2 and 75.8 mM-1 s-1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM-1 s-1 per Gd (188.0 mM-1 s-1 per molecule) and r1 of 18.6 mM-1 s-1 per Gd (37.2 mM-1 s-1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high

  6. Crystal structure of human prostate-specific antigen in a sandwich antibody complex.

    PubMed

    Stura, Enrico A; Muller, Bruno H; Bossus, Marc; Michel, Sandrine; Jolivet-Reynaud, Colette; Ducancel, Frédéric

    2011-12-01

    Human prostate-specific antigen (PSA or human kallikrein-related peptidase 3) present in small quantities in the sera of healthy men becomes elevated in prostate cancer (PCa) and other prostate disorders. The ability to identify the free PSA fraction associated with PCa could increase the reliability of the PSA diagnostic test. Here we present the crystal structure of human PSA from seminal fluid in a sandwich complex with two monoclonal antibodies (mAbs). MAb 5D5A5 captures total PSA with exceptionally high affinity, and mAb 5D3D11 selectively discriminates between free PSA subforms that are more abundant in sera from patients with PCa. Although the antigen is not of seric origin, several insights into cancer diagnosis can be discerned from this complex. MAb 5D3D11 recognizes a PSA conformation different from that previously reported. Interacting with the kallikrein loop, the PSA N-linked glycan attached to asparagine 61 is an uncommonly complex sialated triantennary chain. O-linked glycosylation is observed at threonine 125. The description of how PSA subforms in prostatic fluid can be discriminated using pairs of antibodies is a first step in the design of new strategies that are capable of real discrimination among PSA subforms, which will lead to the formulation of more reliable diagnostic tests. In a companion article [Muller, B. H., Savatier, A., L'Hostis, G., Costa, N., Bossus, M., Michel, S., et al. (2011). In vitro affinity maturation of an anti-PSA antibody for prostate cancer diagnostic assay. J. Mol. Biol.], we describe engineering efforts to improve the affinity of mAb 5D3D11, a first step towards such goal. PMID:22037582

  7. PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges

    PubMed Central

    Rowe, SP; Gorin, MA; Allaf, ME; Pienta, KJ; Tran, PT; Pomper, MG; Ross, AE; Cho, SY

    2016-01-01

    BACKGROUND Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies. METHODS A great deal of progress has been made in defining the clinical utility of this class of PET agents through predominantly small and retrospective clinical studies. The most compelling data to date has been in the setting of biochemically recurrent PCa, where PSMA-targeted radiotracers have been found to be superior to conventional imaging and other molecular imaging agents for the detection of locally recurrent and metastatic PCa. RESULTS Early data, however, suggest that initial lymph node staging before definitive therapy in high-risk primary PCa patients may be limited, although intraoperative guidance may still hold promise. Other examples of potential promising applications for PSMA PET imaging include non-invasive characterization of primary PCa, staging and treatment planning for PSMA-targeted radiotherapeutics, and guidance of focal therapy for oligometastatic disease. CONCLUSIONS However, all of these indications and applications for PCa PSMA PET imaging are still lacking and require large, prospective, systematic clinical trials for validation. Such validation trials are needed and hopefully will be forthcoming as the fields of molecular imaging, urology, radiation oncology and medical oncology continue to define and refine the utility of PSMA-targeted PET imaging to improve the management of PCa patients. PMID:27136743

  8. Results of a study to correlate serum prostate specific antigen and reproductive hormone levels in patients with localized prostate cancer.

    PubMed Central

    Vijayakumar, S.; Quadri, S. F.; Dong, L.; Ignacio, L.; Kathuria, I. N.; Sutton, H.; Halpern, H.

    1995-01-01

    This cross-sectional study was undertaken to determine whether serum hormones (free testosterone, androstenedione, luteinizing hormone, or prolactin) have any influence on serum prostate specific antigen (PSA) levels in patients with stage A-C prostate cancer. Blood samples were collected prior to any treatment in 36 patients; in 19 (group 1), three blood samples were collected 10 minutes apart between 9:00 AM and 9:30 AM for each patient and pooled together to avoid diurnal and episodic variation in serum testosterone values. In the remaining patients, only one sample could be collected (group 2). Free testosterone, androstenedione, luteinizing hormone, prolactin, and PSA levels were determined with appropriate radioimmunoassay techniques. Statistical analyses were performed separately for groups 1 and 2, and then with pooled data. None of the hormones in any of the analyses showed any association to serum PSA values except for prolactin for the pooled data and for group 2. This statistical significance for prolactin disappeared on multivariate analysis. There were 21 African-American men and 15 whites in the study; no racial differences in hormonal levels were found except for lower luteinizing hormone levels in African Americans in group 2 and pooled data. No differences were found between group 1 and group 2 in the mean serum prolactin and luteinizing hormone values. Serum free testosterone, androstenedione, and luteinizing hormone appeared to have no influence on serum PSA values in nonmetastatic cancer patients. Serum prolactin values were inversely associated with PSA values in univariate analysis for the pooled data; this disappeared in multivariate analysis. Unlike other studies that found higher serum testosterone levels in African-American college students than whites, no such differences were seen in this age group. Luteinizing hormone was lower in African-American men than in whites in the pooled study population. Further studies are needed to clarify

  9. Identification of specific DNA methylation sites on the Y-chromosome as biomarker in prostate cancer.

    PubMed

    Yao, Lushuai; Ren, Shancheng; Zhang, Minjie; Du, Fengxia; Zhu, Yasheng; Yu, Hui; Zhang, Chenyu; Li, Xiaohua; Yang, Caiyun; Liu, Huixian; Wang, Dong; Meng, Hao; Chang, Shuang; Han, Xiao; Sun, Yinghao; Sun, Yingli

    2015-12-01

    As a diagnostic biomarker, prostate special antigen (PSA) tests always generate false positive results and lead to unnecessary and/or repeat biopsies. Therefore, there is an urgent need for developing more sensitive, specific diagnostic biomarkers. We epigenotyped methylated sites in cancer tissues and adjacent normal tissues from 66 patients. In comparison with normal adjacent tissues, we observed that there were 6 aberrant methylation sites in prostate cancer tissues on the Y-chromosome. We further performed pyrosequencing using urine of PCa patients and we identified one methylated site (cg05163709) as a potential biomarker. We evaluated the predictive capacity of the aberrant methylated sites using the area under receiver operating characteristic (ROC) curve (AUC). The ROC analysis showed a higher AUC for cg05163709 (0.915) than prostate-specific antigen (PSA, 0.769). These results indicated that aberrant DNA methylation of cg05163709 on the Y-chromosome could serve as a potential diagnostic biomarker with high sensitivity and specificity.

  10. Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer

    PubMed Central

    Böttcher, René; Hoogland, A. Marije; Dits, Natasja; Verhoef, Esther I.; Kweldam, Charlotte; Waranecki, Piotr; Bangma, Chris H.; van Leenders, Geert J.L.H.; Jenster, Guido

    2015-01-01

    Current prostate cancer (PCa) biomarkers such as PSA are not optimal in distinguishing cancer from benign prostate diseases and predicting disease outcome. To discover additional biomarkers, we investigated PCa-specific expression of novel unannotated transcripts. Using the unique probe design of Affymetrix Human Exon Arrays, we identified 334 candidates (EPCATs), of which 15 were validated by RT-PCR. Combined into a diagnostic panel, 11 EPCATs classified 80% of PCa samples correctly, while maintaining 100% specificity. High specificity was confirmed by in situ hybridization for EPCAT4R966 and EPCAT2F176 (SChLAP1) on extensive tissue microarrays. Besides being diagnostic, EPCAT2F176 and EPCAT4R966 showed significant association with pT-stage and were present in PIN lesions. We also found EPCAT2F176 and EPCAT2R709 to be associated with development of metastases and PCa-related death, and EPCAT2F176 to be enriched in lymph node metastases. Functional significance of expression of 9 EPCATs was investigated by siRNA transfection, revealing that knockdown of 5 different EPCATs impaired growth of LNCaP and 22RV1 PCa cells. Only the minority of EPCATs appear to be controlled by androgen receptor or ERG. Although the underlying transcriptional regulation is not fully understood, the novel PCa-associated transcripts are new diagnostic and prognostic markers with functional relevance to prostate cancer growth. PMID:25686826

  11. All care, but whose responsibility? Community juries reason about expert and patient responsibilities in prostate-specific antigen screening for prostate cancer.

    PubMed

    Degeling, Chris; Carter, Stacy M; Rychetnik, Lucie

    2016-09-01

    General practitioners have implicitly been given responsibility for guiding men's decisions about prostate-specific antigen-based screening for prostate cancer, but patients' expectations of the bounds of this responsibility remain unclear. We sought to explore how well-informed members of the public allocate responsibilities in prostate-specific antigen screening decision-making. In 2014, we convened two Community juries in Sydney, Australia, to address questions related to the content and timing of information provision and respective roles of patients and general practitioners in screening decisions. Participants in the first jury were of mixed gender and of all ages (n = 15); the participants in the second jury were all male and of screening age (n = 12). Both juries were presented with balanced factual evidence on the harms and benefits of prostate-specific antigen screening and expert perspectives on ethico-legal aspects of consent in medical practice. In their deliberations, jurors agreed that general practitioners should take responsibility for informing men of the options, risks and benefits of prostate-specific antigen testing, but arrived at different positions on whether or not general practitioners should also guide screening decisions. Jurors also disagreed on how much and when general practitioners should provide detailed information about biopsies and treatments. These responses suggest that for prostate-specific antigen testing, there is a public expectation that both the allocation of responsibility between general practitioners and their male patients, and the level of information provided will be tailored to individual men. In the presence of expert uncertainty, a well-informed public may have reason to embrace or resist shared decision-making processes. PMID:27491944

  12. Prostate specific antigen detection using AlGaN /GaN high electron mobility transistors

    NASA Astrophysics Data System (ADS)

    Kang, B. S.; Wang, H. T.; Lele, T. P.; Tseng, Y.; Ren, F.; Pearton, S. J.; Johnson, J. W.; Rajagopal, P.; Roberts, J. C.; Piner, E. L.; Linthicum, K. J.

    2007-09-01

    Antibody-functionalized Au-gated AlGaN /GaN high electron mobility transistors (HEMTs) were used to detect prostate specific antigen (PSA). The PSA antibody was anchored to the gate area through the formation of carboxylate succinimdyl ester bonds with immobilized thioglycolic acid. The AlGaN /GaN HEMT drain-source current showed a rapid response of less than 5s when target PSA in a buffer at clinical concentrations was added to the antibody-immobilized surface. The authors could detect a wide range of concentrations from 10pg/mlto1μg/ml. The lowest detectable concentration was two orders of magnitude lower than the cutoff value of PSA measurements for clinical detection of prostate cancer. These results clearly demonstrate the promise of portable electronic biological sensors based on AlGaN /GaN HEMTs for PSA screening.

  13. ⁶⁴Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer.

    PubMed

    Banerjee, Sangeeta Ray; Pullambhatla, Mrudula; Foss, Catherine A; Nimmagadda, Sridhar; Ferdani, Riccardo; Anderson, Carolyn J; Mease, Ronnie C; Pomper, Martin G

    2014-03-27

    Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five (64)Cu-labeled inhibitors of PSMA, [(64)Cu]3-7, which are based on the lysine-glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [(64)Cu]3-7 were prepared in high radiochemical yield (60-90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [(64)Cu]3-7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA- PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [(64)Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [(64)Cu]CB-TE2A as compared with [(64)Cu]NOTA, [(64)Cu]PCTA, [(64)Cu]Oxo-DO3A, and [(64)Cu]DOTA chelates in vivo.

  14. Aberrant sialylation of a prostate-specific antigen: Electrochemical label-free glycoprofiling in prostate cancer serum samples.

    PubMed

    Pihikova, Dominika; Kasak, Peter; Kubanikova, Petra; Sokol, Roman; Tkac, Jan

    2016-08-31

    Electrochemical detection method allowing to detect prostate-specific antigen (PSA), a biomarker of prostate cancer (PCa), with PSA glycoprofiling was applied in an analysis of PCa serum samples for the first time. Electrochemical impedance spectroscopy (EIS) as a label-free method with immobilized anti-PSA was applied for PSA detection and lectins to glycoprofile captured PSA on the same surface. A proper choice of blocking agent providing high selectivity of biosensor detection with the immobilized anti-PSA antibody was done. The biosensor could detect PSA down to 100 ag/mL with a linear concentration working range from 100 ag/mL up to 1 μg/mL, i.e. 10 orders of concentration magnitude and the sensitivity of (5.5 ± 0.2)%/decade. The results showed that a commercial carbo-free blocking solution was the best one, reducing non-specific binding 55-fold when compared to the immunosensor surface without any blocking agent applied, while allowing to detect PSA. The biosensor response obtained after addition of lectin (i.e. proportional to the amount of a particular glycan on PSA) divided by the biosensor response obtained after incubation with a sample (i.e. proportional to the PSA level in the sample) was applied to distinguish serum samples of PCa patients from those of healthy individuals. The results showed that Maackia amurensis agglutinin (MAA) recognizing α-2,3-terminal sialic acid can be applied to distinguish between these two sets of samples since the MAA/PSA response obtained from the analysis of the PCa samples was significantly higher (5.3-fold) compared to the MAA/PSA response obtained by the analysis of samples from healthy individuals. Thus, combined analysis of serological PSA levels together with PSA glycoprofiling of aberrant glycosylation of PSA (i.e. increase in the level of α-2,3-terminal sialic acid) has a potential to improve detection of PCa. PMID:27506346

  15. The Prostate Specific Membrane Antigen Regulates the Expression of IL-6 and CCL5 in Prostate Tumour Cells by Activating the MAPK Pathways1

    PubMed Central

    Colombatti, Marco; Fracasso, Giulio; Scupoli, Maria Teresa; Cingarlini, Sara; Poffe, Ornella; Naim, Hassan Y.; Heine, Martin; Tridente, Giuseppe; Mainiero, Fabrizio; Ramarli, Dunia

    2009-01-01

    The interleukin-6 (IL-6) and the chemokine CCL5 are implicated in the development and progression of several forms of tumours including that of the prostate. The expression of the prostate specific membrane antigen (PSMA) is augmented in high-grade and metastatic tumors. Observations of the clinical behaviour of prostate tumors suggest that the increased secretion of IL-6 and CCL5 and the higher expression of PSMA may be correlated. We hypothesized that PSMA could be endowed with signalling properties and that its stimulation might impact on the regulation of the gene expression of IL-6 and CCL5. We herein demonstrate that the cross-linking of cell surface PSMA with specific antibodies activates the small GTPases RAS and RAC1 and the MAPKs p38 and ERK1/2 in prostate carcinoma LNCaP cells. As downstream effects of the PSMA-fostered RAS-RAC1-MAPK pathway activation we observed a strong induction of NF-κB activation associated with an increased expression of IL-6 and CCL5 genes. Pharmacological blockade with specific inhibitors revealed that both p38 and ERK1/2 participate in the phenomenon, although a major role exerted by p38 was evident. Finally we demonstrate that IL-6 and CCL5 enhanced the proliferative potential of LNCaP cells synergistically and in a dose-dependent manner and that CCL5 functioned by receptor-mediated activation of the STAT5-Cyclin D1 pro-proliferative pathway. The novel functions attributable to PSMA which are described in the present report may have profound influence on the survival and proliferation of prostate tumor cells, accounting for the observation that PSMA overexpression in prostate cancer patients is related to a worse prognosis. PMID:19242540

  16. Spent Nuclear Fuel (SNF) Project Product Specification

    SciTech Connect

    PAJUNEN, A.L.

    2000-12-07

    The process for removal of Spent Nuclear Fuel (SNF) from the K Basins has been divided into major sub-systems. The Fuel Retrieval System (FRS) removes fuel from the existing storage canisters, cleans it, and places it into baskets. The multi-canister overpack (MCO) loading system places the baskets into an MCO that has been pre-loaded in a cask. The cask, containing a loaded MCO, is then transferred to the Cold Vacuum Drying (CVD) Facility. After drying at the CVD Facility, the cask, and MCO, are transferred to the Canister Storage Building (CSB), where the MCO is removed from the cask, staged, inspected, sealed (by welding), and stored until a suitable permanent disposal option is implemented. The purpose of this document is to specify the process related characteristics of an MCO at the interface between major process systems. The characteristics are derived from the primary technical documents that form the basis for safety analysis and design calculations. This document translates the calculation assumptions into implementation requirements and describes the method of verifying that the requirement is achieved. These requirements are used to define validation test requirements and describe requirements that influence multiple sub-project safety analysis reports. This product specification establishes limits and controls for each significant process parameter at interfaces between major sub-systems that potentially affect the overall safety and/or quality of the SNF packaged for processing, transport, and interim dry storage. The product specifications in this document cover the SNF packaged in MCOs to be transported throughout the SNF Project. The description of the product specifications are organized in the document as follows: Section 2.0--Summary listing of product specifications at each major sub-system interface. Section 3.0--Summary description providing guidance as to how specifications are complied with by equipment design or processing within a major

  17. Three-dimensional conformal external beam radiotherapy compared with permanent prostate implantation in low-risk prostate cancer based on endorectal magnetic resonance spectroscopy imaging and prostate-specific antigen level

    SciTech Connect

    Pickett, Barby . E-mail: pickett@radonc17.ucsf.edu; Kurhanewicz, John; Pouliot, Jean; Weinberg, Vivian; Shinohara, Katsuto; Coakley, Fergus; Roach, Mack

    2006-05-01

    Purpose: To evaluate the metabolic response by comparing the time to resolution of spectroscopic abnormalities (TRSA) and the time to prostate-specific antigen level in low-risk prostate cancer patients after treatment with three-dimensional conformal external beam radiotherapy (3D-CRT) compared with permanent prostate implantation (PPI). Recent studies have suggested that the treatment of low-risk prostate cancer yields similar results for patients treated with 3D-CRT or PPI. Methods and Materials: A total of 50 patients, 25 in each group, who had been treated with 3D-CRT or PPI, had undergone endorectal magnetic resonance spectroscopy imaging before and/or at varying times after therapy. The 3D-CRT patients had received radiation doses of {>=}72 Gy compared with 144 Gy for the PPI patients. The spectra from all usable voxels were examined for detectable levels of metabolic signal, and the percentages of atrophic and cancerous voxels were tabulated. Results: The median time to resolution of the spectroscopic abnormalities was 32.2 and 24.8 months and the time to the nadir prostate-specific antigen level was 52.4 and 38.0 months for the 3D-CRT and PPI patients, respectively. Of the 3D-CRT patients, 92% achieved negative endorectal magnetic resonance spectroscopy imaging findings, with 40% having complete metabolic atrophy. All 25 PPI patients had negative endorectal magnetic resonance spectroscopy imaging findings, with 60% achieving complete metabolic atrophy. Conclusion: The results of this study suggest that metabolic and biochemical responses of the prostate are more pronounced after PPI. Our results have not proved PPI is more effective at curing prostate cancer, but they have demonstrated that it may be more effective at destroying prostate metabolism.

  18. Presentation of a functional pituitary adenoma as a significant decrease in prostate-specific antigen level in a patient followed for prostate cancer.

    PubMed

    Grotas, Aaron B; Nagler, Harris M

    2006-12-01

    The stimulatory role of testosterone in the production and release of prostate-specific antigen (PSA) has been well characterized. Testosterone production by the testes is dependent on a functional hypothalamic-pituitary-gonadal axis. High prolactin levels have been shown to disrupt this axis, resulting in decreases in gonadotropins and testosterone levels. We report a patient with prostate cancer and elevated PSA levels followed with "watchful waiting" for several years who experienced a precipitous decrease in PSA level over a 3 month period. The patient was found to have an asymptomatic prolactin-secreting pituitary macroadenoma.

  19. Prostate cancer.

    PubMed

    Castillejos-Molina, Ricardo Alonso; Gabilondo-Navarro, Fernando Bernardo

    2016-04-01

    Prostate cancer is the most frequent tumor found in men worldwide and in Mexico in particular. Age and family history are the main risk factors. The diagnosis is made by prostate biopsy in patients with abnormalities detected in their prostate-specific antigen (PSA) levels or digital rectal exam (DRE). This article reviews screening and diagnostic methods as well as treatment options for patients diagnosed with prostate cancer. PMID:27557386

  20. Differential Predictive Roles of A- and B-Type Nuclear Lamins in Prostate Cancer Progression

    PubMed Central

    Saarinen, Irena; Mirtti, Tuomas; Seikkula, Heikki; Boström, Peter J.; Taimen, Pekka

    2015-01-01

    Background Prostate cancer (PCa) is the most common cancer among men in western countries. While active surveillance is increasingly utilized, the majority of patients are currently treated with radical prostatectomy. In order to avoid over-treatment, there is an indisputable need for reliable biomarkers to identify the potentially aggressive and lethal cases. Nuclear intermediate filament proteins called lamins play a role in chromatin organization, gene expression and cell stiffness. The expression of lamin A is associated with poor outcome in colorectal cancer but to date the prognostic value of the lamins has not been tested in other solid tumors. Methods We studied the expression of different lamins with immunohistochemistry in a tissue microarray material of 501 PCa patients undergoing radical prostatectomy and lymph node dissection. Patients were divided into two staining categories (low and high expression). The correlation of lamin expression with clinicopathological variables was tested and the association of lamin status with biochemical recurrence (BCR) and disease specific survival (DSS) was further analyzed. Results Low expression of lamin A associated with lymph node positivity (p<0.01) but not with other clinicopathological variables and low expression had a borderline independent significant association with DSS (HR = 0.4; 95% CI 0.2–1.0; p = 0.052). Similarly, low lamin C expression associated with poorer survival (HR = 0.2; 95% CI 0.1–0.6; p = 0.004). Lamin B1 expression did not associate with clinicopathological variables but high expression independently predicted BCR in multivariable Cox regression analysis (HR = 1.8; 95% CI 1.1–2.9; p = 0.023). Low expression of lamin B2 correlated with lymph node positivity (p<0.01) and predicted unfavorable DSS (HR = 0.4; 95% CI 0.2–1.0; p = 0.047). Conclusions These results suggest differential roles for lamins in PCa progression. Reduced amounts of lamin A/C and B2 increase risk for lymph node

  1. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.

    PubMed

    Zarif, Jelani C; Lamb, Laura E; Schulz, Veronique V; Nollet, Eric A; Miranti, Cindy K

    2015-03-30

    Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

  2. Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.

    PubMed

    Catz, S D; Johnson, J L

    2001-11-01

    This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.

  3. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

    PubMed

    Zecchini, Vincent; Madhu, Basetti; Russell, Roslin; Pértega-Gomes, Nelma; Warren, Anne; Gaude, Edoardo; Borlido, Joana; Stark, Rory; Ireland-Zecchini, Heather; Rao, Roheet; Scott, Helen; Boren, Joan; Massie, Charlie; Asim, Mohammad; Brindle, Kevin; Griffiths, John; Frezza, Christian; Neal, David E; Mills, Ian G

    2014-06-17

    Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.

  4. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer

    PubMed Central

    Zecchini, Vincent; Madhu, Basetti; Russell, Roslin; Pértega-Gomes, Nelma; Warren, Anne; Gaude, Edoardo; Borlido, Joana; Stark, Rory; Ireland-Zecchini, Heather; Rao, Roheet; Scott, Helen; Boren, Joan; Massie, Charlie; Asim, Mohammad; Brindle, Kevin; Griffiths, John; Frezza, Christian; Neal, David E; Mills, Ian G

    2014-01-01

    Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer. PMID:24837709

  5. PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer.

    PubMed

    Chen, Zhihang; Penet, Marie-France; Krishnamachary, Balaji; Banerjee, Sangeeta R; Pomper, Martin G; Bhujwalla, Zaver M

    2016-02-01

    Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive (19)F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer.

  6. Postoperative Prostate-Specific Antigen Velocity Independently Predicts for Failure of Salvage Radiotherapy After Prostatectomy

    SciTech Connect

    King, Christopher R. Presti, Joseph C.; Brooks, James D.; Gill, Harcharan; Spiotto, Michael T.

    2008-04-01

    Purpose: Identification of patients most likely to benefit from salvage radiotherapy (RT) using postoperative (postop) prostate-specific antigen (PSA) kinetics. Methods and Materials: From 1984 to 2004, 81 patients who fit the following criteria formed the study population: undetectable PSA after radical prostatectomy (RP); pathologically negative nodes; biochemical relapse defined as a persistently detectable PSA; salvage RT; and two or more postop PSAs available before salvage RT. Salvage RT included the whole pelvic nodes in 55 patients and 4 months of total androgen suppression in 56 patients. The median follow-up was >5 years. All relapses were defined as a persistently detectable PSA. Kaplan-Meier and Cox proportional hazards multivariable analysis were performed for all clinical, pathological, and treatment factors predicting for biochemical relapse-free survival (bRFS). Results: There were 37 biochemical relapses observed after salvage RT. The 5-year bRFS after salvage RT for patients with postop prostate-specific antigen velocity {<=}1 vs. >1 ng/ml/yr was 59% vs. 29%, p = 0.002. In multivariate analysis, only postop PSAV (p = 0.0036), pre-RT PSA level {<=}1 (p = 0.037) and interval-to-relapse >10 months (p = 0.012) remained significant, whereas pelvic RT, hormone therapy, and RT dose showed a trend (p = {approx}0.06). PSAV, but not prostate-specific antigen doubling time, predicted successful salvage RT, suggesting an association of zero-order kinetics with locally recurrent disease. Conclusions: Postoperative PSA velocity independently predicts for the failure of salvage RT and can be considered in addition to high-risk features when selecting patients in need of systemic therapy following biochemical failure after RP. For well-selected patients, salvage RT can achieve high cure rates.

  7. Coffee inhibits nuclear factor-kappa B in prostate cancer cells and xenografts.

    PubMed

    Kolberg, Marit; Pedersen, Sigrid; Mitake, Maiko; Holm, Kristine Lillebø; Bøhn, Siv Kjølsrud; Blomhoff, Heidi Kiil; Carlsen, Harald; Blomhoff, Rune; Paur, Ingvild

    2016-01-01

    Chronic inflammation contributes to prostate cancer and the transcription factor Nuclear Factor-kappa B (NF-κB) is constitutively active in most such cancers. We examine the effects of coffee on NF-κB and on the regulation of selected genes in human-derived prostate cancer cells (PC3) and in PC3 xenografts in athymic nude mice. PC3 cells stably transduced with an NF-κB-luciferase reporter were used both in vitro and for xenografts. NF-κB activity was measured by reporter assays, DNA binding and in vivo imaging. Gene expression was measured in PC3 cells, xenografts and tumor microenvironment by low-density arrays. Western blotting of activated caspases was used to quantify apoptosis. Coffee inhibited TNFα-induced NF-κB activity and DNA-binding in PC3 cells. Furthermore, coffee increased apoptosis and modulated expression of a number of inflammation- and cancer-related genes in TNFα-treated PC3 cells. In vivo imaging revealed a 31% lower NF-κB-luciferase activation in the xenografts of the mice receiving 5% coffee compared to control mice. Interestingly, we observed major changes in gene expression in the PC3 cells in xenografts as compared to PC3 cells in vitro. In PC3 xenografts, genes related to inflammation, apoptosis and cytoprotection were down-regulated in mice receiving coffee, and coffee also affected the gene expression in the xenograft microenvironment. Our data demonstrate that coffee inhibits NF-κB activity in PC3 cells in vitro and in xenografts. Furthermore, coffee modulates transcription of genes related to prostate cancer and inflammation. Our results are the first to suggest mechanistic links between coffee consumption and prostate cancer in an experimental mouse model.

  8. Coffee inhibits nuclear factor-kappa B in prostate cancer cells and xenografts.

    PubMed

    Kolberg, Marit; Pedersen, Sigrid; Mitake, Maiko; Holm, Kristine Lillebø; Bøhn, Siv Kjølsrud; Blomhoff, Heidi Kiil; Carlsen, Harald; Blomhoff, Rune; Paur, Ingvild

    2016-01-01

    Chronic inflammation contributes to prostate cancer and the transcription factor Nuclear Factor-kappa B (NF-κB) is constitutively active in most such cancers. We examine the effects of coffee on NF-κB and on the regulation of selected genes in human-derived prostate cancer cells (PC3) and in PC3 xenografts in athymic nude mice. PC3 cells stably transduced with an NF-κB-luciferase reporter were used both in vitro and for xenografts. NF-κB activity was measured by reporter assays, DNA binding and in vivo imaging. Gene expression was measured in PC3 cells, xenografts and tumor microenvironment by low-density arrays. Western blotting of activated caspases was used to quantify apoptosis. Coffee inhibited TNFα-induced NF-κB activity and DNA-binding in PC3 cells. Furthermore, coffee increased apoptosis and modulated expression of a number of inflammation- and cancer-related genes in TNFα-treated PC3 cells. In vivo imaging revealed a 31% lower NF-κB-luciferase activation in the xenografts of the mice receiving 5% coffee compared to control mice. Interestingly, we observed major changes in gene expression in the PC3 cells in xenografts as compared to PC3 cells in vitro. In PC3 xenografts, genes related to inflammation, apoptosis and cytoprotection were down-regulated in mice receiving coffee, and coffee also affected the gene expression in the xenograft microenvironment. Our data demonstrate that coffee inhibits NF-κB activity in PC3 cells in vitro and in xenografts. Furthermore, coffee modulates transcription of genes related to prostate cancer and inflammation. Our results are the first to suggest mechanistic links between coffee consumption and prostate cancer in an experimental mouse model. PMID:26419686

  9. D-glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells.

    PubMed

    Rosenberg, Eugenia E; Prudnikova, Tatiana Y; Zabarovsky, Eugene R; Kashuba, Vladimir I; Grigorieva, Elvira V

    2014-04-01

    D-glucuronyl C5-epimerase (GLCE) is involved in breast and lung carcinogenesis as a potential tumor suppressor gene, acting through inhibition of tumor angiogenesis and invasion/metastasis pathways. However, in prostate tumors, increased GLCE expression is associated with advanced disease, suggesting versatile effects of GLCE in different cancers. To investigate further the potential cancer-promoting effect of GLCE in prostate cancer, GLCE was ectopically re-expressed in morphologically different LNCaP and PC3 prostate cancer cells. Transcriptional profiles of normal PNT2 prostate cells, LNCaP, PC3 and DU145 prostate cancer cells, and GLCE-expressing LNCaP and PC3 cells were determined. Comparative analysis revealed the genes whose expression was changed in prostate cancer cells compared with normal PNT2 cells, and those differently expressed between the cancer cell lines (ACTA2, IL6, SERPINE1, TAGLN, SEMA3A, and CDH2). GLCE re-expression influenced mainly angiogenesis-involved genes (ANGPT1, SERPINE1, IGF1, PDGFB, TNF, IL8, TEK, IFNA1, and IFNB1) but in a cell type-specific manner (from basic deregulation of angiogenesis in LNCaP cells to significant activation in PC3 cells). Invasion/metastasis pathway was also affected (MMP1, MMP2, MMP9, S100A4, ITGA1, ITGB3, ERBB2, and FAS). The obtained results suggest activation of angiogenesis as a main molecular mechanism of pro-oncogenic effect of GLCE in prostate cancer. GLCE up-regulation plus expression pattern of a panel of six genes, discriminating morphologically different prostate cancer cell sub-types, is suggested as a potential marker of aggressive prostate cancer.

  10. Lycopene, tomato products and prostate cancer-specific mortality among men diagnosed with nonmetastatic prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

    PubMed

    Wang, Ying; Jacobs, Eric J; Newton, Christina C; McCullough, Marjorie L

    2016-06-15

    While dietary lycopene and tomato products have been inversely associated with prostate cancer incidence, there is limited evidence for an association between consumption of lycopene and tomato products and prostate-cancer specific mortality (PCSM). We examined the associations of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with PCSM in a large prospective cohort. This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992 or 1993 and June 2011. Prediagnosis dietary data, collected at baseline, were available for 8,898 men, of whom 526 died of prostate cancer through 2012. Postdiagnosis dietary data, collected on follow-up surveys in 1999 and/or 2003, were available for 5,643 men, of whom 363 died of prostate cancer through 2012. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for PCSM. Neither prediagnosis nor postdiagnosis dietary lycopene intake was associated with PCSM (fourth vs. first quartile HR = 1.00, 95% CI 0.78-1.28; HR = 1.22, 95% CI 0.91-1.64, respectively). Similarly, neither prediagnosis nor postdiagnosis consumption of tomato products was associated with PCSM. Among men with high-risk cancers (T3-T4 or Gleason score 8-10, or nodal involvement), consistently reporting lycopene intake ≥ median on both postdiagnosis surveys was associated with lower PCSM (HR = 0.41, 95% CI 0.17-0.99, based on ten PCSM cases consistently ≥ median intake) compared to consistently reporting intake < median. Future studies are needed to confirm the potential inverse association of consistently high lycopene intake with PCSM among men with high-risk prostate cancers.

  11. Application of fluorescent substrates to the in situ detection of prostate specific antigen.

    PubMed

    Gooch, James; Daniel, Barbara; Frascione, Nunzianda

    2014-07-01

    The forensic identification of body fluids frequently presents an important source of genetic material and investigative interpretation. However, presumptive testing techniques presently employed in the discrimination of biological fluids are subject to criticism for poor specificity, lack of fluid localisation ability and detrimental effects on DNA recovery rates. The recognition of fluid-specific biomarkers by fluorogenic substrates may provide a novel resolution to these issues but research has yet to establish any pertinent in situ fluid detection applicability. This study therefore utilises a fluorogenic substrate (Mu-HSSKLQ-AFC) specific to the seminal protein prostate specific antigen in an effort to detect human semen deposited on a number of surfaces typical to criminal investigation. The ability of fluorescent fluorogenic substrates to simultaneously identify and visualise biological fluids in situ is demonstrated for the first time, whilst the production of complete STR profiles from fluid sources is also confirmed to be completely unaffected by substrate application.

  12. Social ecological predictors of prostate-specific antigen blood test and digital rectal examination in black American men.

    PubMed Central

    Woods, V. Diane; Montgomery, Susanne B.; Herring, R. Patti; Gardner, Robert W.; Stokols, Daniel

    2006-01-01

    BACKGROUND: Black American men continue to suffer disproportionately from epidemically higher rates of prostate cancer. We hypothesize that complex reasons for persistently higher death rates of prostate cancer in this group are steeped in social factors associated with health access. METHODS: We utilized data from the It's All About U prostate cancer prevention study among black men to investigate: 1) what social ecological factors were predictive of prostate-specific antigen (PSA) testing and digital rectal examinations (DRE); 2) if black men were aware of prostate cancer screening and, if screening was available, would they take the PSA and DRE? Quantitative cross-sectional data from a cohort of 276 black men with no diagnosis of prostate cancer were analyzed to identify characteristics, beliefs, practices and attitudes of this group toward prostate cancer screening. We created a social ecological model to examine which social factors (i.e., environmental, personal, person/environment interplay, black culture and institutional policy) were predictive of PSA and DRE, PSA only and DRE only. To reduce data and identify data patterns, factor analyses (tested for reliability by calculating Cronbach alpha scores) were performed. Variables were standardized with Z scores and analyzed with predictive analytic software technology (SPSS, version 12). A multivariate binary logistic regression was conducted to identify predictors of PSA and DRE. RESULTS: A significant predictor of both PSA and DRE was the physician's direct prostate cancer communication message (P<0.010). Significant correlations exist in PSA and DRE outcomes with a physician's engaging communication style (P<0.012), encouragement to screen (P<0.001) and sharing prostate cancer information (P<0.001); as was men understanding the serious risk of prostate cancer (P<0.001), culture (P<0.004), positive interaction with healthcare staff, significant other(s) and providers (P<0.001), and environmental dimensions

  13. Outcome After Conformal Salvage Radiotherapy in Patients With Rising Prostate-Specific Antigen Levels After Radical Prostatectomy

    SciTech Connect

    Geinitz, Hans; Riegel, Martina G.; Thamm, Reinhard; Astner, Sabrina T.; Lewerenz, Carolin; Zimmermann, Frank; Molls, Michael; Nieder, Carsten

    2012-04-01

    Purpose: This study attempts to improve our understanding of the role of salvage radiotherapy (SRT) in patients with prostate-specific antigen (PSA) relapse after radical prostatectomy with regard to biochemical control, rate of distant metastasis, and survival. Methods and Materials: We performed a retrospective analysis of 96 men treated with conformal prostate bed SRT (median, 64.8 Gy) at a single institution (median follow-up, 70 months). The majority had intermediate- or high-risk prostate cancer. Fifty-four percent underwent a resection with positive margins (R1 resection). The median time interval between surgery and SRT was 22 months. Results: After SRT, 66% of patients reached a PSA nadir of less than 0.2 ng/mL. However, the 5-year biochemical no evidence of disease rate was 35%. Seminal vesicle involvement was predictive for a significantly lower biochemical no evidence of disease rate. All patients with a preoperative PSA level greater than 50 ng/mL relapsed biochemically within 2 years. The 5-year distant metastasis rate was 18%, the 5-year prostate cancer-specific survival rate was 90%, and the 5-year overall survival rate was 88%. Significantly more distant metastases developed in patients with a PSA nadir greater than 0.05 ng/mL after SRT, and they had significantly inferior prostate cancer-specific and overall survival rates. Resection status (R1 vs. R0) was not predictive for any of the endpoints. Conclusions: Men with postoperative PSA relapse can undergo salvage treatment by prostate bed radiotherapy, but durable PSA control is maintained only in about one-third of the patients. Despite a high biochemical failure rate after SRT, prostate cancer-specific survival does not decrease rapidly.

  14. Rising prostate-specific antigen values during neoadjuvant androgen deprivation therapy: The importance of monitoring

    SciTech Connect

    Niblock, Paddy; Pickles, Tom . E-mail: tpickles@bccancer.bc.ca

    2006-05-01

    Purpose: To assess the impact of a rising prostate-specific antigen (PSA) level in patients receiving neoadjuvant androgen deprivation therapy (N-ADT) before external beam radiotherapy for prostate cancer. Methods and Materials: From prospectively collected data, we identified 182 patients who received between 3 and 12 months of N-ADT before definitive external beam radiotherapy and who had at least three PSA readings during the neoadjuvant period. One hundred fifty patients had PSA values that continued to fall (Non-Rise group), but 32 had a PSA value that started to rise (Rise group). The two groups were compared by Mann-Whitney U and Pearson chi-square tests. Kaplan-Meier and log-rank analyses were performed for time to treatment failure, cause-specific survival (CSS), and overall survival (OS). Results: The median follow-up was 62.5 months for the Non-Rise group and 53 months for the Rise group. Patients who sustained a PSA rise during the N-ADT period had a shorter time to PSA relapse (p = 0.013), poorer CSS (p = 0.027), and poorer OS (p = 0.03). Multivariate analysis confirms the significance of a PSA rise during the N-ADT period for CSS (p = 0.035) and OS (p = 0.038). Conclusions:: A subset of patients treated with N-ADT develop a rising PSA profile that likely represents early androgen resistance. They have significantly worse outcome.

  15. Investigation of contactless detection using a giant magnetoresistance sensor for detecting prostate specific antigen.

    PubMed

    Sun, Xuecheng; Zhi, Shaotao; Lei, Chong; Zhou, Yong

    2016-08-01

    This paper presents a contactless detection method for detecting prostate specific antigen with a giant magnetoresistance sensor. In contactless detection case, the prostate specific antigen sample preparation was separated from the sensor that prevented the sensor from being immersed in chemical solvents, and made the sensor implementing in immediately reuse without wash. Experimental results showed that applied an external magnetic field in a range of 50 Oe to 90 Oe, Dynabeads with a concentration as low as 0.1 μg/mL can be detected by this system and could give an approximate quantitation to the logarithmic of Dynabeads concentration. Sandwich immunoassay was employed for preparing PSA samples. The PSA capture was implemented on a gold film modified with a self-assembled monolayer and using biotinylated secondary antibody against PSA and streptavidinylated Dynabeads. With DC magnetic field in the range of 50 to 90 Oe, PSA can be detected with a detection limit as low as 0.1 ng/mL. Samples spiked with different concentrations of PSA can be distinguished clearly. Due to the contactless detection method, the detection system exhibited advantages such as convenient manipulation, reusable, inexpensive, small weight. So, this detection method was a promising candidate in biomarker detection, especially in point of care detection. PMID:27379844

  16. Segmenting CT prostate images using population and patient-specific statistics for radiotherapy

    SciTech Connect

    Feng, Qianjin; Foskey, Mark; Chen Wufan; Shen Dinggang

    2010-08-15

    Purpose: In the segmentation of sequential treatment-time CT prostate images acquired in image-guided radiotherapy, accurately capturing the intrapatient variation of the patient under therapy is more important than capturing interpatient variation. However, using the traditional deformable-model-based segmentation methods, it is difficult to capture intrapatient variation when the number of samples from the same patient is limited. This article presents a new deformable model, designed specifically for segmenting sequential CT images of the prostate, which leverages both population and patient-specific statistics to accurately capture the intrapatient variation of the patient under therapy. Methods: The novelty of the proposed method is twofold: First, a weighted combination of gradient and probability distribution function (PDF) features is used to build the appearance model to guide model deformation. The strengths of each feature type are emphasized by dynamically adjusting the weight between the profile-based gradient features and the local-region-based PDF features during the optimization process. An additional novel aspect of the gradient-based features is that, to alleviate the effect of feature inconsistency in the regions of gas and bone adjacent to the prostate, the optimal profile length at each landmark is calculated by statistically investigating the intensity profile in the training set. The resulting gradient-PDF combined feature produces more accurate and robust segmentations than general gradient features. Second, an online learning mechanism is used to build shape and appearance statistics for accurately capturing intrapatient variation. Results: The performance of the proposed method was evaluated on 306 images of the 24 patients. Compared to traditional gradient features, the proposed gradient-PDF combination features brought 5.2% increment in the success ratio of segmentation (from 94.1% to 99.3%). To evaluate the effectiveness of online

  17. Prostate-specific membrane antigen expression in tumor-associated vasculature of breast cancers.

    PubMed

    Wernicke, Alla Gabriella; Varma, Sonal; Greenwood, Eleni A; Christos, Paul J; Chao, K S Clifford; Liu, He; Bander, Neil H; Shin, Sandra J

    2014-06-01

    Prostate-specific membrane antigen (PSMA) has been found to be expressed in the tumor-associated neovasculature of multiple solid tumor types including breast cancers. However, thus far, the number of cases studied from some tumor types has been limited. In this study, we set out to assess PSMA expression in the tumor-associated vasculature associated with invasive breast carcinomas in a sizable cohort of patients. One hundred and six patients with AJCC stage 0-IV breast cancer were identified. Ninety-two of these patients had primary breast cancer [invasive breast carcinoma with or without co-existing ductal carcinoma in situ (DCIS) (74) or DCIS alone (18)]. In addition, 14 patients with breast cancer metastases to the brain were identified. Immunohistochemical staining for PSMA and CD31 was performed on parallel representative tumor sections in each case. Tumor-associated vascular endothelial cell PSMA immunoreactivity was semi-quantitatively assessed based on two parameters: overall percent of endothelial positivity and staining intensity. PSMA expression for tumor-associated vascular endothelial cells was scored 0 if there was no detectable PSMA expression, 1 if PSMA staining was detectable in 5-50%, and 2 if PSMA expression was positive in >50% of microvessels. CD 31 staining was concurrently reviewed to confirm the presence of vasculature in each case. Tumor-associated vasculature was PSMA-positive in 68/92 (74%) of primary breast cancers and in 14/14 (100%) of breast cancers metastatic to brain. PSMA was not detected in normal breast tissue or carcinoma cells. All but 2 cases (98%) showed absence of PSMA expression in normal breast tissue-associated vasculature. The 10-year overall survival was 88.7% (95% CI = 80.0%, 93.8%) in patients without brain metastases. When overall survival (OS) was stratified based on PSMA score group, patients with PSMA scores of 0, 1, and 2 had 10-year OS of 95.8%, 96.0%, and 79.7%, respectively (p = 0.12). When PSMA scores

  18. Prostate biopsy

    MedlinePlus

    ... prostate biopsy; Fine needle biopsy of the prostate; Core biopsy of the prostate; Targeted prostate biopsy; Prostate biopsy - transrectal ultrasound (TRUS); Stereotactic transperineal prostate biopsy (STPB)

  19. Transcription variants of the prostate-specific PrLZ gene and their interaction with 14-3-3 proteins

    SciTech Connect

    Wang, Ruoxiang; He, Hui; Sun, Xiaojuan; Xu, Jianchun; Marshall, Fray F.; Zhau, Haiyen; Chung, Leland W.K.; Fu, Haian; He, Dalin

    2009-11-20

    We have reported isolation and characterization of the prostate-specific and androgen-regulated PrLZ gene abnormally expressed in prostate cancer. PrLZ is a potential biomarker for prostate cancer and a candidate oncogene promoting cell proliferation and survival in prostate cancer cells. A full delineation of the PrLZ gene and its gene products may provide clues to the mechanisms regulating its expression and function. In this report, we identified three additional exons in the PrLZ gene and recognized five transcript variants from alternative splicing that could be detected by RT-PCR and Western blotting. Structural comparison demonstrated that the PrLZ proteins are highly conserved among species. PrLZ contains multiple potential sites for interaction with other proteins. We used mammalian two-hybrid assays to demonstrate that PrLZ isoforms interact with 14-3-3 proteins, and multiple sites in the PrLZ may be involved in the interaction. Alternative splicing may contribute to abnormally enhanced PrLZ levels in prostate cancer, and interaction with 14-3-3 proteins may be a mechanism by which PrLZ promotes cell proliferation and survival during prostate cancer development and progression. This information is a valuable addition to the investigation of the oncogenic properties of the PrLZ gene.

  20. Prostate-specific antigen testing in inner London general practices: are those at higher risk most likely to get tested?

    PubMed Central

    Nderitu, Paul; Van Hemelrijck, Mieke; Ashworth, Mark; Mathur, Rohini; Hull, Sally; Dudek, Alexandra; Chowdhury, Simon

    2016-01-01

    Objectives To investigate the association between factors influencing prostate-specific antigen (PSA) testing prevalence including prostate cancer risk factors (age, ethnicity, obesity) and non-risk factors (social deprivation and comorbidity). Setting A cross-sectional database of 136 inner London general practices from 1 August 2009 to 31 July 2014. Participants Men aged ≥40 years without prostate cancer were included (n=150 481). Primary outcome Logistic regression analyses were used to estimate the association between PSA testing and age, ethnicity, social deprivation, body mass index (BMI) and comorbidity while adjusting for age, benign prostatic hypertrophy, prostatitis and tamsulosin or finasteride use. Results PSA testing prevalence was 8.2% (2013–2014), and the mean age was 54 years (SD 11). PSA testing was positively associated with age (OR 70–74 years compared to 40–44 years: 7.34 (95% CI 6.82 to 7.90)), ethnicity (black) (OR compared to white: 1.78 (95% CI 1.71 to 1.85)), increasing BMI and cardiovascular comorbidity. Testing was negatively associated with Chinese ethnicity and with increasing social deprivation. Conclusions PSA testing among black patients was higher compared to that among white patients, which differs from lower testing rates seen in previous studies. PSA testing was positively associated with prostate cancer risk factors and non-risk factors. Association with non-risk factors may increase the risk of unnecessary invasive diagnostic procedures. PMID:27406644

  1. Development of an ELISA detecting Tumor Protein 53-Induced Nuclear Protein 1 in serum of prostate cancer patients.

    PubMed

    Saadi, Houda; Seillier, Marion; Sandi, Maria José; Peuget, Sylvain; Kellenberger, Christine; Gravis, Gwenaëlle; Dusetti, Nelson J; Iovanna, Juan L; Rocchi, Palma; Amri, Mohamed; Carrier, Alice

    2013-01-01

    Tumor Protein 53-Induced Nuclear Protein 1 (TP53INP1) plays an important role during cell stress response in synergy with the potent "genome-keeper" p53. In human, the gene encoding TP53INP1 is expressed at very high level in some pathological situations, such as inflammation and prostate cancer (PC). TP53INP1 overexpression in PC seems to be a worse prognostic factor, particularly predictive of biological cancer relapse, making TP53INP1 a relevant specific target for molecular therapy of Castration Resistant (CR) PC. In that context, detection of TP53INP1 in patient biological fluids is a promising diagnostic avenue. We report here successful development of a new Enzyme-Linked Immunosorbent Assay (ELISA) detecting TP53INP1, taking advantage of molecular tools (monoclonal antibodies (mAbs) and recombinant proteins) generated in the laboratory during the course of basic functional investigations devoted to TP53INP1. The ELISA principle is based on a sandwich immunoenzymatic system, TP53INP1 protein being trapped by a first specific mAb coated on microplate then recognized by a second specific mAb. This new assay allows specific detection of TP53INP1 in serum of several PC patients. This breakthrough paves the way towards investigation of a large cohort of patients and assessment of clinical applications of TP53INP1 dosage. PMID:24600558

  2. Quantitative [Fe]MRI of PSMA-targeted SPIONs specifically discriminates among prostate tumor cell types based on their PSMA expression levels.

    PubMed

    Sillerud, Laurel O

    2016-01-01

    We report the development, experimental verification, and application of a general theory called [Fe]MRI (pronounced fem-ree) for the non-invasive, quantitative molecular magnetic resonance imaging (MRI) of added magnetic nanoparticles or other magnetic contrast agents in biological tissues and other sites. [Fe]MRI can easily be implemented on any MRI instrument, requiring only measurements of the background nuclear magnetic relaxation times (T1, T2) of the tissue of interest, injection of the magnetic particles, and the subsequent acquisition of a pair of T1-weighted and T2-weighted images. These images, converted into contrast images, are subtracted to yield a contrast difference image proportional to the absolute nanoparticle, iron concentration, ([Fe]) image. [Fe]MRI was validated with the samples of superparamagnetic iron oxide nanoparticles (SPIONs) both in agarose gels and bound to human prostate tumor cells. The [Fe]MRI measurement of the binding of anti-prostate specific membrane antigen (PSMA) conjugated SPIONs to PSMA-positive LNCaP and PSMA-negative DU145 cells in vitro allowed a facile discrimination among prostate tumor cell types based on their PSMA expression level. The low [Fe] detection limit of ~2 μM for SPIONs allows sensitive MRI of added iron at concentrations considerably below the US Food and Drug Administration's human iron dosage guidelines (<90 μM, 5 mg/kg). PMID:26855574

  3. Quantitative [Fe]MRI of PSMA-targeted SPIONs specifically discriminates among prostate tumor cell types based on their PSMA expression levels

    PubMed Central

    Sillerud, Laurel O

    2016-01-01

    We report the development, experimental verification, and application of a general theory called [Fe]MRI (pronounced fem-ree) for the non-invasive, quantitative molecular magnetic resonance imaging (MRI) of added magnetic nanoparticles or other magnetic contrast agents in biological tissues and other sites. [Fe]MRI can easily be implemented on any MRI instrument, requiring only measurements of the background nuclear magnetic relaxation times (T1, T2) of the tissue of interest, injection of the magnetic particles, and the subsequent acquisition of a pair of T1-weighted and T2-weighted images. These images, converted into contrast images, are subtracted to yield a contrast difference image proportional to the absolute nanoparticle, iron concentration, ([Fe]) image. [Fe]MRI was validated with the samples of superparamagnetic iron oxide nanoparticles (SPIONs) both in agarose gels and bound to human prostate tumor cells. The [Fe]MRI measurement of the binding of anti-prostate specific membrane antigen (PSMA) conjugated SPIONs to PSMA-positive LNCaP and PSMA-negative DU145 cells in vitro allowed a facile discrimination among prostate tumor cell types based on their PSMA expression level. The low [Fe] detection limit of ~2 μM for SPIONs allows sensitive MRI of added iron at concentrations considerably below the US Food and Drug Administration’s human iron dosage guidelines (<90 μM, 5 mg/kg). PMID:26855574

  4. Laminin receptor specific therapeutic gold nanoparticles (198AuNP-EGCg) show efficacy in treating prostate cancer

    SciTech Connect

    Shukla, R.; Chanda, N.; Zambre, A.; Upendran, A.; Katti, K.; Kulkarni, R. R.; Nune, S. K.; Casteel, S. W.; Smith, C. J.; Vimal, J.; Boote, E.; Robertson, J. D.; Kan, P.; Engelbrecht, H.; Watkinson, L. D.; Carmack, T. L.; Lever, J. R.; Cutler, C. S.; Caldwell, C.; Kannan, R.; Katti, K. V.

    2012-07-16

    Systemic delivery of therapeutic agents to solid tumors is hindered by vascular and interstitial barriers. We hypothesized that prostate tumor specific epigallocatechingallate( EGCg) functionalized radioactive gold nanoparticles, when delivered intratumorally (IT), will circumvent transport barriers, resulting in targeted delivery of therapeutic payloads. The results described herein provide unequivocal validation of our hypothesis. We report the development of inherently therapeutic gold nanoparticles derived from Au-198 isotope; the range of 198Au β-particle ( ~ 11 mm in tissue or ~1100 cell diameters) is sufficiently long to provide cross-fire effects of radiation dose delivered to cells within the prostate gland and short enough to minimize radiation dose to critical tissues near the periphery of the capsule. The formulation of biocompatible 198AuNPs utilizes the redox chemistry of prostate tumor specific phytochemical EGCg as it converts gold salt into gold nanoparticles and also selectively binds with excellent affinity to Laminin67R receptors which are over expressed in prostate tumor cells. Pharmacokinetic studies in PC-3 xenograft SCID mice showed ~72% retention of 198AuNP-EGCg in tumors 24 h after intratumoral administration. Therapeutic studies showed 80% reduction of tumor volumes after 28 days demonstrating significant inhibition of tumor growth compared to controls. This innovative “green nanotechnological“approach serves as a basis for designing target specific antineoplastic agents. This novel intratumorally injectable 198AuNP-EGCg nanotherapeutic agent may provide significant advances in oncology for use as an effective treatment for prostate and other solid tumors.

  5. Obesity inversely correlates with prostate-specific antigen levels in a population with normal screening results of prostate cancer in northwestern China.

    PubMed

    Zhang, J; Ma, M; Nan, X; Sheng, B

    2016-07-11

    Serum prostate-specific antigen (PSA) is a diagnostic biomarker of prostate cancer and is possibly associated with obesity. This study aimed to explore the relationships between obesity indicators [body mass index (BMI) and waist circumference (WC)] with PSA in Chinese men. A cross-sectional study of men aged 30-85 years undergoing prostate cancer screening was conducted from August 2008 to July 2013 in Xi'an, China. Data were obtained from clinical reports, condition was recorded based on self-report including demographics, weight, height, and WC (>90 cm=obese). Fasting blood glucose (FBG) and prostate volume (PV) were assessed clinically. Patients were grouped by BMI (normal=22.9, overweight=23-27.4, obese≥27.5 kg/m2). PSA parameters of density (PSAD), PSA serum level, and PSA increasing rate per year (PSAR) were calculated per BMI and age groups (30-40, 41-59, 60-85 years). Obesity indicators (BMI and WC) and PSA parameter relationships were modeled by age-stratified linear regression. Of 35,632 Chinese men surveyed, 13,084 were analyzed, including 13.44% obese, 57.44% overweight, and 29.12% normal weight, according to BMI; 25.84% were centrally (abdominally) obese according to WC. BMI and WC were negatively associated with all PSA parameters, except PSAD and PSAR [P<0.05, BMI: β=-0.081 (95%CI=-0.055 to -0.036), WC: β=-0.101 (-0.021 to -0.015)], and independent of FBG and PV (P<0.05) in an age-adjusted model. In conclusion, obesity was associated with lower PSA in Chinese men. Therefore, an individual's BMI and WC should be considered when PSA is used to screen for prostate cancer. PMID:27409334

  6. Obesity inversely correlates with prostate-specific antigen levels in a population with normal screening results of prostate cancer in northwestern China

    PubMed Central

    Zhang, J.; Ma, M.; Nan, X.; Sheng, B.

    2016-01-01

    Serum prostate-specific antigen (PSA) is a diagnostic biomarker of prostate cancer and is possibly associated with obesity. This study aimed to explore the relationships between obesity indicators [body mass index (BMI) and waist circumference (WC)] with PSA in Chinese men. A cross-sectional study of men aged 30-85 years undergoing prostate cancer screening was conducted from August 2008 to July 2013 in Xi'an, China. Data were obtained from clinical reports, condition was recorded based on self-report including demographics, weight, height, and WC (>90 cm=obese). Fasting blood glucose (FBG) and prostate volume (PV) were assessed clinically. Patients were grouped by BMI (normal=22.9, overweight=23-27.4, obese≥27.5 kg/m2). PSA parameters of density (PSAD), PSA serum level, and PSA increasing rate per year (PSAR) were calculated per BMI and age groups (30-40, 41-59, 60-85 years). Obesity indicators (BMI and WC) and PSA parameter relationships were modeled by age-stratified linear regression. Of 35,632 Chinese men surveyed, 13,084 were analyzed, including 13.44% obese, 57.44% overweight, and 29.12% normal weight, according to BMI; 25.84% were centrally (abdominally) obese according to WC. BMI and WC were negatively associated with all PSA parameters, except PSAD and PSAR [P<0.05, BMI: β=-0.081 (95%CI=-0.055 to -0.036), WC: β=-0.101 (-0.021 to -0.015)], and independent of FBG and PV (P<0.05) in an age-adjusted model. In conclusion, obesity was associated with lower PSA in Chinese men. Therefore, an individual's BMI and WC should be considered when PSA is used to screen for prostate cancer. PMID:27409334

  7. Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer

    PubMed Central

    FAN, WEIWEI; ZHANG, ZHIWEI; ZHU, ZHENG; YANG, DEYONG; CHEN, XIAOCHI; WANG, JIANBO; CHEN, FENG; SONG, XISHUANG

    2015-01-01

    In recent years, single-photon emission computed tomography and positron emission tomography (PET) have also been used, in addition to computed tomography and magnetic resonance imaging, in targeting the diagnosis of prostate cancer. The aim of this study was to synthesize the prostate-specific membrane antigen (PSMA)-based imaging agent 2-{3-[1-Carboxy-5-(4-[18F] fluoro-benzoylamino)-pentyl]-ureido}-pentanedioic acid (18F-Glu-Urea-Lys, [18F]3) and to detect its PET imaging efficiency for high PSMA expression in prostate cancer. In this study, 18F-Glu-Urea-Lys was synthesized in two steps from the p-methoxybenzyl-protected Glu-Urea-Lys precursor using N-Hydroxysuccinimidyl-4-[18F] fluorobenzoate ([18F]SFB). PET imaging evaluation was conducted in nude mice using LNCaP (PSMA+), and PC-3, 231 and A549 (all PSMA−) xenograft models. The results indicated that 18F-Glu-Urea-Lys was produced in radiochemical yields of 28.7%. The radiochemical purity was 99.1% and the mean total synthesis time was 168 min. In nude mice models 18F-Glu-Urea-Lys clearly delineated PSMA+ LNCaP prostate tumor xenografts on PET imaging. At 4 h post-injection, the contrast agents were only observed in renal, liver, bladder and PSMA+ LNCaP tumors. The PSMA− tumor (PC-3, 231 and A549) was clear. In conclusion, 18F-Glu-Urea-Lys was found to be easily synthesized. This radiotracer demonstrated high tumor and low-to-normal tissue uptake, fast clearance from non-target tissues and retention in PSMA+ prostate tumor xenografts. PMID:26622838

  8. p,p'-Dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) repress prostate specific antigen levels in human prostate cancer cell lines.

    PubMed

    Wong, Lilian I L; Labrecque, Mark P; Ibuki, Naokazu; Cox, Michael E; Elliott, John E; Beischlag, Timothy V

    2015-03-25

    Despite stringent restrictions on their use by many countries since the 1970s, the endocrine disrupting chemicals, DDT and DDE are still ubiquitous in the environment. However, little attention has been directed to p,p'-DDT and the anti-androgen, p,p'-DDE on androgen receptor (AR) target gene transcription in human cells. Inhibitors of androgenic activity may have a deleterious clinical outcome in prostate cancer screens and progression, therefore we determined whether environmentally relevant concentrations of p,p'-DDT and p,p'-DDE negatively impact AR-regulated expression of prostate-specific antigen (PSA), and other AR target genes in human LNCaP and VCaP prostate cancer cells. Quantitative real-time PCR and immuno-blotting techniques were used to measure intracellular PSA, PSMA and AR mRNA and protein levels. We have shown for the first time that p,p'-DDT and p,p'-DDE repressed R1881-inducible PSA mRNA and protein levels in a dose-dependent manner. Additionally, we used the fully automated COBAS PSA detection system to determine that extracellular PSA levels were also significantly repressed. These chemicals achieve this by blocking the recruitment of AR to the PSA promoter region at 10 μM, as demonstrated by the chromatin immunoprecipitation (ChIP) in LNCaP cells. Both p,p'-DDT and p,p'-DDE repressed R1881-inducible AR protein accumulation at 10 μM. Thus, we conclude that men who have been exposed to either DDT or DDE may produce a false-negative PSA test when screening for prostate cancer, resulting in an inaccurate clinical diagnosis. More importantly, prolonged exposure to these anti-androgens may mimic androgen ablation therapy in individuals with prostate cancer, thus exacerbating the condition by inadvertently forcing adaptation to this stress early in the disease.

  9. The Impact of Brachytherapy on Prostate Cancer-Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis

    SciTech Connect

    Shen Xinglei; Keith, Scott W.; Mishra, Mark V.; Dicker, Adam P.; Showalter, Timothy N.

    2012-07-15

    Purpose: This population-based analysis compared prostate cancer-specific mortality (PCSM) in a cohort of patients with high-risk prostate cancer after nonsurgical treatment with external beam radiation therapy (EBRT), brachytherapy (BT), or combination (BT + EBRT). Methods and Materials: We identified from the Surveillance, Epidemiology and End Results database patients diagnosed from 1988 through 2002 with T1-T3N0M0 prostate adenocarcinoma of poorly differentiated grade and treated with BT, EBRT, or BT + EBRT. During this time frame, the database defined high grade as prostate cancers with Gleason score 8-10, or Gleason grade 4-5 if the score was not recorded. This corresponds to a cohort primarily with high-risk prostate cancer, although some cases where only Gleason grade was recorded may have included intermediate-risk cancer. We used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on PCSM. Results: There were 12,745 patients treated with EBRT (73.5%), BT (7.1%), or BT + EBRT (19.4%) included in the analysis. The median follow-up time for all patients was 6.4 years. The use of BT or BT + EBRT increased from 5.1% in 1988-1992 to 31.4% in 1998-2002. Significant predictors of use of BT or BT + EBRT were younger age, later year of diagnosis, urban residence, and earlier T-stage. On multivariate analysis, treatment with either BT (hazard ratio, 0.66; 95% confidence interval, 0.49-0.86) or BT + EBRT (hazard ratio, 0.77; 95% confidence ratio, 0.66-0.90) was associated with significant reduction in PCSM compared with EBRT alone. Conclusion: In patients with high-grade prostate cancer, treatment with brachytherapy is associated with reduced PCSM compared with EBRT alone. Our results suggest that brachytherapy should be investigated as a component of definitive treatment strategies for patients with high-risk prostate cancer.

  10. Human kallikrein 3 (prostate specific antigen) and human kallikrein 5 expression in salivary gland tumors.

    PubMed

    Darling, M R; Tsai, S; Jackson-Boeters, L; Daley, T D; Diamandis, E P

    2006-01-01

    The human kallikrein 5 protein (hK5) is expressed in many normal tissues, most notably in skin, breast, salivary gland and esophagus. It has also been shown to be a potential biomarker for breast, ovarian and testicular cancer. Human kallikrein 3 (hK3; prostate-specific antigen) is the most useful marker for adenocarcinoma of the prostate gland. The aim of this study was to determine whether hK3 and hK5 are expressed in salivary gland tissues and salivary gland tumors (both benign and malignant), in order to compare normal with tumor tissues. Pleomorphic adenomas, adenoid cystic carcinomas, polymorphous low-grade adenocarcinomas, acinic cell carcinomas, mucoepidermoid carcinomas and adenocarcinomas not otherwise specified of both minor and major salivary glands were examined. The results of this study indicate that most salivary gland tumors do not show high levels of expression of hK5. Staining was most prominent in keratinizing epithelia in pleomorphic adenomas. hK3 is not expressed in salivary gland tumors.

  11. ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells.

    PubMed

    Tome-Garcia, Jessica; Li, Dan; Ghazaryan, Seda; Shu, Limin; Wu, Lizhao

    2014-01-01

    Despite all the blood-based biomarkers used to monitor prostate cancer patients, prostate cancer remains as the second common cause of cancer mortality in men in the United States. This is largely due to a lack of understanding of the molecular pathways that are responsible for the aggressive forms of prostate cancers, the castrate-resistant prostate cancer and the metastatic prostate cancer. Cell signaling pathways activated by the ERBB2 oncogene or the RAS oncogene are frequently found to be altered in metastatic prostate cancers. To evaluate and define the role of the ERBB2/RAS pathway in prostate cancer metastasis, we have evaluated the impact of ERBB2- or RAS-overexpression on the metastatic potentials for four prostate cancer cell lines derived from tumors with different androgen sensitivities. To do so, we transfected the human DU145, LnCaP, and PC3 prostate cancer cells and the murine Myc-CaP prostate cancer cells with the activated form of ERBB2 or H-RAS and assessed their metastatic potentials by three complementary assays, a wound healing assay, a transwell motility assay, and a transwell invasion assay. We showed that while overexpression of ERBB2 increased the metastatic potential of the androgen-insensitive prostate cancer cells (i.e. PC3 and DU145), it did not affect metastatic potentials of the androgen-sensitive prostate cancer cells (i.e. LnCaP and Myc-CaP). In contrast, overexpression of H-RAS only increased the cell motility of Myc-CaP cells, which overexpress the human c-MYC oncogene. Our data suggest that ERBB2 collaborates with androgen signaling to promote prostate cancer metastasis, and that although RAS is one of the critical downstream effectors of ERBB2, it does not phenocopy ERBB2 for its impact on the metastatic potentials of prostate cancer cell lines. PMID:24937171

  12. Prostate Cancer Imaging with Novel PET Tracers.

    PubMed

    Lindenberg, Liza; Choyke, Peter; Dahut, William

    2016-03-01

    Molecular imaging of prostate cancer is in a dynamic phase of development. Currently approved techniques are limited and researchers have been working on novel agents to improve accuracy in targeting and detecting prostate tumors. In addition, the complexity of various prostate cancer states also contributes to the challenges in evaluating suitable radiotracer candidates. We have highlighted nuclear medicine tracers that focus on mechanisms involved in bone metastasis, prostate cancer cell membrane synthesis, amino acid analogs, androgen analogs, and the prostate specific membrane antigen. Encouraging results with many of these innovative radiotracer compounds will not only advance diagnostic capabilities for prostate cancer but open opportunities for theranostic applications to treat this worldwide malignancy. PMID:26874530

  13. Walnut polyphenol metabolites, urolithins A and B, inhibit the expression of the prostate-specific antigen and the androgen receptor in prostate cancer cells.

    PubMed

    Sánchez-González, Claudia; Ciudad, Carlos J; Noé, Véronique; Izquierdo-Pulido, Maria

    2014-11-01

    Walnuts have been gathering attention for their health-promoting properties. They are rich in polyphenols, mainly ellagitannins (ETs) that after consumption are hydrolyzed to release ellagic acid (EA). EA is further metabolized by microbiota to form urolithins, such as A and B, which are absorbed. ETs, EA and urolithins have shown to slow the proliferation and growth of different types of cancer cells but the mechanisms remain unclear. We investigate the role of urolithins in the regulatory mechanisms in prostate cancer, specifically those related to the androgen receptor (AR), which have been linked to the development of this type of cancer. In our study, urolithins down-regulated the mRNA and protein levels of both prostate specific antigen (PSA) and AR in LNCaP cells. The luciferase assay performed with a construct containing three androgen response elements (AREs) showed that urolithins inhibit AR-mediated PSA expression at the transcriptional level. Electrophoretic mobility shift assays revealed that urolithins decreased AR binding to its consensus response element. Additionally, urolithins induced apoptosis in LNCaP cells, and this effect correlated with a decrease in Bcl-2 protein levels. In summary, urolithins attenuate the function of the AR by repressing its expression, causing a down-regulation of PSA levels and inducing apoptosis. Our results suggest that a diet rich in ET-containing foods, such as walnuts, could contribute to the prevention of prostate cancer.

  14. Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

    PubMed Central

    Mooso, Benjamin A.; Vinall, Ruth L.; Tepper, Clifford G.; Savoy, Rosalinda M.; Cheung, Jean P.; Singh, Sheetal; Siddiqui, Salma; Wang, Yu; Bedolla, Roble G.; Martinez, Anthony; Mudryj, Maria; Kung, Hsing-Jien; deVere White, Ralph W.; Ghosh, Paramita M.

    2013-01-01

    Since prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280kDa structural protein Filamin A (FlnA) to a 90kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein-combined-polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization, and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration; indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP. PMID:22993077

  15. Predictors of Prostate Cancer-Specific Mortality in Elderly Men With Intermediate-Risk Prostate Cancer Treated With Brachytherapy With or Without External Beam Radiation Therapy

    SciTech Connect

    Nanda, Akash; Moran, Brian J.; Braccioforte, Michelle H.; Dosoretz, Daniel; Salenius, Sharon; Katin, Michael; Ross, Rudi; D'Amico, Anthony V.

    2010-05-01

    Purpose: To identify clinical factors associated with prostate cancer-specific mortality (PCSM), adjusting for comorbidity, in elderly men with intermediate-risk prostate cancer treated with brachytherapy alone or in conjunction with external beam radiation therapy. Methods and Materials: The study cohort comprised 1,978 men of median age 71 (interquartile range, 66-75) years with intermediate-risk disease (Gleason score 7, prostate-specific antigen (PSA) 20 ng/mL or less, tumor category T2c or less). Fine and Gray's multivariable competing risks regression was used to assess whether prevalent cardiovascular disease (CVD), age, treatment, year of brachytherapy, PSA level, or tumor category was associated with the risk of PCSM. Results: After a median follow-up of 3.2 (interquartile range, 1.7-5.4) years, the presence of CVD was significantly associated with a decreased risk of PCSM (adjusted hazard ratio, 0.20; 95% CI 0.04-0.99; p = 0.05), whereas an increasing PSA level was significantly associated with an increased risk of PCSM (adjusted hazard ratio 1.14; 95% CI 1.02-1.27; p = 0.02). In the absence of CVD, cumulative incidence estimates of PCSM were higher (p = 0.03) in men with PSA levels above as compared with the median PSA level (7.3 ng/mL) or less; however, in the setting of CVD there was no difference (p = 0.27) in these estimates stratified by the median PSA level (6.9 ng/mL). Conclusions: In elderly men with intermediate-risk prostate cancer, CVD status is a negative predictor of PCSM and affects the prognostic capacity of pretreatment PSA level. These observations support the potential utility of prerandomization stratification by comorbidity to more accurately assess prognostic factors and treatment effects within this population.

  16. Gold Nanoparticle Based Activatable Probe for Sensing Ultra-Low Levels of Prostate Specific Antigen

    PubMed Central

    Liu, Dingbin; Huang, Xinglu; Wang, Zhantong; Jin, Albert; Sun, Xiaolian; Zhu, Lei; Wang, Fu; Ma, Ying; Niu, Gang; HightWalker, Angela R.; Chen, Xiaoyuan

    2013-01-01

    It is still in high demand to develop extremely sensitive and accurate clinical tools for biomarkers of interest for early diagnosis and monitoring of diseases. In this report, we present a highly sensitive and compatible gold nanoparticle (AuNP)-based fluorescence activatable probe for sensing ultra-low levels of prostate-specific antigen (PSA) in patient serum samples. The limit of detection of the newly-developed probe for PSA was pushed down to 0.032 pg/mL, which is more than two orders of magnitude lower than that of the conventional fluorescence probe. The ultrahigh sensitivity of this probe was attributed to the high loading efficiency of the dyes on AuNP surfaces and high fluorescence quenching unquenching abilities of the dye-AuNP pairs. The efficiency and robustness of this probe was investigated in patient serum samples, demonstrating the great potential of this probe in real-world applications. PMID:23683064

  17. Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

    PubMed

    Conway, Rebecca E; Rojas, Camilo; Alt, Jesse; Nováková, Zora; Richardson, Spencer M; Rodrick, Tori C; Fuentes, Julio L; Richardson, Noah H; Attalla, Jonathan; Stewart, Samantha; Fahmy, Beshoy; Barinka, Cyril; Ghosh, Mallika; Shapiro, Linda H; Slusher, Barbara S

    2016-10-01

    Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies. PMID:27387982

  18. Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device.

    PubMed

    Kirby, Brian J; Jodari, Mona; Loftus, Matthew S; Gakhar, Gunjan; Pratt, Erica D; Chanel-Vos, Chantal; Gleghorn, Jason P; Santana, Steven M; Liu, He; Smith, James P; Navarro, Vicente N; Tagawa, Scott T; Bander, Neil H; Nanus, David M; Giannakakou, Paraskevi

    2012-01-01

    Cancer metastasis accounts for the majority of cancer-related deaths owing to poor response to anticancer therapies. Molecular understanding of metastasis-associated drug resistance remains elusive due to the scarcity of available tumor tissue. Isolation of circulating tumor cells (CTCs) from the peripheral blood of patients has emerged as a valid alternative source of tumor tissue that can be subjected to molecular characterization. However, issues with low purity and sensitivity have impeded adoption to clinical practice. Here we report a novel method to capture and molecularly characterize CTCs isolated from castrate-resistant prostate cancer patients (CRPC) receiving taxane chemotherapy. We have developed a geometrically enhanced differential immunocapture (GEDI) microfluidic device that combines an anti-prostate specific membrane antigen (PSMA) antibody with a 3D geometry that captures CTCs while minimizing nonspecific leukocyte adhesion. Enumeration of GEDI-captured CTCs (defined as intact, nucleated PSMA+/CD45- cells) revealed a median of 54 cells per ml identified in CRPC patients versus 3 in healthy donors. Direct comparison with the commercially available CellSearch® revealed a 2-400 fold higher sensitivity achieved with the GEDI device. Confocal microscopy of patient-derived GEDI-captured CTCs identified the TMPRSS2:ERG fusion protein, while sequencing identified specific androgen receptor point mutation (T868A) in blood samples spiked with only 50 PC C4-2 cells. On-chip treatment of patient-derived CTCs with docetaxel and paclitaxel allowed monitoring of drug-target engagement by means of microtubule bundling. CTCs isolated from docetaxel-resistant CRPC patients did not show any evidence of drug activity. These measurements constitute the first functional assays of drug-target engagement in living circulating tumor cells and therefore have the potential to enable longitudinal monitoring of target response and inform the development of new anticancer

  19. Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide.

    PubMed

    Conway, Rebecca E; Rojas, Camilo; Alt, Jesse; Nováková, Zora; Richardson, Spencer M; Rodrick, Tori C; Fuentes, Julio L; Richardson, Noah H; Attalla, Jonathan; Stewart, Samantha; Fahmy, Beshoy; Barinka, Cyril; Ghosh, Mallika; Shapiro, Linda H; Slusher, Barbara S

    2016-10-01

    Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.

  20. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.

    PubMed

    Grimm, Peter; Billiet, Ignace; Bostwick, David; Dicker, Adam P; Frank, Steven; Immerzeel, Jos; Keyes, Mira; Kupelian, Patrick; Lee, W Robert; Machtens, Stefan; Mayadev, Jyoti; Moran, Brian J; Merrick, Gregory; Millar, Jeremy; Roach, Mack; Stock, Richard; Shinohara, Katsuto; Scholz, Mark; Weber, Ed; Zietman, Anthony; Zelefsky, Michael; Wong, Jason; Wentworth, Stacy; Vera, Robyn; Langley, Stephen

    2012-02-01

    What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient

  1. A novel nuclear role for the Vav3 nucleotide exchange factor in androgen receptor coactivation in prostate cancer.

    PubMed

    Rao, S; Lyons, L S; Fahrenholtz, C D; Wu, F; Farooq, A; Balkan, W; Burnstein, K L

    2012-02-01

    Increased androgen receptor (AR) transcriptional activity mediated by coactivator proteins may drive castration-resistant prostate cancer (CRPC) growth. Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is overexpressed in human prostate cancers, particularly in models of CRPC progression. Vav3 coactivates AR in a Vav3 pleckstrin homology (PH) domain-dependent but GEF-independent manner. Ectopic expression of Vav3 in androgen-dependent human prostate cancer cells conferred robust castration-resistant xenograft tumor growth. Vav3 but not a Vav3 PH mutant greatly stimulated interaction between the AR amino and carboxyl termini (N-C interaction), which is required for maximal receptor transcriptional activity. Vav3 was distributed between the cytoplasm and nucleus with nuclear localization-dependent on the Vav3 PH domain. Membrane targeting of Vav3 abolished Vav3 potentiation of AR activity, whereas nuclear targeting of a Vav3 PH mutant rescued AR coactivation, suggesting that nuclear localization is an important function of the Vav3 PH domain. A nuclear role for Vav3 was further demonstrated by sequential chromatin immunoprecipitation assays, which revealed that Vav3 and AR were recruited to the same transcriptional complexes of an AR target gene enhancer. These data demonstrate the importance of Vav3 in CRPC and define a novel nuclear function of Vav3 in regulating AR activity.

  2. Development of Prostate Specific Membrane Antigen (PSMA) Inhibitors Coupled to 99mTc(CO)3+ with Enhanced Specific Activity for SPECT Imaging

    SciTech Connect

    Paul; D.; Benny,; Clifford; Berkman,; Jeffery; Bryan

    2011-12-20

    The overall objectives of the project were two fold: 1) the development of new facile reactions for coupling radioactive complexes with biomolecules and 2) the development of a novel molecular imaging targeting vector for Prostate Specific Membrane Antigen (PSMA) for prostate cancer. The didactic approach allowed the synergistic exploration of new technologies for coupling reactions of radioactive complexes that can be applied to a novel targeting moiety. As part of the project, a number of students (undergraduate, graduate and post-doctoral) were trained in radiochemical techniques for preparing and characterizing radiometal complexes. Results from the experiments within the project have generated several presentations and publications.

  3. A Remote Arene-Binding Site on Prostate Specific Membrane Antigen Revealed by Antibody-Recruiting Small Molecules

    SciTech Connect

    Zhang, Andrew X.; Murelli, Ryan P.; Barinka, Cyril; Michel, Julien; Cocleaza, Alexandra; Jorgensen, William L.; Lubkowski, Jacek; Spiegel, David A.

    2010-09-27

    Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule-protein interactions.

  4. NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth.

    PubMed

    Papaioannou, Maria; Schleich, Sonja; Roell, Daniela; Schubert, Undine; Tanner, Tamzin; Claessens, Frank; Matusch, Rudolf; Baniahmad, Aria

    2010-12-01

    Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The ligand-activated human androgen receptor (AR) is known to control the growth of the prostate gland. Inhibition of human AR is therefore a major goal in treatment of patients. Here, we characterize the compound N-butylbenzene-sulfonamide (NBBS) isolated from P. africanum as a specific AR antagonist. This antihormonal activity inhibits AR- and progesterone receptor- (PR) mediated transactivation, but not the related human glucocorticoid receptor (GR) or the estrogen receptors (ERα or ERβ). Importantly, NBBS inhibits both endogenous PSA expression and growth of human PCa cells. Mechanistically, NBBS binds to AR and inhibits its translocation to the cell nucleus. Furthermore, using a battery of chemically synthesized derivatives of NBBS we revealed important structural aspects for androgen antagonism and have identified more potent AR antagonistic compounds. Our data suggest that NBBS is one of the active compounds of P. africanum bark and may serve as a naturally occurring, novel therapeutic agent for treatment of prostatic diseases. Thus, NBBS and its derivatives may serve as novel chemical platform for treatment prostatitis, BPH and PCa.

  5. Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.

    PubMed

    Dannoon, Shorouk; Ganguly, Tanushree; Cahaya, Hendry; Geruntho, Jonathan J; Galliher, Matthew S; Beyer, Sophia K; Choy, Cindy J; Hopkins, Mark R; Regan, Melanie; Blecha, Joseph E; Skultetyova, Lubica; Drake, Christopher R; Jivan, Salma; Barinka, Cyril; Jones, Ella F; Berkman, Clifford E; VanBrocklin, Henry F

    2016-06-23

    A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials. PMID:27228467

  6. Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer

    PubMed Central

    Tsavachidou, Dimitra; McDonnell, Timothy J.; Wen, Sijin; Wang, Xuemei; Vakar-Lopez, Funda; Pisters, Louis L.; Pettaway, Curtis A.; Wood, Christopher G.; Do, Kim-Anh; Thall, Peter F.; Stephens, Clifton; Efstathiou, Eleni; Taylor, Robert; Menter, David G.; Troncoso, Patricia; Lippman, Scott M.; Logothetis, Christopher J.

    2009-01-01

    Background Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation. Methods Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 μg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided. Results The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance

  7. External Beam Radiotherapy for Clinically Localized Hormone-Refractory Prostate Cancer: Clinical Significance of Nadir Prostate-Specific Antigen Value Within 12 Months

    SciTech Connect

    Ogawa, Kazuhiko Nakamura, Katsumasa; Sasaki, Tomonari; Onishi, Hiroshi; Koizumi, Masahiko; Shioyama, Yoshiyuki; Araya, Masayuki; Mukumoto, Nobutaka M.S.; Mitsumori, Michihide; Teshima, Teruki

    2009-07-01

    Purpose: To analyze retrospectively the results of external beam radiotherapy for clinically localized hormone-refractory prostate cancer and investigate the clinical significance of nadir prostate-specific antigen (PSA) value within 12 months (nPSA12) as an early estimate of clinical outcomes after radiotherapy. Methods and Materials: Eighty-four patients with localized hormone-refractory prostate cancer treated with external beam radiotherapy were retrospectively reviewed. The total radiation doses ranged from 30 to 76 Gy (median, 66 Gy), and the median follow-up period for all 84 patients was 26.9 months (range, 2.7-77.3 months). Results: The 3-year actuarial overall survival, progression-free survival (PFS), and local control rates in all 84 patients after radiotherapy were 67%, 61%, and 93%, respectively. Although distant metastases and/or regional lymph node metastases developed in 34 patients (40%) after radiotherapy, local progression was observed in only 5 patients (6%). Of all 84 patients, the median nPSA12 in patients with clinical failure and in patients without clinical failure was 3.1 ng/mL and 0.5 ng/mL, respectively. When dividing patients according to low (<0.5 ng/mL) and high ({>=}0.5 ng/mL) nPSA12 levels, the 3-year PFS rate in patients with low nPSA12 and in those with high nPSA12 was 96% and 44%, respectively (p < 0.0001). In univariate analysis, nPSA12 and pretreatment PSA value had a significant impact on PFS, and in multivariate analysis nPSA12 alone was an independent prognostic factor for PFS after radiotherapy. Conclusions: External beam radiotherapy had an excellent local control rate for clinically localized hormone-refractory prostate cancer, and nPSA12 was predictive of clinical outcomes after radiotherapy.

  8. Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy

    SciTech Connect

    Merrick, Gregory S. . E-mail: gmerrick@wheelinghospital.com; Butler, Wayne M.; Wallner, Kent E.; Galbreath, Robert W.; Allen, Zachariah A. M.S.; Adamovich, Edward

    2006-07-01

    Purpose: To determine if androgen-deprivation therapy (ADT) has an impact on cause-specific, biochemical progression-free, or overall survival after prostate brachytherapy. Methods and Materials: From April 1995 through June 2002, 938 consecutive patients underwent brachytherapy for clinical Stage T1b to T3a (2002 AJCC) prostate cancer. All patients underwent brachytherapy more than 3 years before analysis. A total of 382 patients (40.7%) received ADT with a duration of 6 months or less in 277 and more than 6 months in 105. The median follow-up was 5.4 years. Multiple clinical, treatment, and dosimetric parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. Results: The 10-year cause-specific, biochemical progression-free, and overall survival rates for the entire cohort were 96.4%, 95.9%, and 78.1%, respectively. Except for biochemical progression-free survival in high-risk patients, ADT did not statistically impact any of the three survival categories. A Cox linear-regression analysis demonstrated that Gleason score was the best predictor of cause-specific survival, whereas percent-positive biopsies, prostate volume, and risk group predicted for biochemical progression-free survival. Patient age and tobacco use were the strongest predictors of overall survival. One hundred two patients have died, with 80 of the deaths a result of cardiovascular disease (54) and second malignancies (26). To date, only 12 patients have died of metastatic prostate cancer. Conclusions: After brachytherapy, androgen-deprivation therapy did not have an impact on cause-specific or overall survival for any risk group; however, ADT had a beneficial effect on biochemical progression-free survival in high-risk patients. Cardiovascular disease and second malignancies far outweighed prostate cancer as competing causes of death.

  9. Tissue specificity in the nuclear envelope supports its functional complexity

    PubMed Central

    de las Heras, Jose I; Meinke, Peter; Batrakou, Dzmitry G; Srsen, Vlastimil; Zuleger, Nikolaj; Kerr, Alastair RW; Schirmer, Eric C

    2013-01-01

    Nuclear envelope links to inherited disease gave the conundrum of how mutations in near-ubiquitous proteins can yield many distinct pathologies, each focused in different tissues. One conundrum-resolving hypothesis is that tissue-specific partner proteins mediate these pathologies. Such partner proteins may have now been identified with recent proteome studies determining nuclear envelope composition in different tissues. These studies revealed that the majority of the total nuclear envelope proteins are tissue restricted in their expression. Moreover, functions have been found for a number these tissue-restricted nuclear envelope proteins that fit with mechanisms proposed to explain how the nuclear envelope could mediate disease, including defects in mechanical stability, cell cycle regulation, signaling, genome organization, gene expression, nucleocytoplasmic transport, and differentiation. The wide range of functions to which these proteins contribute is consistent with not only their involvement in tissue-specific nuclear envelope disease pathologies, but also tissue evolution. PMID:24213376

  10. Detection of prostate-specific antigen with biomolecule-gated AlGaN/GaN high electron mobility transistors

    NASA Astrophysics Data System (ADS)

    Li, Jia-dong; Cheng, Jun-jie; Miao, Bin; Wei, Xiao-wei; Xie, Jie; Zhang, Jin-cheng; Zhang, Zhi-qiang; Wu, Dong-min

    2014-07-01

    In order to improve the sensitivity of AlGaN/GaN high electron mobility transistor (HEMT) biosensors, a simple biomolecule-gated AlGaN/GaN HEMT structure was designed and successfully fabricated for prostate specific antigen (PSA) detection. UV/ozone was used to oxidize the GaN surface and then a 3-aminopropyl trimethoxysilane (APTES) self-assembled monolayer was bound to the sensing region. This monolayer serves as a binding layer for attachment of the prostate specific antibody (anti-PSA). The biomolecule-gated AlGaN/GaN HEMT sensor shows a rapid and sensitive response when the target prostate-specific antigen in buffer solution was added to the antibody-immobilized sensing area. The current change showed a logarithm relationship against the PSA concentration from 0.1 pg/ml to 0.993 ng/ml. The sensitivity of 0.215% is determined for 0.1 pg/ml PSA solution. The above experimental result of the biomolecule-gated AlGaN/GaN HEMT biosensor suggested that this biosensor might be a useful tool for prostate cancer screening.

  11. Issues on standardization of immunoassays for prostate-specific antigen: a review.

    PubMed

    Graves, H C

    1993-12-01

    The proposed use of serum prostate-specific antigen (PSA) for annual screening of men over age 50 will require careful standardization of the various commercial immunoassays to allow year-to-year comparisons for individual patients. Some current PSA assays give significantly different results on testing the same sample. The standardization process will require several steps. First, a primary antigen standard should be purified from seminal plasma (a convenient source), using a reproducible technique. The modified Sensabaugh-Blake purification of PSA yields a suitable pure antigen. Next, PSA values need to be assigned to PSA-containing serum samples. These secondary serum-based reference materials can be used by manufacturers and regulatory agencies to develop and monitor the performance of PSA assays. In serum, 2 forms of PSA are detected immunologically: a free form (M(r) = 30 kD) and a form complexed with alpha-1-antichymotrypsin (M(r) = 100 kD). Different immunoassays for PSA detect these 2 forms in different molar ratios. The most promising approach to this problem is to select a reference immunoassay that detects both forms of PSA in equal molar ratios. A series of samples containing various and known levels of naturally occurring serum PSA can then serve as secondary serum-based reference materials for calibration of other commercial PSA immunoassays. Equimolar standardization is a useful method for any set of assays that detect free and bound forms of a ligand in differing molar ratios. The technical simplicity and power of this approach should allow early agreement on standardization of PSA immunoassays and will greatly assist PSA screening programs for prostate cancer now in progress.

  12. TR4 nuclear receptor functions as a tumor suppressor for prostate tumorigenesis via modulation of DNA damage/repair system.

    PubMed

    Lin, Shin-Jen; Lee, Soo Ok; Lee, Yi-Fen; Miyamoto, Hiroshi; Yang, Dong-Rong; Li, Gonghui; Chang, Chawnshang

    2014-06-01

    Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia development. Knocking down TR4 in human RWPE1 and mouse mPrE normal prostate cells promoted tumorigenesis under carcinogen challenge, suggesting TR4 may play a suppressor role in PCa initiation. Mechanism dissection in both in vitro cell lines and in vivo mice studies found that knocking down TR4 led to increased DNA damage with altered DNA repair system that involved the modulation of ATM expression at the transcriptional level, and addition of ATM partially interrupted the TR4 small interfering RNA-induced tumorigenesis in cell transformation assays. Immunohistochemical staining in human PCa tissue microarrays revealed ATM expression is highly correlated with TR4 expression. Together, these results suggest TR4 may function as a tumor suppressor to prevent or delay prostate tumorigenesis via regulating ATM expression at the transcriptional level. PMID:24583925

  13. Comprehensively evaluating cis-regulatory variation in the human prostate transcriptome by using gene-level allele-specific expression.

    PubMed

    Larson, Nicholas B; McDonnell, Shannon; French, Amy J; Fogarty, Zach; Cheville, John; Middha, Sumit; Riska, Shaun; Baheti, Saurabh; Nair, Asha A; Wang, Liang; Schaid, Daniel J; Thibodeau, Stephen N

    2015-06-01

    The identification of cis-acting regulatory variation in primary tissues has the potential to elucidate the genetic basis of complex traits and further our understanding of transcriptomic diversity across cell types. Expression quantitative trait locus (eQTL) association analysis using RNA sequencing (RNA-seq) data can improve upon the detection of cis-acting regulatory variation by leveraging allele-specific expression (ASE) patterns in association analysis. Here, we present a comprehensive evaluation of cis-acting eQTLs by analyzing RNA-seq gene-expression data and genome-wide high-density genotypes from 471 samples of normal primary prostate tissue. Using statistical models that integrate ASE information, we identified extensive cis-eQTLs across the prostate transcriptome and found that approximately 70% of expressed genes corresponded to a significant eQTL at a gene-level false-discovery rate of 0.05. Overall, cis-eQTLs were heavily concentrated near the transcription start and stop sites of affected genes, and effects were negatively correlated with distance. We identified multiple instances of cis-acting co-regulation by using phased genotype data and discovered 233 SNPs as the most strongly associated eQTLs for more than one gene. We also noted significant enrichment (25/50, p = 2E-5) of previously reported prostate cancer risk SNPs in prostate eQTLs. Our results illustrate the benefit of assessing ASE data in cis-eQTL analyses by showing better reproducibility of prior eQTL findings than of eQTL mapping based on total expression alone. Altogether, our analysis provides extensive functional context of thousands of SNPs in prostate tissue, and these results will be of critical value in guiding studies examining disease of the human prostate.

  14. Molecular Form Differences Between Prostate-Specific Antigen (PSA) Standards Create Quantitative Discordances in PSA ELISA Measurements

    NASA Astrophysics Data System (ADS)

    McJimpsey, Erica L.

    2016-02-01

    The prostate-specific antigen (PSA) assays currently employed for the detection of prostate cancer (PCa) lack the specificity needed to differentiate PCa from benign prostatic hyperplasia and have high false positive rates. The PSA calibrants used to create calibration curves in these assays are typically purified from seminal plasma and contain many molecular forms (intact PSA and cleaved subforms). The purpose of this study was to determine if the composition of the PSA molecular forms found in these PSA standards contribute to the lack of PSA test reliability. To this end, seminal plasma purified PSA standards from different commercial sources were investigated by western blot (WB) and in multiple research grade PSA ELISAs. The WB results revealed that all of the PSA standards contained different mass concentrations of intact and cleaved molecular forms. Increased mass concentrations of intact PSA yielded higher immunoassay absorbance values, even between lots from the same manufacturer. Standardization of seminal plasma derived PSA calibrant molecular form mass concentrations and purification methods will assist in closing the gaps in PCa testing measurements that require the use of PSA values, such as the % free PSA and Prostate Health Index by increasing the accuracy of the calibration curves.

  15. Betulinic Acid Selectively Increases Protein Degradation and Enhances Prostate Cancer-Specific Apoptosis: Possible Role for Inhibition of Deubiquitinase Activity

    PubMed Central

    Reiner, Teresita; Parrondo, Ricardo; de las Pozas, Alicia; Palenzuela, Deanna; Perez-Stable, Carlos

    2013-01-01

    Inhibition of the ubiquitin-proteasome system (UPS) of protein degradation is a valid anti-cancer strategy and has led to the approval of bortezomib for the treatment of multiple myeloma. However, the alternative approach of enhancing the degradation of oncoproteins that are frequently overexpressed in cancers is less developed. Betulinic acid (BA) is a plant-derived small molecule that can increase apoptosis specifically in cancer but not in normal cells, making it an attractive anti-cancer agent. Our results in prostate cancer suggested that BA inhibited multiple deubiquitinases (DUBs), which resulted in the accumulation of poly-ubiquitinated proteins, decreased levels of oncoproteins, and increased apoptotic cell death. In normal fibroblasts, however, BA did not inhibit DUB activity nor increased total poly-ubiquitinated proteins, which was associated with a lack of effect on cell death. In the TRAMP transgenic mouse model of prostate cancer, treatment with BA (10 mg/kg) inhibited primary tumors, increased apoptosis, decreased angiogenesis and proliferation, and lowered androgen receptor and cyclin D1 protein. BA treatment also inhibited DUB activity and increased ubiquitinated proteins in TRAMP prostate cancer but had no effect on apoptosis or ubiquitination in normal mouse tissues. Overall, our data suggests that BA-mediated inhibition of DUBs and induction of apoptotic cell death specifically in prostate cancer but not in normal cells and tissues may provide an effective non-toxic and clinically selective agent for chemotherapy. PMID:23424652

  16. Construction of novel electrochemical immunosensor for detection of prostate specific antigen using ferrocene-PAMAM dendrimers.

    PubMed

    Çevik, Emre; Bahar, Özlem; Şenel, Mehmet; Abasıyanık, M Fatih

    2016-12-15

    In this study, an immunosensor was designed to utilize for the detection of prostate specific antigen (PSA) based on three different generations (G1, G2 and G3) of ferrocene (Fc) cored polyamidiamine dendrimers (Fc-PAMAM) gold (Au) electrode. The self-assembled monolayer principle (SAM) was used to fabricate the sensitive, selective and disposable immunosensor electrodes. In electrode fabrication cysteamine (Cys) was the first agent covalently linked on the Au electrode surface. Immobilized redox center (ferrocene) cored PAMAM dendrimers served as a layer for the further binding of biological components. The monoclonal antibody of PSA (anti-PSA) was covalently immobilized on dendrimers which were attached onto the modified Au surface (Au/Cys/Fc-PAMAMs/anti-PSA). PSA levels were quantitatively analyzed by using electrochemical differential pulse voltammetry (DPV) whose lowest detection limit was calculated as 0.001ngmL(-1). The Au/Cys/FcPAMAM/anti-PSA immunosensor showed excellent performance for PSA at the pulse amplitude; 50mV and the scan rate; 10mV/s in a wide linear concentration range of 0.01ng-100ngmL(-1). Analytical performance and specificity assays were carried out using human serum and different proteins.

  17. Aptamer-MIP hybrid receptor for highly sensitive electrochemical detection of prostate specific antigen.

    PubMed

    Jolly, Pawan; Tamboli, Vibha; Harniman, Robert L; Estrela, Pedro; Allender, Chris J; Bowen, Jenna L

    2016-01-15

    This study reports the design and evaluation of a new synthetic receptor sensor based on the amalgamation of biomolecular recognition elements and molecular imprinting to overcome some of the challenges faced by conventional protein imprinting. A thiolated DNA aptamer with established affinity for prostate specific antigen (PSA) was complexed with PSA prior to being immobilised on the surface of a gold electrode. Controlled electropolymerisation of dopamine around the complex served to both entrap the complex, holding the aptamer in, or near to, it's binding conformation, and to localise the PSA binding sites at the sensor surface. Following removal of PSA, it was proposed that the molecularly imprinted polymer (MIP) cavity would act synergistically with the embedded aptamer to form a hybrid receptor (apta-MIP), displaying recognition properties superior to that of aptamer alone. Electrochemical impedance spectroscopy (EIS) was used to evaluate subsequent rebinding of PSA to the apta-MIP surface. The apta-MIP sensor showed high sensitivity with a linear response from 100pg/ml to 100ng/ml of PSA and a limit of detection of 1pg/ml, which was three-fold higher than aptamer alone sensor for PSA. Furthermore, the sensor demonstrated low cross-reactivity with a homologous protein (human Kallikrein 2) and low response to human serum albumin (HSA), suggesting possible resilience to the non-specific binding of serum proteins.

  18. Construction of novel electrochemical immunosensor for detection of prostate specific antigen using ferrocene-PAMAM dendrimers.

    PubMed

    Çevik, Emre; Bahar, Özlem; Şenel, Mehmet; Abasıyanık, M Fatih

    2016-12-15

    In this study, an immunosensor was designed to utilize for the detection of prostate specific antigen (PSA) based on three different generations (G1, G2 and G3) of ferrocene (Fc) cored polyamidiamine dendrimers (Fc-PAMAM) gold (Au) electrode. The self-assembled monolayer principle (SAM) was used to fabricate the sensitive, selective and disposable immunosensor electrodes. In electrode fabrication cysteamine (Cys) was the first agent covalently linked on the Au electrode surface. Immobilized redox center (ferrocene) cored PAMAM dendrimers served as a layer for the further binding of biological components. The monoclonal antibody of PSA (anti-PSA) was covalently immobilized on dendrimers which were attached onto the modified Au surface (Au/Cys/Fc-PAMAMs/anti-PSA). PSA levels were quantitatively analyzed by using electrochemical differential pulse voltammetry (DPV) whose lowest detection limit was calculated as 0.001ngmL(-1). The Au/Cys/FcPAMAM/anti-PSA immunosensor showed excellent performance for PSA at the pulse amplitude; 50mV and the scan rate; 10mV/s in a wide linear concentration range of 0.01ng-100ngmL(-1). Analytical performance and specificity assays were carried out using human serum and different proteins. PMID:27641479

  19. Specificity of anti-prostate cancer CYP17A1 inhibitors on androgen biosynthesis.

    PubMed

    Udhane, Sameer S; Dick, Bernhard; Hu, Qingzhong; Hartmann, Rolf W; Pandey, Amit V

    2016-09-01

    The orteronel, abiraterone and galeterone, which were developed to treat castration resistant prostate cancer, inhibit 17,20 lyase activity but little is known about their effects on adrenal androgen biosynthesis. We studied the effect of several inhibitors and found that orteronel was selective towards 17,20 lyase activity than abiraterone and galeterone. Gene expression analysis showed that galeterone altered the expression of HSD3B2 but orteronel did not change the expression of HSD3B2, CYP17A1 and AKR1C3. The CYP19A1 activity was not inhibited except by compound IV which lowered activity by 23%. Surprisingly abiraterone caused complete blockade of CYP21A2 activity. Analysis of steroid metabolome by gas chromatography - mass spectrometry revealed changes in steroid levels caused by different inhibitors. We can conclude that orteronel is a highly specific inhibitor of 17,20 lyase activity. The discovery of these specific drug actions on steroidogenic enzyme activities would be valuable for understanding the regulation of androgens. PMID:27395338

  20. Prostate-specific antigen nadir after high-dose-rate brachytherapy predicts long-term survival outcomes in high-risk prostate cancer

    PubMed Central

    Satoh, Takefumi; Ishiyama, Hiromichi; Tabata, Ken-ichi; Komori, Shouko; Sekiguchi, Akane; Ikeda, Masaomi; Kurosaka, Shinji; Fujita, Tetsuo; Kitano, Masashi; Hayakawa, Kazushige; Iwamura, Masatsugu

    2016-01-01

    Purpose To evaluate the prognostic value of prostate-specific antigen nadir (nPSA) after high-dose-rate (HDR) brachytherapy in clinically non-metastatic high-risk prostate cancer patients. Material and methods Data from 216 patients with high-risk or locally advanced prostate cancer who underwent HDR brachytherapy and external beam radiation therapy with long-term androgen deprivation therapy (ADT) between 2003 and 2008 were analyzed. The median prostate-specific antigen (PSA) level at diagnosis was 24 ng/ml (range: 3-338 ng/ml). The clinical stage was T1c-2a in 55 cases (26%), T2b-2c in 48 (22%), T3a in 75 (35%), and T3b-4 in 38 (17%). The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After 5 fractions, external beam radiation therapy with 10 fractions of 3 Gy was administered. All patients initially underwent neoadjuvant ADT for at least 6 months, and adjuvant ADT was continued for 36 months. The median follow-up was 7 years from the start of radiotherapy. Results The 7-year PSA relapse-free rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 94%, compared with 23% for patients with higher nPSA values (HR = 28.57; 95% CI: 12.04-66.66; p < 0.001). Multivariate analysis revealed that the nPSA value after radiotherapy was a significant independent predictor of biochemical failure, whereas pretreatment predictive values for worse biochemical control including higher level of initial PSA, Gleason score ≥ 8, positive biopsy core rate ≥ 67%, and T3b-T4, failed to reach independent predictor status. The 7-year cancer-specific survival rate among patients with a post-radiotherapy nPSA level of ≤ 0.02 ng/ml was 99%, compared with 82% for patients with higher nPSA values (HR = 32.25; 95% CI: 3.401-333.3; p = 0.002). Conclusions A post-radiotherapy nPSA value of ≤ 0.02 ng/ml was associated with better long-term biochemical tumor control even if patients had pretreatment predictive values for worse

  1. Urinary microRNA-based signature improves accuracy of detection of clinically relevant prostate cancer within the prostate-specific antigen grey zone.

    PubMed

    Salido-Guadarrama, Alberto Ivan; Morales-Montor, Jorge Gustavo; Rangel-Escareño, Claudia; Langley, Elizabeth; Peralta-Zaragoza, Oscar; Cruz Colin, Jose Luis; Rodriguez-Dorantes, Mauricio

    2016-06-01

    At present, prostate-specific antigen (PSA) is used as a clinical biomarker for prostate cancer (PCa) diagnosis; however, a large number of patients with benign prostate hyperplasia (BPH) with PSA levels in the 'gray area' (4-10 ng/ml) are currently subjected to unnecessary biopsy due to overdiagnosis. Certain microRNAs (miRs) have been proven to be useful biomarkers, several of which are detectable in bodily fluids. The present study identified and validated a urinary miR‑based signature to enhance the specificity of PCa diagnosis and to reduce the number of patients with benign conditions undergoing biopsy. Seventy‑three urine samples from Mexican patients with diagnosis of PCa with a Gleason score ≥7 and 70 patients diagnosed with BPH were collected after digital rectal examination (DRE) of the prostate. miR expression profiles were determined using TaqMan Low Density Array experiments, and normalized Ct values for the miRs were compared between PCa and BPH groups. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether miR detection in urine is suitable for distinguishing patients with PCa from those with BPH. The identified miR‑100/200b signature was significantly correlated with PCa. Using a multivariable logistic regression approach, a base model including the clinical variables age, prostate‑specific antigen (PSA), the percentage of free PSA and DRE was generated, and a second base model additionally contained the miR‑100/200b signature. ROC analysis demonstrated that the combined model significantly outperformed the capacity of PSA (P<0.001) and the base model (P=0.01) to discriminate between PCa and BPH patients. In terms of evaluation of the sub‑group of patients in the gray zone of PSA levels, the performance of the combined model for predicting PCa cases was significantly superior to PSA level determination (P<0.001) and the base model (P=0.009). In addition, decision curve analysis demonstrated that the

  2. What pretreatment prostate-specific antigen level warrants long-term androgen deprivation?

    SciTech Connect

    Feigenberg, Steven J. . E-mail: S_Feigenberg@fccc.edu; Hanlon, Alexandra L.; Horwitz, Eric M.; Uzzo, Robert G.; Eisenberg, Debra F.; Pollack, Alan

    2005-03-15

    Purpose: Several large randomized prospective studies have demonstrated a survival benefit with the addition of long-term androgen deprivation to definitive radiotherapy for patients with Gleason score 8-10 or T3-T4 prostate cancer. However, these studies were performed before the routine use of prostate-specific antigen (PSA) measurement. The purpose of this study was to determine what pretreatment (initial) PSA (iPSA) level, if any, warrants the addition of long-term androgen deprivation in the PSA era. Methods and materials: The data set evaluated consisted of 1003 prostate cancer patients treated definitively with three-dimensional conformal radiotherapy between May 1, 1989 and November 30, 1999 (median follow-up, 61 months). Specifically excluded were patients with T3-T4 disease or Gleason score greater than 7 or those who had undergone androgen deprivation as a part of their initial therapy. The median radiation dose was 76 Gy. Patients were randomly split into two data sets, with the first (n = 487) used to evaluate the optimal iPSA cutpoint for which a statistically significant difference in outcome was noted. The second data set (n = 516) served as a validation data set for the initial modeling. The analysis of the optimal iPSA cutpoint was based on a recursive partitioning approach for censored data using the log-rank test for nodal separation of freedom from biochemical failure (FFBF) as defined by the American Society for Therapeutic Radiology and Oncology definition. Cox multivariate regression analysis was used to confirm independent predictors of outcome among the clinical and treatment-related factors: iPSA (grouped as defined by the recursive partitioning analysis), Gleason score (2-6 vs. 7), T stage (T1c-T2a vs. T2b-T2c), and total radiation dose (continuous). Results: The recursive partitioning analysis data set resulted in an optimal iPSA cutpoint of 35 ng/mL, such that the 5-year Kaplan-Meier estimate of FFBF was 80%, 69%, and 19% for i

  3. Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells.

    PubMed

    Johnston, Paul A; Nguyen, Minh M; Dar, Javid A; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P; Hua, Yun; Huryn, Donna M; Wilson, Gabriela Mustata; Lazo, John S; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2016-05-01

    Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

  4. Cysteine (C)-X-C Receptor 4 Undergoes Transportin 1-Dependent Nuclear Localization and Remains Functional at the Nucleus of Metastatic Prostate Cancer Cells

    PubMed Central

    Don-Salu-Hewage, Ayesha S.; Chan, Siu Yuen; McAndrews, Kathleen M.; Chetram, Mahandranauth A.; Dawson, Michelle R.; Bethea, Danaya A.; Hinton, Cimona V.

    2013-01-01

    The G-protein coupled receptor (GPCR), Cysteine (C)-X-C Receptor 4 (CXCR4), plays an important role in prostate cancer metastasis. CXCR4 is generally regarded as a plasma membrane receptor where it transmits signals that support transformation, progression and eventual metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutics approaches such as antagonist and monoclonal antibodies have focused on receptors that exist on the plasma membrane. An emerging concept for G-protein coupled receptors is that they may localize to and associate with the nucleus where they retain function and mediate nuclear signaling. Herein, we demonstrate that CXCR4 associated with the nucleus of malignant prostate cancer tissues. Likewise, expression of CXCR4 was detected in nuclear fractions among several prostate cancer cell lines, compared to normal prostate epithelial cells. Our studies identified a nuclear pool of CXCR4 and we defined a nuclear transport pathway for CXCR4. We reveal a putative nuclear localization sequence (NLS), ‘RPRK’, within CXCR4 that contributed to nuclear localization. Additionally, nuclear CXCR4 interacted with Transportinβ1 and Transportinβ1-binding to CXCR4 promoted its nuclear translocation. Importantly, Gαi immunoprecipitation and calcium mobilization studies indicated that nuclear CXCR4 was functional and participated in G-protein signaling, revealing that the nuclear pool of CXCR4 retained function. Given the suggestion that functional, nuclear CXCR4 may be a mechanism underlying prostate cancer recurrence, increased metastatic ability and poorer prognosis after tumors have been treated with therapy that targets plasma membrane CXCR4, these studies addresses a novel mechanism of nuclear signaling for CXCR4, a novel mechanism of clinical targeting, and demonstrate an active nuclear pool that provides important new information to illuminate what has been primarily clinical reports of nuclear CXCR4. PMID:23468933

  5. Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Tagawa, Scott T.; Akhtar, Naveed H.; Nikolopoulou, Anastasia; Kaur, Gurveen; Robinson, Brian; Kahn, Renee; Vallabhajosula, Shankar; Goldsmith, Stanley J.; Nanus, David M.; Bander, Neil H.

    2013-01-01

    Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT. PMID:23986881

  6. Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen monoclonal antibody j591 in men with metastatic castration-resistant prostate cancer.

    PubMed

    Tagawa, Scott T; Akhtar, Naveed H; Nikolopoulou, Anastasia; Kaur, Gurveen; Robinson, Brian; Kahn, Renee; Vallabhajosula, Shankar; Goldsmith, Stanley J; Nanus, David M; Bander, Neil H

    2013-01-01

    Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin's lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing (177)Lu- or (90)Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT.

  7. Proteomic Upregulation of Fatty Acid Synthase and Fatty Acid Binding Protein 5 and Identification of Cancer- and Race-Specific Pathway Associations in Human Prostate Cancer Tissues

    PubMed Central

    Myers, Jennifer S.; von Lersner, Ariana K.; Sang, Qing-Xiang Amy

    2016-01-01

    Protein profiling studies of prostate cancer have been widely used to characterize molecular differences between diseased and non-diseased tissues. When combined with pathway analysis, profiling approaches are able to identify molecular mechanisms of prostate cancer, group patients by cancer subtype, and predict prognosis. This strategy can also be implemented to study prostate cancer in very specific populations, such as African Americans who have higher rates of prostate cancer incidence and mortality than other racial groups in the United States. In this study, age-, stage-, and Gleason score-matched prostate tumor specimen from African American and Caucasian American men, along with non-malignant adjacent prostate tissue from these same patients, were compared. Protein expression changes and altered pathway associations were identified in prostate cancer generally and in African American prostate cancer specifically. In comparing tumor to non-malignant samples, 45 proteins were significantly cancer-associated and 3 proteins were significantly downregulated in tumor samples. Notably, fatty acid synthase (FASN) and epidermal fatty acid-binding protein (FABP5) were upregulated in human prostate cancer tissues, consistent with their known functions in prostate cancer progression. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3) was also upregulated in tumor samples. The Metastasis Associated Protein 3 (MTA3) pathway was significantly enriched in tumor samples compared to non-malignant samples. While the current experiment was unable to detect statistically significant differences in protein expression between African American and Caucasian American samples, differences in overrepresentation and pathway enrichment were found. Structural components (Cytoskeletal Proteins and Extracellular Matrix Protein protein classes, and Biological Adhesion Gene Ontology (GO) annotation) were overrepresented in African American but not Caucasian American tumors. Additionally, 5

  8. Proteomic Upregulation of Fatty Acid Synthase and Fatty Acid Binding Protein 5 and Identification of Cancer- and Race-Specific Pathway Associations in Human Prostate Cancer Tissues.

    PubMed

    Myers, Jennifer S; von Lersner, Ariana K; Sang, Qing-Xiang Amy

    2016-01-01

    Protein profiling studies of prostate cancer have been widely used to characterize molecular differences between diseased and non-diseased tissues. When combined with pathway analysis, profiling approaches are able to identify molecular mechanisms of prostate cancer, group patients by cancer subtype, and predict prognosis. This strategy can also be implemented to study prostate cancer in very specific populations, such as African Americans who have higher rates of prostate cancer incidence and mortality than other racial groups in the United States. In this study, age-, stage-, and Gleason score-matched prostate tumor specimen from African American and Caucasian American men, along with non-malignant adjacent prostate tissue from these same patients, were compared. Protein expression changes and altered pathway associations were identified in prostate cancer generally and in African American prostate cancer specifically. In comparing tumor to non-malignant samples, 45 proteins were significantly cancer-associated and 3 proteins were significantly downregulated in tumor samples. Notably, fatty acid synthase (FASN) and epidermal fatty acid-binding protein (FABP5) were upregulated in human prostate cancer tissues, consistent with their known functions in prostate cancer progression. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3) was also upregulated in tumor samples. The Metastasis Associated Protein 3 (MTA3) pathway was significantly enriched in tumor samples compared to non-malignant samples. While the current experiment was unable to detect statistically significant differences in protein expression between African American and Caucasian American samples, differences in overrepresentation and pathway enrichment were found. Structural components (Cytoskeletal Proteins and Extracellular Matrix Protein protein classes, and Biological Adhesion Gene Ontology (GO) annotation) were overrepresented in African American but not Caucasian American tumors. Additionally, 5

  9. Proteomic Upregulation of Fatty Acid Synthase and Fatty Acid Binding Protein 5 and Identification of Cancer- and Race-Specific Pathway Associations in Human Prostate Cancer Tissues.

    PubMed

    Myers, Jennifer S; von Lersner, Ariana K; Sang, Qing-Xiang Amy

    2016-01-01

    Protein profiling studies of prostate cancer have been widely used to characterize molecular differences between diseased and non-diseased tissues. When combined with pathway analysis, profiling approaches are able to identify molecular mechanisms of prostate cancer, group patients by cancer subtype, and predict prognosis. This strategy can also be implemented to study prostate cancer in very specific populations, such as African Americans who have higher rates of prostate cancer incidence and mortality than other racial groups in the United States. In this study, age-, stage-, and Gleason score-matched prostate tumor specimen from African American and Caucasian American men, along with non-malignant adjacent prostate tissue from these same patients, were compared. Protein expression changes and altered pathway associations were identified in prostate cancer generally and in African American prostate cancer specifically. In comparing tumor to non-malignant samples, 45 proteins were significantly cancer-associated and 3 proteins were significantly downregulated in tumor samples. Notably, fatty acid synthase (FASN) and epidermal fatty acid-binding protein (FABP5) were upregulated in human prostate cancer tissues, consistent with their known functions in prostate cancer progression. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3) was also upregulated in tumor samples. The Metastasis Associated Protein 3 (MTA3) pathway was significantly enriched in tumor samples compared to non-malignant samples. While the current experiment was unable to detect statistically significant differences in protein expression between African American and Caucasian American samples, differences in overrepresentation and pathway enrichment were found. Structural components (Cytoskeletal Proteins and Extracellular Matrix Protein protein classes, and Biological Adhesion Gene Ontology (GO) annotation) were overrepresented in African American but not Caucasian American tumors. Additionally, 5

  10. Biochemical characterization of nuclear receptors for vitamin D{sub 3} and glucocorticoids in prostate stroma cell microenvironment

    SciTech Connect

    Hidalgo, Alejandro A.; Montecinos, Viviana P.; Paredes, Roberto; Godoy, Alejandro S.; McNerney, Eileen M.; Tovar, Heribelt; Pantoja, Diego; Johnson, Candace; Trump, Donald; Onate, Sergio A.

    2011-08-19

    Highlights: {yields} Fibroblasts from benign and carcinoma-associated stroma were biochemically characterized for VDR and GR function as transcription factors in prostate stroma cell microenvironment. {yields} Decreased SRC-1/CBP coactivators recruitment to VDR and GR may result in hormone resistance to 1,25D{sub 3} in stromal cell microenvironment prostate cancer. {yields} 1a,25-Dyhidroxyvitamin D{sub 3} (1,25D{sub 3}) and glucocorticoids, either alone or in combination, may not be an alternative for 'some' advanced prostate cancers that fails androgen therapies. -- Abstract: The disruption of stromal cell signals in prostate tissue microenvironment influences the development of prostate cancer to androgen independence. 1{alpha},25-Dihydroxyvitamin D{sub 3} (1,25D{sub 3}) and glucocorticoids, either alone or in combination, have been investigated as alternatives for the treatment of advanced prostate cancers that fails androgen therapies. The effects of glucocorticoids are mediated by the intracellular glucocorticoid receptor (GR). Similarly, the effect of 1,25D{sub 3} is mediated by the 1,25D{sub 3} nuclear receptor (VDR). In this study, fibroblasts from benign- (BAS) and carcinoma-associated stroma (CAS) were isolated from human prostates to characterize VDR and GR function as transcription factors in prostate stroma. The VDR-mediated transcriptional activity assessed using the CYP24-luciferase reporter was limited to 3-fold induction by 1,25D{sub 3} in 9 out of 13 CAS (70%), as compared to >10-fold induction in the BAS clinical sample pair. Expression of His-tagged VDR (Ad-his-VDR) failed to recover the low transcriptional activity of the luciferase reporter in 7 out of 9 CAS. Interestingly, expression of Ad-his-VDR successfully recovered receptor-mediated induction in 2 out of the 9 CAS analyzed, suggesting that changes in the receptor protein itself was responsible for decreased response and resistance to 1,25D{sub 3} action. Conversely, VDR

  11. In vitro characterization of radiolabeled monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen.

    PubMed

    Smith-Jones, P M; Vallabahajosula, S; Goldsmith, S J; Navarro, V; Hunter, C J; Bastidas, D; Bander, N H

    2000-09-15

    Prostate-specific membrane antigen (PSMA) is a well-characterized cell surface antigen expressed by virtually all prostate cancers (PCas). PSMA has been successfully targeted in vivo with (111)In-labeled 7E11 monoclonal antibody (mAb; ProstaScint; Cytogen, Princeton, NJ), which binds to an intracellular epitope of PSMA. This work reports the in vitro characterization of three recently developed mAbs that bind the extracellular domain of PSMA (PSMAext). Murine mAbs J415, J533, J591, and 7E11 were radiolabeled with 131I and evaluated in competitive and saturation binding studies with substrates derived from LNCaP cells. J415 and J591 were conjugated to 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid labeled with (111)In. The uptake and cellular processing of these antibodies were evaluated in viable LNCaP cells. All four mAbs could be labeled with 131I up to a specific activity of 350 MBq/mg with no or little apparent loss of immunoreactivity. Competition assays revealed that J415 and J591 compete for binding to PSMAext antigen. J533 bound to a region close to the J591 binding epitope, but J533 did not interfere with J415 binding to PSMA. mAb 7E11 did not inhibit the binding of J415, J533, or J591 (or vice versa), consistent with earlier work that these latter mAbs bind PSMAext whereas 7E11 binds the intracellular domain of PSMA. Saturation binding studies demonstrated that J415 and J591 bound with a similar affinity (Kds 1.76 and 1.83 nM), whereas J533 had a lower affinity (Kd, 18 nM). In parallel studies, all four mAbs bound to a similar number of PSMA sites expressed by permeabilized cells (1,000,000-1,300,000 sites/cell). In parallel studies performed with viable LNCaP cells, J415, J533, and J591 bound to a similar number of PSMA sites (i.e., 600,000-800,000 sites/cell), whereas 7E11 bound only to a subpopulation of the available PSMA sites (95,000 sites/cell). This apparent binding of 7E11 to viable cells can be accounted for by a 5

  12. Standard specification for nuclear grade hafnium oxide pellets. ASTM standard

    SciTech Connect

    1998-05-01

    This specification is under the jurisdiction of ASTM Committee C-26 on Nuclear Fuel Cycle and is the direct responsibility of Subcommittee C26.03 on Neutron Absorber Materials Specifications. Current edition approved May 10, 1997. Published May 1998. Originally published as C 1076-87. Last previous edition C 1076-92.

  13. Inhibitor of p52 NF-κB subunit and androgen receptor (AR) interaction reduces growth of human prostate cancer cells by abrogating nuclear translocation of p52 and phosphorylated AR(ser81).

    PubMed

    Mehraein-Ghomi, Farideh; Church, Dawn R; Schreiber, Cynthia L; Weichmann, Ashley M; Basu, Hirak S; Wilding, George

    2015-09-01

    Accumulating evidence shows that androgen receptor (AR) activation and signaling plays a key role in growth and progression in all stages of prostate cancer, even under low androgen levels or in the absence of androgen in the castration-resistant prostate cancer. Sustained activation of AR under androgen-deprived conditions may be due to its interaction with co-activators, such as p52 NF-κB subunit, and/or an increase in its stability by phosphorylation that delays its degradation. Here we identified a specific inhibitor of AR/p52 interaction, AR/p52-02, via a high throughput screen based on the reconstitution of Gaussia Luciferase. We found that AR/p52-02 markedly inhibited growth of both castration-resistant C4-2 (IC50 ∼6 μM) and parental androgen-dependent LNCaP (IC50 ∼4 μM) human prostate cancer cells under low androgen conditions. Growth inhibition was associated with significantly reduced nuclear p52 levels and DNA binding activity, as well as decreased phosphorylation of AR at serine 81, increased AR ubiquitination, and decreased AR transcriptional activity as indicated by decreased prostate-specific antigen (PSA) mRNA levels in both cell lines. AR/p52-02 also caused a reduction in levels of p21(WAF/CIP1), which is a direct AR targeted gene in that its expression correlates with androgen stimulation and mitogenic proliferation in prostate cancer under physiologic levels of androgen, likely by disrupting the AR signaling axis. The reduced level of cyclinD1 reported previously for this compound may be due to the reduction in nuclear presence and activity of p52, which directly regulates cyclinD1 expression, as well as the reduction in p21(WAF/CIP1), since p21(WAF/CIP1) is reported to stabilize nuclear cyclinD1 in prostate cancer. Overall, the data suggest that specifically inhibiting the interaction of AR with p52 and blocking activity of p52 and pARser81 may be an effective means of reducing castration-resistant prostate cancer cell growth.

  14. Improvement of Prostate Cancer Diagnosis by Detecting PSA Glycosylation-Specific Changes.

    PubMed

    Llop, Esther; Ferrer-Batallé, Montserrat; Barrabés, Sílvia; Guerrero, Pedro Enrique; Ramírez, Manel; Saldova, Radka; Rudd, Pauline M; Aleixandre, Rosa N; Comet, Josep; de Llorens, Rafael; Peracaula, Rosa

    2016-01-01

    New markers based on PSA isoforms have recently been developed to improve prostate cancer (PCa) diagnosis. However, novel approaches are still required to differentiate aggressive from non-aggressive PCa to improve decision making for patients. PSA glycoforms have been shown to be differentially expressed in PCa. In particular, changes in the extent of core fucosylation and sialylation of PSA N-glycans in PCa patients compared to healthy controls or BPH patients have been reported. The objective of this study was to determine these specific glycan structures in serum PSA to analyze their potential value as markers for discriminating between BPH and PCa of different aggressiveness. In the present work, we have established two methodologies to analyze the core fucosylation and the sialic acid linkage of PSA N-glycans in serum samples from BPH (29) and PCa (44) patients with different degrees of aggressiveness. We detected a significant decrease in the core fucose and an increase in the α2,3-sialic acid percentage of PSA in high-risk PCa that differentiated BPH and low-risk PCa from high-risk PCa patients. In particular, a cut-off value of 0.86 of the PSA core fucose ratio, could distinguish high-risk PCa patients from BPH with 90% sensitivity and 95% specificity, with an AUC of 0.94. In the case of the α2,3-sialic acid percentage of PSA, the cut-off value of 30% discriminated between high-risk PCa and the group of BPH, low-, and intermediate-risk PCa with a sensitivity and specificity of 85.7% and 95.5%, respectively, with an AUC of 0.97. The latter marker exhibited high performance in differentiating between aggressive and non-aggressive PCa and has the potential for translational application in the clinic. PMID:27279911

  15. Improvement of Prostate Cancer Diagnosis by Detecting PSA Glycosylation-Specific Changes

    PubMed Central

    Llop, Esther; Ferrer-Batallé, Montserrat; Barrabés, Sílvia; Guerrero, Pedro Enrique; Ramírez, Manel; Saldova, Radka; Rudd, Pauline M.; Aleixandre, Rosa N.; Comet, Josep; de Llorens, Rafael; Peracaula, Rosa

    2016-01-01

    New markers based on PSA isoforms have recently been developed to improve prostate cancer (PCa) diagnosis. However, novel approaches are still required to differentiate aggressive from non-aggressive PCa to improve decision making for patients. PSA glycoforms have been shown to be differentially expressed in PCa. In particular, changes in the extent of core fucosylation and sialylation of PSA N-glycans in PCa patients compared to healthy controls or BPH patients have been reported. The objective of this study was to determine these specific glycan structures in serum PSA to analyze their potential value as markers for discriminating between BPH and PCa of different aggressiveness. In the present work, we have established two methodologies to analyze the core fucosylation and the sialic acid linkage of PSA N-glycans in serum samples from BPH (29) and PCa (44) patients with different degrees of aggressiveness. We detected a significant decrease in the core fucose and an increase in the α2,3-sialic acid percentage of PSA in high-risk PCa that differentiated BPH and low-risk PCa from high-risk PCa patients. In particular, a cut-off value of 0.86 of the PSA core fucose ratio, could distinguish high-risk PCa patients from BPH with 90% sensitivity and 95% specificity, with an AUC of 0.94. In the case of the α2,3-sialic acid percentage of PSA, the cut-off value of 30% discriminated between high-risk PCa and the group of BPH, low-, and intermediate-risk PCa with a sensitivity and specificity of 85.7% and 95.5%, respectively, with an AUC of 0.97. The latter marker exhibited high performance in differentiating between aggressive and non-aggressive PCa and has the potential for translational application in the clinic. PMID:27279911

  16. Evaluating Quantum Dot Performance in Homogeneous FRET Immunoassays for Prostate Specific Antigen

    PubMed Central

    Bhuckory, Shashi; Lefebvre, Olivier; Qiu, Xue; Wegner, Karl David; Hildebrandt, Niko

    2016-01-01

    The integration of semiconductor quantum dots (QDs) into homogeneous Förster resonance energy transfer (FRET) immunoassay kits for clinical diagnostics can provide significant advantages concerning multiplexing and sensitivity. Here we present a facile and functional QD-antibody conjugation method using three commercially available QDs with different photoluminescence (PL) maxima (605 nm, 655 nm, and 705 nm). The QD-antibody conjugates were successfully applied for FRET immunoassays against prostate specific antigen (PSA) in 50 µL serum samples using Lumi4-Tb (Tb) antibody conjugates as FRET donors and time-gated PL detection on a KRYPTOR clinical plate reader. Förster distance and Tb donor background PL were directly related to the analytical sensitivity for PSA, which resulted in the lowest limits of detection for Tb-QD705 (2 ng/mL), followed by Tb-QD655 (4 ng/mL), and Tb-QD605 (23 ng/mL). Duplexed PSA detection using the Tb-QD655 and Tb-QD705 FRET-pairs demonstrated the multiplexing ability of our immunoassays. Our results show that FRET based on QD acceptors is suitable for multiplexed and sensitive biomarker detection in clinical diagnostics. PMID:26861327

  17. Portable smartphone quantitation of prostate specific antigen (PSA) in a fluoropolymer microfluidic device.

    PubMed

    Barbosa, Ana I; Gehlot, Poonam; Sidapra, Kalpita; Edwards, Alexander D; Reis, Nuno M

    2015-08-15

    We present a new, power-free and flexible detection system named MCFphone for portable colorimetric and fluorescence quantitative sandwich immunoassay detection of prostate specific antigen (PSA). The MCFphone is composed by a smartphone integrated with a magnifying lens, a simple light source and a miniaturised immunoassay platform, the Microcapillary Film (MCF). The excellent transparency and flat geometry of fluoropolymer MCF allowed quantitation of PSA in the range 0.9 to 60 ng/ml with<7% precision in 13 min using enzymatic amplification and a chromogenic substrate. The lower limit of detection was further improved from 0.4 to 0.08 ng/ml in whole blood samples with the use of a fluorescence substrate. The MCFphone has shown capable of performing rapid (13 to 22 min total assay time) colorimetric quantitative and highly sensitive fluorescence tests with good %Recovery, which represents a major step in the integration of a new generation of inexpensive and portable microfluidic devices with commercial immunoassay reagents and off-the-shelf smartphone technology.

  18. Portable smartphone quantitation of prostate specific antigen (PSA) in a fluoropolymer microfluidic device.

    PubMed

    Barbosa, Ana I; Gehlot, Poonam; Sidapra, Kalpita; Edwards, Alexander D; Reis, Nuno M

    2015-08-15

    We present a new, power-free and flexible detection system named MCFphone for portable colorimetric and fluorescence quantitative sandwich immunoassay detection of prostate specific antigen (PSA). The MCFphone is composed by a smartphone integrated with a magnifying lens, a simple light source and a miniaturised immunoassay platform, the Microcapillary Film (MCF). The excellent transparency and flat geometry of fluoropolymer MCF allowed quantitation of PSA in the range 0.9 to 60 ng/ml with<7% precision in 13 min using enzymatic amplification and a chromogenic substrate. The lower limit of detection was further improved from 0.4 to 0.08 ng/ml in whole blood samples with the use of a fluorescence substrate. The MCFphone has shown capable of performing rapid (13 to 22 min total assay time) colorimetric quantitative and highly sensitive fluorescence tests with good %Recovery, which represents a major step in the integration of a new generation of inexpensive and portable microfluidic devices with commercial immunoassay reagents and off-the-shelf smartphone technology. PMID:25775968

  19. Parallel optical read-out of micromechanical pillars applied to prostate specific membrane antigen detection.

    PubMed

    Tardivo, Martina; Toffoli, Valeria; Fracasso, Giulio; Borin, Daniele; Dal Zilio, Simone; Colusso, Andrea; Carrato, Sergio; Scoles, Giacinto; Meneghetti, Moreno; Colombatti, Marco; Lazzarino, Marco

    2015-10-15

    Micro and nanomechanical resonators represent a promising platform for proteins label-free detection because of their extreme sensitivity, fast response and low cost. Micro-pillars are columnar resonators that can be easily arranged in dense arrays of several thousand sensors in a squared mm. To exploit such a large density, however, a method for tracking independently micropillars resonance frequency is required. Here we present a detection method based on CCD imaging and software image analysis, which can measure the resonance frequency of tens of pillars in parallel. Acquiring simultaneously the frequency shift of up to 40 sensors and applying a proper statistical analysis, we were able to overcome the variability of the single measures improving the device sensitivity at low analyte concentration range. As a proof of concept, this method has been tested for the detection of a tumor marker, the Prostate Specific Membrane Antigen (PSMA). Pillars have been functionalized with an antibody against PSMA. The tumor marker (PSMA) has been detected in a range of concentrations between 300 pM and 100 nM, in buffer and in diluted bovine serum. The sensitivity of our method was limited only by the affinity constant of the antigen-antibody recognition. Moreover, this detection technique demonstrated to be effective in the 1-6 nM range, which is the window of PSMA concentration of clinical interest.

  20. Association of prostate specific antigen concentration with lifestyle characteristics in Korean men.

    PubMed

    Woo, Hee-Yeon; Park, Hyosoon; Kwon, Min-Jung; Chang, Yoosoo; Ryu, Seungho

    2012-01-01

    We investigated the relationships between demographics, lifestyle characteristics, and serum total prostate specific antigen (PSA) concentration and examined the population-based distribution of total PSA by age among 2,246 Korean men with a median age of 45 years. We obtained data about demographic and lifestyle characteristics based on self-reporting using a questionnaire. We also performed physical examinations, anthropometric measurements, and biochemical measurements. The PSA concentration increased with age and there was a significant difference in total PSA concentration between the age groups of 21-60 years and >60 years. Age>60 years, height≥1.8 m, a low frequency of alcohol consumption, and taking nutritional supplements showed a significantly increased odds ratio for increased PSA when 3.0 ng/ mL was chosen as the PSA cut-off level. Smoking status, BMI, percent body fat, diabetes mellitus, fatty liver, herbal medicine use, vitamin use, and diet were not significantly associated with total PSA regardless of the cut-off level. When interpreting a single PSA test, height, alcohol consumption, and nutritional supplement use should be considered, in addition to age. PMID:23317241

  1. ‘It's a maybe test’: men's experiences of prostate specific antigen testing in primary care

    PubMed Central

    Evans, Rhodri; Edwards, Adrian GK; Elwyn, Glyn; Watson, Eila; Grol, Richard; Brett, Jo; Austoker, Joan

    2007-01-01

    Background Prostate specific antigen (PSA) testing in primary care is an important and contentious issue. Due to concerns about the test and the value of early detection, countries such as the UK advocate ‘informed choice’ instead of population screening. It is not known whether this policy is actually adhered to in primary care. Furthermore, little is known of the experiences of men who face this decision. Aim To explore the experiences, understanding, and views of men who considered or undertook PSA testing in UK primary care. Design of study Qualitative interview-based study. Setting Primary care, Wales, UK. Method Semi-structured one-to-one interviews were conducted with 28 men, representing a range of clinical outcomes. Transcripts were coded and subjected to thematic analysis. Results Three themes were identified: the decision-making context, the locus of decision making, and uncertainty related to the PSA test. Conclusion The decision to undertake PSA testing was affected by both social and media factors and it did not appear to be a patient-led decision. The decision created considerable uncertainty for men and this uncertainty persisted after the test, even if the result was normal. Raised PSA led to further investigations and this exacerbated the uncertainty. Anxiety and regret were consequences of this uncertainty. PMID:17394734

  2. National Evidence on the Use of Shared Decision Making in Prostate-Specific Antigen Screening

    PubMed Central

    Han, Paul K. J.; Kobrin, Sarah; Breen, Nancy; Joseph, Djenaba A.; Li, Jun; Frosch, Dominick L.; Klabunde, Carrie N.

    2013-01-01

    PURPOSE Recent clinical practice guidelines on prostate cancer screening using the prostate-specific antigen (PSA) test (PSA screening) have recommended that clinicians practice shared decision making—a process involving clinician-patient discussion of the pros, cons, and uncertainties of screening. We undertook a study to determine the prevalence of shared decision making in both PSA screening and nonscreening, as well as patient characteristics associated with shared decision making. METHODS A nationally representative sample of 3,427 men aged 50 to 74 years participating in the 2010 National Health Interview Survey responded to questions on the extent of shared decision making (past physician-patient discussion of advantages, disadvantages, and scientific uncertainty associated with PSA screening), PSA screening intensity (tests in past 5 years), and sociodemographic and health-related characteristics. RESULTS Nearly two-thirds (64.3%) of men reported no past physician-patient discussion of advantages, disadvantages, or scientific uncertainty (no shared decision making); 27.8% reported discussion of 1 to 2 elements only (partial shared decision making); 8.0% reported discussion of all 3 elements (full shared decision making). Nearly one-half (44.2%) reported no PSA screening, 27.8% reported low-intensity (less-than-annual) screening, and 25.1% reported high-intensity (nearly annual) screening. Absence of shared decision making was more prevalent in men who were not screened; 88% (95% CI, 86.2%–90.1%) of nonscreened men reported no shared decision making compared with 39% (95% CI, 35.0%–43.3%) of men undergoing high-intensity screening. Extent of shared decision making was associated with black race, Hispanic ethnicity, higher education, health insurance, and physician recommendation. Screening intensity was associated with older age, higher education, usual source of medical care, and physician recommendation, as well as with partial vs no or full shared

  3. Determinants of Change in Prostate-Specific Antigen Over Time and Its Association With Recurrence After External Beam Radiation Therapy for Prostate Cancer in Five Large Cohorts

    SciTech Connect

    Proust-Lima, Cecile; Taylor, Jeremy M.G. Williams, Scott G.; Ankerst, Donna P.; Liu Ning; Kestin, Larry L.; Bae, Kyounghwa; Sandler, Howard M.

    2008-11-01

    Purpose: To assess the relationship between prognostic factors, postradiation prostate-specific antigen (PSA) dynamics, and clinical failure after prostate cancer radiation therapy using contemporary statistical models. Methods and Materials: Data from 4,247 patients with 40,324 PSA measurements treated with external beam radiation monotherapy in five cohorts were analyzed. Temporal change of PSA after treatment completion was described by a specially developed linear mixed model that included standard prognostic factors. These factors, along with predicted PSA evolution, were incorporated into a Cox model to establish their predictive value for the risk of clinical recurrence over time. Results: Consistent relationships were found across cohorts. The initial PSA decline after radiation therapy was associated with baseline PSA and T-stage (p < 0.001). The long-term PSA rise was associated with baseline PSA, T-stage, and Gleason score (p < 0.001). The risk of clinical recurrence increased with current level (p < 0.001) and current slope of PSA (p < 0.001). In a pooled analysis, higher doses of radiation were associated with a lower long-term PSA rise (p < 0.001) but not with the risk of recurrence after adjusting for PSA trajectory (p = 0.63). Conversely, after adjusting for other factors, increased age at diagnosis was not associated with long-term PSA rise (p = 0.85) but was directly associated with decreased risk of recurrence (p < 0.001). Conclusions: We conclude that a linear mixed model can be reliably used to construct typical patient PSA profiles after prostate cancer radiation therapy. Pretreatment factors along with PSA evolution and the associated risk of recurrence provide an efficient and quantitative way to assess the impact of risk factors on disease progression.

  4. Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer

    PubMed Central

    Tagawa, Scott T.; Milowsky, Matthew I.; Morris, Michael; Vallabhajosula, Shankar; Christos, Paul; Akhtar, Naveed H.; Osborne, Joseph; Goldsmith, Stanley J.; Larson, Steve; Taskar, Neeta Pandit; Scher, Howard I.; Bander, Neil H.; Nanus, David M.

    2013-01-01

    Purpose To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival. Experimental Design In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results 47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced ≥ 50% decline in PSA, 36.2% experienced ≥ 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising. PMID:23714732

  5. Determinants of change of prostate-specific antigen over time and its association with recurrence following external beam radiation therapy of prostate cancer in 5 large cohorts

    PubMed Central

    Proust-Lima, Cécile; Taylor, Jeremy M.G.; Williams, Scott G.; Ankerst, Donna P.; Liu, Ning; Kestin, Larry L.; Bae, Kyounghwa; Sandler, Howard M.

    2008-01-01

    Purpose To assess the relationship between prognostic factors, post-radiation prostate-specific antigen (PSA) dynamics, and clinical failure following prostate cancer radiation therapy using contemporary statistical models. Methods and materials Data from 4,247 patients with 40,324 PSA measurements treated with external beam radiation monotherapy in five cohorts were analyzed. Temporal change of PSA following treatment completion was described by a specially developed linear mixed model (LMM), including standard prognostic factors. These factors, along with predicted PSA evolution, were incorporated into a Cox model to establish their predictive value for the risk of clinical recurrence over time. Results Consistent relationships were found across cohorts. The initial PSA decline after radiation therapy was associated with baseline PSA and T-stage (p<0.001). The long-term PSA rise was associated with baseline PSA, T-stage and Gleason score (p<0.001). The risk of clinical recurrence increased with current level (p<0.001) and current slope of PSA (p<0.001). In a pooled analysis, higher doses of radiation were associated with a lower long-term PSA rise (p<0.001) but not with the risk of recurrence after adjusting for PSA trajectory (p=0.63). Conversely, after adjusting for other factors, increased age at diagnosis was not associated with long-term PSA rise (p=0.85) but directly associated with increased risk of recurrence (p<0.001). Conclusions LMM can be reliably used to construct typical patient PSA profiles following prostate cancer radiation therapy. Pre-treatment factors along with PSA evolution and the associated risk of recurrence provide an efficient and quantitative way to assess impact of risk factors on disease progression. PMID:19014779

  6. Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade.

    PubMed

    Olson, Brian M; Jankowska-Gan, Ewa; Becker, Jordan T; Vignali, Dario A A; Burlingham, William J; McNeel, Douglas G

    2012-12-15

    Regulatory T cells play important roles in cancer development and progression by limiting the generation of innate and adaptive anti-tumor immunity. We hypothesized that in addition to natural CD4(+)CD25(+) regulatory T cells (Tregs) and myeloid-derived suppressor cells, tumor Ag-specific Tregs interfere with the detection of anti-tumor immunity after immunotherapy. Using samples from prostate cancer patients immunized with a DNA vaccine encoding prostatic acid phosphatase (PAP) and a trans-vivo delayed-type hypersensitivity (tvDTH) assay, we found that the detection of PAP-specific effector responses after immunization was prevented by the activity of PAP-specific regulatory cells. These regulatory cells were CD8(+)CTLA-4(+), and their suppression was relieved by blockade of CTLA-4, but not IL-10 or TGF-β. Moreover, Ag-specific CD8(+) Tregs were detected prior to immunization in the absence of PAP-specific effector responses. These PAP-specific CD8(+)CTLA-4(+) suppressor T cells expressed IL-35, which was decreased after blockade of CTLA-4, and inhibition of either CTLA-4 or IL-35 reversed PAP-specific suppression of tvDTH response. PAP-specific CD8(+)CTLA-4(+) T cells also suppressed T cell proliferation in an IL-35-dependent, contact-independent fashion. Taken together, these findings suggest a novel population of CD8(+)CTLA-4(+) IL-35-secreting tumor Ag-specific Tregs arise spontaneously in some prostate cancer patients, persist during immunization, and can prevent the detection of Ag-specific effector responses by an IL-35-dependent mechanism.

  7. Prostatic cancer surveillance following whole-gland high-intensity focused ultrasound: comparison of MRI and prostate-specific antigen for detection of residual or recurrent disease

    PubMed Central

    Punwani, S; Emberton, M; Walkden, M; Sohaib, A; Freeman, A; Ahmed, H; Allen, C; Kirkham, A

    2012-01-01

    Objective This retrospective study compares dynamic contrast-enhanced (DCE) MRI with the serial prostate-specific antigen (PSA) measurement for detection of residual disease following whole-gland high-intensity focused ultrasound (HIFU) therapy of prostate cancer. Methods Patients in whom post-HIFU DCE-MRI was followed within 3 months by ultrasound-guided transrectal biopsy were selected from a local database. 26 patients met the study inclusion criteria. Serial PSA levels following HIFU and post-HIFU follow-up MRI were retrieved for each patient. Three radiologists unaware of other investigative results independently assessed post-HIFU MRI studies for the presence of cancer, scoring on a four-point scale (1, no disease; 2, probably no disease; 3, probably residual disease; and 4, residual disease). Sensitivity, specificity and receiver operating characteristic (ROC) analysis were performed for each reader, post-HIFU PSA nadir and pre-biopsy PSA level thresholds of >0.2 and >0.5 ng ml−1. Results The sensitivity of DCE-MRI for detection of residual disease for the three readers ranged between 73% and 87%, and the specificity between 73% and 82%. There was good agreement between readers (κ=0.69–0.77). The sensitivity and specificity of PSA thresholds was 60–87% and 73–100%, respectively. The area under the ROC curve was greatest for pre-biopsy PSA (0.95). Conclusion DCE-MRI performed following whole-gland HIFU has similar sensitivity and specificity and ROC performance to serial PSA measurements for detection of residual or recurrent disease. PMID:22253342

  8. Micro-PET/CT Monitoring of Herpes Thymidine Kinase Suicide Gene Therapy in a Prostate Cancer Xenograft: The Advantage of a Cell-specific Transcriptional Targeting Approach

    PubMed Central

    Johnson, Mai; Sato, Makoto; Burton, Jeremy; Gambhir, Sanjiv S.; Carey, Michael; Wu, Lily

    2010-01-01

    Cancer gene therapy based on tissue-restricted expression of cytotoxic gene should achieve superior therapeutic index over an unrestricted method. This study compared the therapeutic effects of a highly augmented, prostate-specific gene expression method to a strong constitutive promoter-driven approach. Molecular imaging was coupled to gene therapy to ascertain real-time therapeutic activity. The imaging reporter gene (luciferase) and the cytotoxic gene (herpes simplex thymidine kinase) were delivered by adenoviral vectors injected directly into human prostate tumors grafted in SCID mice. Serial bioluminescence imaging, positron emission tomography, and computed tomography revealed restriction of gene expression to the tumors when prostate-specific vector was employed. In contrast, administration of constitutive active vector resulted in strong signals in the liver. Liver serology, tissue histology, and frail condition of animals confirmed liver toxicity suffered by the constitutive active cohorts, whereas the prostate-targeted group was unaffected. The extent of tumor killing was analyzed by apoptotic staining and human prostate marker (prostate-specific antigen). Overall, the augmented prostate-specific expression system was superior to the constitutive approach in safeguarding against systemic toxicity, while achieving effective tumor killing. Integrating noninvasive imaging into cytotoxic gene therapy will provide a useful strategy to monitor gene expression and therapeutic efficacy in future clinical protocols. PMID:16285908

  9. Prostate-Specific Antigen at 4 to 5 Years After Low-Dose-Rate Prostate Brachytherapy Is a Strong Predictor of Disease-Free Survival

    SciTech Connect

    Lo, Andrea C.; Morris, W. James; Lapointe, Vincent; Hamm, Jeremy; Keyes, Mira; Pickles, Tom; McKenzie, Michael; Spadinger, Ingrid

    2014-01-01

    Purpose: To determine (1) the prognostic utility of prostate-specific antigen (PSA) concentration at 45 to 60 months (48mPSA) after low-dose-rate prostate brachytherapy (LDR-PB); (2) the predictors of 48mPSA; and (3) the prognostic utility of directional trends between PSA levels at 24, 36, and 48 months after LDR-PB. Methods and Materials: Between 1998 and 2008, 2223 patients with low- and intermediate-risk prostate cancer received LDR-PB monotherapy. A cohort of 1434 of these patients was identified with a documented 48mPSA and no evidence of disease relapse prior to the 48mPSA. In addition, a subset of this cohort (n=585) was identified with ≥72 months of follow-up and documented PSA values at both 24 and 36 months after implantation. Results: Median follow-up time was 76 months. Eight-year Kaplan-Meier disease-free survival (DFS) rates were 100% vs 73.4% for patients with 48mPSA ≤0.2 vs those with >0.2 ng/mL; 99.1% versus 53.8% for a 48mPSA threshold of ≤0.4 versus >0.4 ng/mL, respectively; and 97.3% versus 0% for a threshold of ≤1.0 versus >1.0 ng/mL, respectively. On multivariate analysis, the only factor predictive of DFS was 48mPSA (P<.0001). On subset analysis (n=585), 29 patients had a PSA rise (defined as >0.2 ng/mL) between 24 and 36 months, 24 patients had a rise between 36 and 48 months, and 11 patients had rises over both intervals. Failure rates in these patients were 52%, 79%, and 100%, respectively. On multivariate analysis, initial PSA, androgen deprivation therapy, and dose to 90% of the prostate significantly correlated with 48mPSA but together accounted for only ∼5% of its total variance. Conclusions: The 48mPSA after LDR-PB is highly predictive of long-term DFS. Patients with 48mPSA ≤0.4 ng/mL had a <1% risk of disease relapse at 8 years, whereas all patients with 48mPSA >1.0 ng/mL relapsed. Consecutive PSA rises of >0.2 ng/mL from 24 to 36 months and from 36 to 48 months were also highly predictive of subsequent failure.

  10. PDEF in prostate cancer.

    PubMed

    Sood, Ashwani K; Kim, Hyung; Geradts, Joseph

    2012-05-01

    Prostate-derived Ets factor (PDEF) is a relatively recently described member of the Ets family of transcription factors. It differs from other family members in its restricted and epithelial-specific expression in normal tissues and its unique DNA-binding motif that together may impart interesting specificity to its function. This communication reviews our current understanding of the expression characteristics of PDEF in normal prostate and in prostate cancer. Also, the biochemical and genetic evidence relating to the role of this transcription factor in prostate cancer is reviewed. Most evidence is consistent with an oncogenic role for PDEF in prostate cancer. Specific observations about the loss of PDEF expression in prostate tumors and its apparent role as a prostate tumor suppressor are also discussed. PDEF is one of the few transcription factors with potential to have a significant impact on the management of prostate cancer. A better understanding of its biology and its role in prostate cancer is urgently needed.

  11. Cadmium may impair prostate function as measured by prostate specific antigen in semen: A cross-sectional study among European and Inuit men.

    PubMed

    Andreucci, Alessandro; Mocevic, Emina; Jönsson, Bo A G; Giwercman, Aleksander; Giwercman, Yvonne Lundberg; Toft, Gunnar; Lundh, Thomas; Bizzaro, Davide; Specht, Ina Olmer; Bonde, Jens Peter

    2015-06-01

    We investigated the association between cadmium in blood and the concentration of the prostate specific antigen (PSA) in semen, including the modifying effects of zinc or the CAG polymorphism in the androgen receptor (AR). Blood and semen samples were collected from 504 partners of pregnant women in Greenland, Poland and Ukraine. We found an inverse trend between cadmium and PSA (log(β) = -0.121, 95% confidence interval (CI): -0.213; -0.029, P = 0.0103) in Greenlandic men. Similar results were observed in men with a high number of CAG repeats (CAG 24) (log(β) = -0.231, 95% CI: -0.363; -0.098, P = 0.0009). Inverse trends between cadmium and PSA were found when semen zinc concentrations were below the median value for men from Ukraine and Greenland. These outcomes suggest that cadmium may impair prostate function, as measured by PSA in semen, while high zinc levels and a low number of CAG repeats protects against this action.

  12. The Role of Positron Emission Tomography With (68)Gallium (Ga)-Labeled Prostate-specific Membrane Antigen (PSMA) in the Management of Patients With Organ-confined and Locally Advanced Prostate Cancer Prior to Radical Treatment and After Radical Prostatectomy.

    PubMed

    Rai, Bhavan Prasad; Baum, Richard Paul; Patel, Amit; Hughes, Robert; Alonzi, Roberto; Lane, Tim; Adshead, Jim; Vasdev, Nikhil

    2016-09-01

    The role of positron emission tomography (PET) with (68)Gallium (Ga)-labeled prostate-specific membrane antigen (PSMA) imaging for prostate cancer is gaining prominence. Current imaging strategies, despite having progressed significantly, have limitations, in particular their ability to diagnose metastatic lymph node involvement. Preliminary results of PET with (68)Ga-labeled PSMA have shown encouraging results, particularly in the recurrent prostate cancer setting. Furthermore, the ability of PET with (68)Ga-labeled PSMA of playing a dual diagnostic and therapeutic setting (theranostics) is currently being investigated as well. PET with (68)Ga-labeled PSMA certainly has a role to play in bridging some of the voids in contemporary prostate cancer imaging tools. PMID:26790588

  13. Impact of the US Preventive Services Task Force Grade D Recommendation: Assessment of Evaluations for Elevated Prostate-specific Antigen and Prostate Biopsies in a Large Urology Group Practice Following Statement Revision

    PubMed Central

    McGinley, Kathleen F; McMahon, Gregory C; Brown, Gordon A

    2015-01-01

    On October 7, 2011, the United States Preventive Services Task Force (USPSTF) released their evidence statement and grade D recommendation against prostate-specific antigen (PSA)-based prostate cancer screening. Using a time series design, we assessed the effect of this recommendation upon evaluations for elevated PSA levels and prostate biopsies in our large urology group practice. We found that, despite a 24.1% increase in total visits, the 32 urologists in our practice completed 16.4% fewer evaluations for elevated PSA levels (317 fewer evaluations per month; P = .017) and 21.4% fewer prostate biopsies (42 fewer biopsies per month; P = .001) in the 2 years following the USPSTF grade D recommendation. PMID:26543432

  14. Single chip SPR and fluorescent ELISA assay of prostate specific antigen.

    PubMed

    Breault-Turcot, J; Poirier-Richard, H-P; Couture, M; Pelechacz, D; Masson, J-F

    2015-12-01

    A multi-channel system combining fluidics and micropatterned plasmonic materials with wavelength interrogation surface plasmon resonance (SPR) and fluorescence detection was integrated from the combination of a small and motorized fluorescence microscope mounted on a portable 4-channel SPR instrument. The SPR and fluorescent measurements were performed based on the same detection area in a multi-channel fluidic, with a sensing scheme for prostate-specific antigen (PSA) consisting of a sandwich assay with a capture anti-PSA immobilized onto the SPR sensor and a detection anti-PSA modified with horseradish peroxidase (HRP). In this dual-detection instrument, fluorescence was measured from the solution side of the micropatterned gold film, while the interface between the glass prism and the gold film served to interrogate the SPR response. The SPR sensors were comprised of microhole arrays fabricated by photolithography to enhance the instrumental response for PSA detection by approximately a factor of 2 to 3 and they were coated with a self-assembled monolayer of a peptide (3-MPA-HHHDD-OH) to minimize nonspecific adsorption. PSA was successfully detected at clinical concentrations from 10 pM to 50 nM with this integrated system in a single assay lasting 12 minutes, almost centering on the desired range for PSA diagnostic tests (>4 ng mL(-1) or >150 pM). The combination of two robust techniques in a single chip and instrument has led to a simple and effective assay that can be carried out on a small and portable instrument providing rapid biodetection of an important cancer biomarker with a dynamic range of nearly 4 orders of magnitude in the clinical range.

  15. Power-free chip enzyme immunoassay for detection of prostate specific antigen (PSA) in serum.

    PubMed

    Adel Ahmed, Heba; Azzazy, Hassan M E

    2013-11-15

    A power-free, portable "Chip EIA" was designed to render the popular Enzyme Linked Immunosorbent Assay (ELISA) more suitable for point-of-care testing. A number of microfluidic platforms have enabled miniaturization of the conventional microtitre plate ELISA, however, they require external pumping systems, valves, and electric power supply. The Chip EIA platform has eliminated the need for pumps and valves through utilizing a simple permanent magnet and magnetic nanoparticles. The magnetic nanoparticles act as solid support to capture the target and are then moved through chambers harboring different reagents necessary to perform a sandwich ELISA. The use of magnetic nanoparticles increases the volume-to-surface ratio reducing the assay time to 30 min. Changing the color of horseradish peroxidase (HRP) substrate to green indicates a positive result. In addition, a quantitative read-out was obtained through the use of cellphone camera imaging and analyzing the images using Matlab®. Cell phones, including smart ones, are readily available almost everywhere. The Chip EIA device was used to assay total prostate specific antigen (tPSA) in 19 serum samples. The PSA Chip EIA was tested for accuracy, precision, repeatability, and the results were correlated to the commercial Beckman Colter, Hybritech immunoassay® for determination of tPSA in serum samples with a Pearson correlation coefficient (R(2)=0.96). The lower detection limit of the PSA Chip EIA was 3.2 ng/mL. The assay has 88.9% recovery and good reproducibility (% CV of 6.5). We conclude that the developed Chip EIA can be used for detection of protein biomarkers in biological specimens.

  16. Evaluation of a two-site immunoradiometric assay for measuring noncomplexed (free) prostate-specific antigen.

    PubMed

    Cuny, C; Pham, L; Kramp, W; Sharp, T; Soriano, T F

    1996-08-01

    Serum prostate-specific antigen (PSA) in men is present as two different molecular forms separable by gel-filtration chromatography (GFC). We have evaluated a two-site IRMA that measures only the noncomplexed (free) form of PSA (F-PSA). Verification that the F-PSA assay measures solely F-PSA was obtained by assaying GFC-fractionated serum samples with both the F-PSA IRMA and a commercial PSA assay that measures total PSA (T-PSA: F-PSA plus alpha 1-antichymotrypsin-complexed PSA). The F-PSA assay detected only the 30-kDa peak corresponding to the free form of PSA, whereas the T-PSA assay detected two peaks: complexed PSA at approximately 90 kDa and F-PSA at approximately 30 kDa. The F-PSA assay had an analytical detection limit of 0.03 microgram/L and a measuring range up to 50 micrograms/L. The intraassay CV was 1.7-10% in the concentration range of 0.2-30 micrograms/L. The interassay CV was 3.4-12.5% in the same concentration range. Dilution and recovery studies showed no significant deviation from linearity across the assay range. The assay was insensitive to interference from hemoglobin, bilirubin, and total lipids up to concentrations of 5, 0.2, and 10 g/L, respectively. No significant loss of immunological activity (analyte stability) was seen day-to-day ( < or = 5) or after repeated freeze/thaw ( < or = 5) cycles. We conclude that the F-PSA IRMA is an accurate, precise, and reliable tool for measuring F-PSA in human serum. PMID:8697584

  17. TU-F-BRF-02: MR-US Prostate Registration Using Patient-Specific Tissue Elasticity Property Prior for MR-Targeted, TRUS-Guided HDR Brachytherapy

    SciTech Connect

    Yang, X; Rossi, P; Ogunleye, T; Jani, A; Curran, W; Liu, T

    2014-06-15

    Purpose: High-dose-rate (HDR) brachytherapy has become a popular treatment modality for prostate cancer. Conventional transrectal ultrasound (TRUS)-guided prostate HDR brachytherapy could benefit significantly from MR-targeted, TRUS-guided procedure where the tumor locations, acquired from the multiparametric MRI, are incorporated into the treatment planning. In order to enable this integration, we have developed a MR-TRUS registration with a patient-specific biomechanical elasticity prior. Methods: The proposed method used a biomechanical elasticity prior to guide the prostate volumetric B-spline deformation in the MRI and TRUS registration. The patient-specific biomechanical elasticity prior was generated using ultrasound elastography, where two 3D TRUS prostate images were acquired under different probe-induced pressures during the HDR procedure, which takes 2-4 minutes. These two 3D TRUS images were used to calculate the local displacement (elasticity map) of two prostate volumes. The B-spline transformation was calculated by minimizing the Euclidean distance between the normalized attribute vectors of the prostate surface landmarks on the MR and TRUS. This technique was evaluated through two studies: a prostate-phantom study and a pilot study with 5 patients undergoing prostate HDR treatment. The accuracy of our approach was assessed through the locations of several landmarks in the post-registration and TRUS images; our registration results were compared with the surface-based method. Results: For the phantom study, the mean landmark displacement of the proposed method was 1.29±0.11 mm. For the 5 patients, the mean landmark displacement of the surface-based method was 3.25±0.51 mm; our method, 1.71±0.25 mm. Therefore, our proposed method of prostate registration outperformed the surfaced-based registration significantly. Conclusion: We have developed a novel MR-TRUS prostate registration approach based on patient-specific biomechanical elasticity prior

  18. Association of serum EPCA-2 level with prostate cancer in Chinese Han population

    PubMed Central

    Wang, Lei; Ma, Ling; Wang, Xinli; Li, Bing; Guo, Shan; Qiao, Qingdong

    2015-01-01

    Background: Early prostate cancer antigen 2 (EPCA-2), a kind of nuclear matrix protein, may relate to prostate cancer. However, the association of EPCA-2 level in serum with prostate diseases has not been clarified in Chinese Han population. Methods: EPCA-2 and prostate-specific antigen (PSA) levels in serum were detected by enzyme linked immunosorbent assay in 116 patients with prostate cancer (PCa), 342 patients with benign prostatic hyperplasia (BPH), and 174 healthy controls (Control) in Chinese population. Associations of serum EPCA-2 and PSA level with prostate diseases were analyzed by ANOVA. Comparison of diagnostic effect for prostate cancer between EPCA-2 and PSA was evaluated by Receiver Operator Curve, Chi-square test, and others. Results: Serum EPCA-2 and PSA levels in PCa group were significantly higher than BPH and Control group (EPCA-2: F=200.05, P<0.01; PSA: F=210.65, P<0.01). However, EPCA-2 levels in the prostate cancers with different pathological grade were no significant difference. Furthermore, for detection of prostate cancer, EPCA-2 had a sensitivity of 81.9% and a specificity of 87.6%. Conclusions: Serum EPCA-2 could be used as a potential serological marker to diagnose prostate cancer in Chinese Han population, which was more specific than PSA and did not associate with pathological grades of prostate cancer. PMID:26464694

  19. Human prostate-specific antigen: structural and functional similarity with serine proteases.

    PubMed

    Watt, K W; Lee, P J; M'Timkulu, T; Chan, W P; Loor, R

    1986-05-01

    The complete amino acid sequence of the prostate-specific antigen (PA) from human seminal plasma has been determined from analyses of the peptides generated by cyanogen bromide, hydroxylamine, endoproteinases Arg-C and Lys-C. The single polypeptide chain of PA contains 240-amino acid residues and has a calculated Mr of 26,496. An N-linked carbohydrate side chain is predicted at asparagine-45, and O-linked carbohydrate side chains are possibly attached to serine-69, threonine-70, and serine-71. The primary structure of PA shows a high degree of sequence homology with other serine proteases of the kallikrein family. The active site residues of histidine, aspartic acid, and serine comprising the charge-relay system of typical serine proteases were found in similar positions in PA (histidine-41, aspartic acid-96, and serine-192). At pH 7.8, PA hydrolyzed insulin A and B chains, recombinant interleukin 2, and--to a lesser extent--gelatin, myoglobin, ovalbumin, and fibrinogen. The cleavage sites of these proteins by PA were chemically analyzed as the alpha-carboxyl side of some hydrophobic residues, tyrosine, leucine, valine, and phenylalanine, and of basic residues histidine, lysine, and arginine. The chymotrypsin-like activity of PA exhibited with the chromogenic substrate N-succinyl-L-alanyl-L-alanyl-L-prolyl-L-phenylalanine p-nitroanilide yielded a specific activity of 9.21 microM per min per mg of PA and Km and kcat values of 15.3 mM and 0.075s-1, respectively. "Trypsin-like" activity of PA was also detected with N alpha-benzoyl-DL-arginine p-nitroanilide and gave a specific activity of 1.98 microM per min per mg of PA. Protease inhibitors such as phenylmethylsulfonyl fluoride, diisopropyl fluorophosphate, L-1-tosylamido-2-phenylethyl chloromethyl ketone, aprotinin, leupeptin, soybean trypsin inhibitor as well as Zn2+ and spermidine were effective inhibitors of PA enzymatic activity.

  20. Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator.

    PubMed

    Mistry, H B; Fabre, M-A; Young, J; Clack, G; Dickinson, P A

    2016-05-01

    First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program. PMID:27299938

  1. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer

    PubMed Central

    2012-01-01

    Background Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu‐ureido‐Lys via the 68Ga chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics. Methods The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu‐ureido‐Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts. Results Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5). Conclusions The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression. PMID:22673157

  2. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    SciTech Connect

    Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham; Kuk, Deborah; Zhang, Zhigang; Zelefsky, Michael J.

    2013-03-15

    Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

  3. The Variation with Age of 67 Macro- and Microelement Contents in Nonhyperplastic Prostate Glands of Adult and Elderly Males Investigated by Nuclear Analytical and Related Methods.

    PubMed

    Zaichick, Vladimir

    2015-11-01

    To clarify age-related changes of 67 macro- and microelement contents in prostate gland of adult and geriatric males, a quantitative measurement by five analytical methods was performed. The nonhyperplastic prostate glands of 65 subjects (European-Caucasian aged 21-87 years) were investigated by energy dispersive X-ray fluorescence (EDXRF), instrumental neutron activation analysis with high resolution spectrometry of short-lived radionuclides (INAA-SLR), instrumental neutron activation analysis with high resolution spectrometry of long-lived radionuclides (INAA-LLR), inductively coupled plasma atomic emission spectrometry (ICP-AES), and inductively coupled plasma mass spectrometry (ICP-MS). The prostates were obtained at autopsy from subjects who died from acute illness (cardiac insufficiency, stroke, embolism of pulmonary artery, alcohol poisoning) and trauma. None of the subjects had any symptoms of prostatic disease, and all prostates were classified as histologically normal. The combination of nuclear (EDXRF, INAA-SLR, and INAA-LLR) and inductively coupled plasma (ICP-AES and ICP-MS) analytical methods allowed estimation of the contents of 67 chemical elements and precisely determined the mass fraction of 54 elements in the tissue samples of nonhyperplastic adult and geriatric prostate glands. This work's results reveal that there is a significant increase with age of Bi, Cd, Co, Fe, Hg, Pb, Sc, Sn, Th, U, and Zn mass fractions in the prostate tissue of healthy individuals of ages from 21 to 60 years, as well as an increase in Ba from age 61 up to 87 years. It implies that an age-related increase and excess in Ba, Bi, Cd, Co, Fe, Hg, Pb, Sc, Sn, Th, U, and Zn mass fraction in prostatic tissue may be one of the main factors in the etiology of benign prostatic hyperplasia (BPH) and prostate carcinoma (PCa). PMID:25940729

  4. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

    PubMed

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. PMID:27052111

  5. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

    PubMed

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

    2016-04-07

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  6. Biodistribution and Radiation Dosimetry for a Probe Targeting Prostate-Specific Membrane Antigen for Imaging and Therapy

    PubMed Central

    Herrmann, Ken; Bluemel, Christina; Weineisen, Martina; Schottelius, Margret; Wester, Hans-Jürgen; Czernin, Johannes; Eberlein, Uta; Beykan, Seval; Lapa, Constantin; Riedmiller, Hubertus; Krebs, Markus; Kropf, Saskia; Schirbel, Andreas; Buck, Andreas K.; Lassmann, Michael

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-68Ga-DOTAGA (68Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. Methods Five patients with a history of prostate cancer were injected intravenously with 91–148 MBq of 68Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Results Injection of 150 MBq of 68Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). Conclusion 68Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by 18F-FDG. PMID:25883128

  7. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    PubMed Central

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W.; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B.; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Zheng, Wei; Signorello, Lisa B.; Blot, William J.; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, J. Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J.; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes L.; Freedman, Matthew L.; Haiman, Christopher A.; Pasaniuc, Bogdan

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa. PMID:27052111

  8. Use of selenium-silymarin mix reduces lower urinary tract symptoms and prostate specific antigen in men.

    PubMed

    Vostalova, Jitka; Vidlar, Ales; Ulrichova, Jitka; Vrbkova, Jana; Simanek, Vilim; Student, Vladimir

    2013-12-15

    The aim of this double-blind, placebo controlled clinical trial was to assess the effects of a combination of selenium and silymarin in men with lower urinary tract symptoms, benign prostatic hyperplasia and a prostate specific antigen (PSA) ≤2.5ng/ml. The volunteers were randomized to two groups: the first one (n=26) received 240μg selenium (in the form of yeast l-selenomethionine) plus 570mg silymarin daily for 6 months and the second (n=29) received placebo. Outcome measures were changes in the International Prostate Symptom Score (IPSS), bladder volume (V), urinary flow rate, ultrasound estimated postvoid residual urine volume (RV), serum PSA, testosterone and selenium levels, safety clinical biochemistry, hematology and oxidative stress parameters at baseline and on day 180. The results showed statistically significant differences (p<0.05) between treatment and control groups for the following parameters: IPSS score, urodynamic parameters: maximal rate of urine flow (Qmax), average flow (Qave), V and RV, total PSA value and serum selenium levels. There was a significant reduction in PSA in the selenium-silymarin group but no effect on blood testosterone level. Overall the treatment was well-tolerated with no adverse effects.

  9. Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread.

    PubMed

    Giannoni, Elisa; Taddei, Maria Letizia; Morandi, Andrea; Comito, Giuseppina; Calvani, Maura; Bianchini, Francesca; Richichi, Barbara; Raugei, Giovanni; Wong, Nicholas; Tang, Damu; Chiarugi, Paola

    2015-09-15

    Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma.

  10. Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs OXPHOS and prostate cancer metastatic spread

    PubMed Central

    Giannoni, Elisa; Taddei, Maria Letizia; Morandi, Andrea; Comito, Giuseppina; Calvani, Maura; Bianchini, Francesca; Richichi, Barbara; Raugei, Giovanni; Wong, Nicholas; Tang, Damu; Chiarugi, Paola

    2015-01-01

    Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma. PMID:26183399

  11. Antitumor vaccination of prostate cancer patients elicits PD-1/PD-L1 regulated antigen-specific immune responses.

    PubMed

    Rekoske, Brian T; Olson, Brian M; McNeel, Douglas G

    2016-06-01

    We have previously reported that tumor antigen-specific DNA vaccination in mice led to an increase in IFNγ-secreting T cells and an increase in tumor expression of PD-L1. Further, we demonstrated that increasing the encoded antigen's MHC-binding affinity led to increased PD-1 expression on antigen-specific CD8(+) T cells. Together these phenomena provided resistance to antitumor immunization that was abrogated with PD-1/PD-L1 blockade. We consequently sought to determine whether similar regulation occurred in human patients following antitumor immunization. Using clinical samples from prostate cancer patients who were previously immunized with a DNA vaccine, we analyzed changes in checkpoint receptor expression on antigen-specific CD8(+) T cells, the effect of PD-1 blockade on elicited immune responses, and for changes in checkpoint ligand expression on patients' circulating tumor cells (CTCs). We observed no significant changes in T-cell expression of PD-1 or other checkpoint receptors, but antigen-specific immune responses were detected and/or augmented with PD-1 blockade as detected by IFNγ and granzyme B secretion or trans vivo DTH testing. Moreover, PD-L1 expression was increased on CTCs following vaccination, and this PD-L1 upregulation was associated with the development of sustained T-cell immunity and longer progression-free survival. Finally, similar results were observed with patients treated with sipuleucel-T, another vaccine targeting the same prostate antigen. These findings provide in-human rationale for combining anticancer vaccines with PD-1 blocking antibodies, particularly for the treatment of prostate cancer, a disease for which vaccines have demonstrated benefit and yet PD-1 inhibitors have shown little clinical benefit to date as monotherapies. PMID:27471641

  12. Quality-of-life effects of prostate-specific antigen screening

    PubMed Central

    Heijnsdijk, EAM; Wever, EM; Auvinen, A; Hugosson, J; Ciatto, S; Nelen, V; Kwiatkowski, M; Villers, A; Páez, A; Moss, SM; Zappa, M; Tammela, TLJ; Mäkinen, T; Carlsson, S; Korfage, IJ; Essink-Bot, ML; Otto, SJ; Draisma, G; Bangma, CH; Roobol, MJ; Schröder, FH; de Koning, HJ

    2016-01-01

    Background The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% prostate cancer mortality reduction among screened men after 11 years. However, it is uncertain to what extent harms from overdiagnosis and treatment on quality of life counterbalance this benefit. Methods Based on ERSPC follow-up data, we used micro-simulation modeling (MISCAN) to predict the number of prostate cancers, treatments, deaths and quality-adjusted life-years (QALYs) gained following the introduction of screening. Various screening strategies, efficacies, and quality of life assumptions were modeled. Results Per 1,000 men of all ages followed for their entire lifespan we predicted for annual screening from age 55–69 years: 9 fewer deaths due to prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and 73 life-years gained (average 8.4 years per prostate cancer death avoided). QALYs gained were 56 (range: −21, 97), a reduction of 23% from unadjusted life-years gained. The number needed to screen (NNS) was 98 and number needed to detect (NND) 5. Also inviting men aged 70–74 resulted in more life-years (82) but similar QALYs (56). Conclusions Although NNS and NND are more favorable than previously calculated, the benefit of PSA screening is diminished by loss of QALYs, that is dependent primarily on post-diagnosis long-term effects. Longer follow-up data from both the ERSPC and quality of life are essential before making universal recommendations regarding screening. PMID:22894572

  13. Determination of Carbohydrate Structure Recognized by Prostate-specific F77 Monoclonal Antibody through Expression Analysis of Glycosyltransferase Genes*

    PubMed Central

    Nonaka, Motohiro; Fukuda, Michiko N.; Gao, Chao; Li, Zhen; Zhang, Hongtao; Greene, Mark I.; Peehl, Donna M.; Feizi, Ten; Fukuda, Minoru

    2014-01-01

    This study reports the determination of the carbohydrate epitope of monoclonal antibody F77 previously raised against human prostate cancer PC-3 cells (Zhang, G., Zhang, H., Wang, Q., Lal, P., Carroll, A. M., de la Llera-Moya, M., Xu, X., and Greene, M. I. (2010) Proc. Natl. Acad. Sci. U. S. A. 107, 732–737). We performed a series of co-transfections using mammalian expression vectors encoding specific glycosyltransferases. We thereby identified branching enzymes and FUT1 (required for Fucα1→2Gal linkage) as being essential for F77 antigen formation. When immortalized normal prostate 267B1 cells were transfected with FUT1 alone, cells showed weak expression of F77 antigen. By contrast, cells co-transfected with FUT1 plus either GCNT1, GCNT2, or GCNT3 (an enzyme required to form GlcNAcβ1→6Gal/GalNAc) showed robust F77 antigen expression, suggesting that F77 specifically binds to Fucα1→2Galβ1→4GlcNAcβ1→6Gal/GalNAc. RT-PCR for FUT1, GCNT1, GCNT2, and GCNT3 showed that F77-positive cell lines indeed express transcripts encoding FUT1 plus one GCNT. F77-positive prostate cancer cells transfected with siRNAs targeting FUT1, GCNT2, and GCNT3 showed significantly reduced F77 antigen, confirming the requirement of these enzymes for epitope synthesis. We also found that hypoxia induces F77 epitope expression in immortalized prostate RWPE1 cells, which express F77 antigen moderately under normoxia but at an elevated level under hypoxia. Quantitative RT-PCR demonstrated up-regulation of FUT1, GCNT2, and GCNT3 transcripts in RWPE1 cells under hypoxia, suggesting that hypoxia up-regulates glycosyltransferase expression required for F77 antigen synthesis. These results define the F77 epitope and provide a potential mechanism for F77 antigen synthesis in malignant prostate cancer. PMID:24753248

  14. Prostate Specific Antigen/Solvent Interaction Analysis (PSA/SIA): A Preliminary Evaluation of a New Assay Concept for Detecting Prostate Cancer Using Urinary Samples

    PubMed Central

    Stovsky, Mark; Ponsky, Lee; Vourganti, Srinivas; Stuhldreher, Peter; Siroky, Mike B.; Kipnis, Victor; Fedotoff, Olga; Mikheeva, Larissa; Zaslavsky, Boris; Chait, Arnon; Jones, J. Stephen

    2011-01-01

    Objectives To provide preliminary clinical performance evaluation of a novel CaP assay, PSA/SIA (Solvent Interaction Analysis) that focused on changes to the structure of PSA. Methods 222 men undergoing prostate biopsy for accepted clinical criteria at three sites (University Hospitals Case Medical Center in Cleveland, Cleveland Clinic, and Veterans Administration Boston Healthcare System) were enrolled in IRB approved study. Prior to TRUS guided biopsy, patients received DRE with systematic prostate massage followed by collection of urine. The PSA/SIA assay determined the relative partitioning of heterogeneous PSA isoform populations in urine between two aqueous phases. A structural index, K, whose numerical value is defined as the ratio of the concentration of all PSA isoforms, was determined by total PSA ELISA and used to set a diagnostic threshold for CaP. Performance was assessed using ROC analysis with biopsy as the gold standard. Results Biopsies were pathologically classified as case (malignant, n=100) or control (benign, n=122). ROC performance demonstrated AUC=0.90 for PSA/SIA and 0.58 for serum tPSA. At a cutoff value of K=1.73, PSA/SIA displayed sensitivity=100%, specificity=80.3%, PPV=80.6%, and NPV=100%. No attempt was made in this preliminary study to further control patient population or selection criteria for biopsy, nor did we analytically investigate the type of structural differences in PSA that led to changes in K value. Conclusions PSA/SIA provides ratiometric information independently of PSA concentration. In this preliminary study, analysis of the overall structurally heterogeneous PSA isoform population using the SIA assay showed promising results to be further evaluated in future studies. PMID:21783231

  15. A Novel Prostate-Specific Membrane-Antigen (PSMA) Targeted Micelle-Encapsulating Wogonin Inhibits Prostate Cancer Cell Proliferation via Inducing Intrinsic Apoptotic Pathway

    PubMed Central

    Zhang, Hailong; Liu, Xiaogang; Wu, Fengbo; Qin, Feifei; Feng, Ping; Xu, Ting; Li, Xiang; Yang, Li

    2016-01-01

    Prostate cancer (PCa) is a malignant tumor for which there are no effective treatment strategies. In this study, we developed a targeted strategy for prostate-specific membrane-antigen (PSMA)-positive PCa in vitro based on 2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (ACUPA) modified polyethylene glycol (PEG)-Cholesterol micelles containing wogonin (WOG), which was named ACUPA-M-WOG. ACUPA-M-WOG was conventionally prepared using a self-assembling method, which produced stable particle size and ζ potential. Moreover, ACUPA-M-WOG showed good drug encapsulating capacity and drug release profiles. Fluorescence activated cell sorting (FACS) results suggested that ACUPA modified PEG-Cholesterol micelles could effectively enhance the drug uptake on PSMA(+) PCa cells, and the cytotoxicity of ACUPA-M-WOG was stronger than other controls according to in vitro cellular proliferation and apoptosis assays, separately through methyl thiazolyl tetrazolium (MTT) and Annexin V/Propidium Iodide (PI) staining. Finally, the molecular mechanisms of ACUPA-M-WOG’s effects on human PSMA(+) PCa were investigated, and were mainly the intrinsic or extrinsic apoptosis signaling pathways. The Western blot results suggested that ACUPA-M-WOG could enhance the WOG-induced apoptosis, which was mainly via the intrinsic signaling pathway rather than the extrinsic signaling pathway. In conclusion, ACUPA-M-WOG was successfully developed for WOG-selective delivery to PSMA(+) PCa cells and had stronger inhibition than free drugs, which might make it an effective strategy for PSMA(+) PCa. PMID:27196894

  16. The PXR rs7643645 Polymorphism Is Associated with the Risk of Higher Prostate-Specific Antigen Levels in Prostate Cancer Patients

    PubMed Central

    Reyes-Hernández, Octavio D.; Vega, Libia; Jiménez-Ríos, Miguel A.; Martínez-Cervera, Pedro F.; Lugo-García, Juan A.; Hernández-Cadena, Leticia; Ostrosky-Wegman, Patricia; Orozco, Lorena; Elizondo, Guillermo

    2014-01-01

    Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related CYP3A4*1B allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 PXR polymorphisms modify CYP3A4 expression levels. To evaluate whether PXR-HNF3β/T (rs2472677), PXR-HNF4/G (rs7643645), and CYP3A4*1B (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the PXR-HNF4/G polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the CYP3A4*1B/*1B genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and PXR-HNF3β/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis. PMID:24924803

  17. The PXR rs7643645 polymorphism is associated with the risk of higher prostate-specific antigen levels in prostate cancer patients.

    PubMed

    Reyes-Hernández, Octavio D; Vega, Libia; Jiménez-Ríos, Miguel A; Martínez-Cervera, Pedro F; Lugo-García, Juan A; Hernández-Cadena, Leticia; Ostrosky-Wegman, Patricia; Orozco, Lorena; Elizondo, Guillermo

    2014-01-01

    Levels of enzymes that determine testosterone catabolism such as CYP3A4 have been associated with prostate cancer (PCa) risk. Although some studies have related CYP3A4*1B allele, a gene polymorphism that modifies CYP3A4 expression level, with PCa risk, others have failed, suggesting that additional genetic variants may be involved. Expression of CYP3A4 is largely due to the activation of Pregnane X Receptor (PXR). Particularly, rs2472677 and rs7643645 PXR polymorphisms modify CYP3A4 expression levels. To evaluate whether PXR-HNF3β/T (rs2472677), PXR-HNF4/G (rs7643645), and CYP3A4*1B (rs2740574) polymorphisms are associated with PCa a case control-study was performed. The multiple testing analysis showed that the PXR-HNF4/G polymorphism was associated with higher levels of prostate-specific antigen (PSA) in patients with PCa (OR = 3.99, p = 0.03). This association was stronger in patients diagnosed at the age of 65 years or older (OR = 10.8, p = 0.006). Although the CYP3A4*1B/*1B genotype was overrepresented in PCa patients, no differences were observed in the frequency of this and PXR-HNF3β/T alleles between controls and cases. Moreover, no significant association was found between these polymorphisms and PSA, Gleason grade, or tumor lymph node metastasis. PMID:24924803

  18. Plasma Carotenoids and Tocopherols in Relation to Prostate-specific Antigen (PSA) Levels Among Men with Biochemical Recurrence of Prostate Cancer

    PubMed Central

    Antwi, Samuel; Steck, Susan E.; Zhang, Hongmei; Stumm, Lareissa; Zhang, Jiajia; Hurley, Thomas G.; Hebert, James R.

    2015-01-01

    Background Although men presenting with clinically localized prostate cancer (PrCA) often are treated with radical prostatectomy or radiation therapy with curative intent, about 25–40% develop biochemically recurrent PrCA within 5 years of treatment, which has no known cure. Studies suggest that carotenoid and tocopherol intake may be associated with PrCA risk and progression. We examined plasma carotenoid and tocopherol levels in relation to prostate-specific antigen (PSA) levels among men with PSA-defined biochemical recurrence of PrCA. Methods Data analyzed were from a 6-month diet, physical activity and stress-reduction intervention trial conducted in South Carolina among biochemically recurrent PrCA patients (n=39). Plasma carotenoids and tocopherol levels were measured using high-performance liquid chromatography (HPLC). Linear regression was used to estimate least-square means comparing PSA levels of men with high versus low carotenoid/tocopherol levels, adjusting for covariates. Results After adjusting for baseline PSA level, plasma cis-lutein/zeaxanthin level at 3 months was related inversely to PSA level at 3 months (P=0.0008), while α-tocopherol (P=0.01), β-cryptoxanthin (P=0.01), and all-trans-lycopene (P=0.004) levels at 3 months were related inversely to PSA levels at 6-months. Percent increase in α-tocopherol and trans-β-carotene levels from baseline to month 3 were associated with lower PSA levels at 3 and 6 months. Percent increase in β−cryptoxanthin, cislutein/zeaxanthin and all-trans-lycopene were associated with lower PSA levels at 6 months only. Conclusions Certain plasma carotenoids and tocopherols were related inversely to PSA levels at various timepoints, suggesting that greater intake of foods containing these micronutrients might be beneficial to men with PSA-defined PrCA recurrence. PMID:26165176

  19. A Novel Prostate-Specific Membrane-Antigen (PSMA) Targeted Micelle-Encapsulating Wogonin Inhibits Prostate Cancer Cell Proliferation via Inducing Intrinsic Apoptotic Pathway.

    PubMed

    Zhang, Hailong; Liu, Xiaogang; Wu, Fengbo; Qin, Feifei; Feng, Ping; Xu, Ting; Li, Xiang; Yang, Li

    2016-01-01

    Prostate cancer (PCa) is a malignant tumor for which there are no effective treatment strategies. In this study, we developed a targeted strategy for prostate-specific membrane-antigen (PSMA)-positive PCa in vitro based on 2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (ACUPA) modified polyethylene glycol (PEG)-Cholesterol micelles containing wogonin (WOG), which was named ACUPA-M-WOG. ACUPA-M-WOG was conventionally prepared using a self-assembling method, which produced stable particle size and ζ potential. Moreover, ACUPA-M-WOG showed good drug encapsulating capacity and drug release profiles. Fluorescence activated cell sorting (FACS) results suggested that ACUPA modified PEG-Cholesterol micelles could effectively enhance the drug uptake on PSMA(+) PCa cells, and the cytotoxicity of ACUPA-M-WOG was stronger than other controls according to in vitro cellular proliferation and apoptosis assays, separately through methyl thiazolyl tetrazolium (MTT) and Annexin V/Propidium Iodide (PI) staining. Finally, the molecular mechanisms of ACUPA-M-WOG's effects on human PSMA(+) PCa were investigated, and were mainly the intrinsic or extrinsic apoptosis signaling pathways. The Western blot results suggested that ACUPA-M-WOG could enhance the WOG-induced apoptosis, which was mainly via the intrinsic signaling pathway rather than the extrinsic signaling pathway. In conclusion, ACUPA-M-WOG was successfully developed for WOG-selective delivery to PSMA(+) PCa cells and had stronger inhibition than free drugs, which might make it an effective strategy for PSMA(+) PCa. PMID:27196894

  20. The Interval to Biochemical Failure Is Prognostic for Metastasis, Prostate Cancer-Specific Mortality, and Overall Mortality After Salvage Radiation Therapy for Prostate Cancer

    SciTech Connect

    Johnson, Skyler; Jackson, William; Li, Darren; Song, Yeohan; Foster, Corey; Foster, Ben; Zhou, Jessica; Vainshtein, Jeffrey; Feng, Felix; Hamstra, Daniel

    2013-07-01

    Purpose: To investigate the utility of the interval to biochemical failure (IBF) after salvage radiation therapy (SRT) after radical prostatectomy (RP) for prostate cancer as a surrogate endpoint for distant metastasis (DM), prostate cancer-specific mortality (PCSM), and overall mortality (OM). Methods and Materials: A retrospective analysis of 575 patients treated with SRT after RP from a single institution. Of those, 250 patients experienced biochemical failure (BF), with the IBF defined as the time from commencement of SRT to BF. The IBF was evaluated by Kaplan-Meier and Cox proportional hazards models for its association with DM, PCSM, and OM. Results: The median follow-up time was 85 (interquartile range [IQR] 49.8-121.1) months, with a median IBF of 16.8 (IQR, 8.5-37.1) months. With a cutoff time of 18 months, as previously used, 129 (52%) of patients had IBF ≤18 months. There were no differences among any clinical or pathologic features between those with IBF ≤ and those with IBF >18 months. On log–rank analysis, IBF ≤18 months was prognostic for increased DM (P<.0001, HR 4.9, 95% CI 3.2-7.4), PCSM (P<.0001, HR 4.1, 95% CI 2.4-7.1), and OM (P<.0001, HR 2.7, 95% CI 1.7-4.1). Cox proportional hazards models with adjustment for other clinical variables demonstrated that IBF was independently prognostic for DM (P<.001, HR 4.9), PCSM (P<.0001, HR 4.0), and OM (P<.0001, HR 2.7). IBF showed minimal change in performance regardless of androgen deprivation therapy (ADT) use. Conclusion: After SRT, a short IBF can be used for early identification of patients who are most likely to experience progression to DM, PCSM, and OM. IBF ≤18 months may be useful in clinical practice or as an endpoint for clinical trials.

  1. Cholesterol and the risk of grade-specific prostate cancer incidence: evidence from two large prospective cohort studies with up to 37 years' follow up

    PubMed Central

    2012-01-01

    Background High cholesterol may be a modifiable risk factor for prostate cancer but results have been inconsistent and subject to potential "reverse causality" where undetected disease modifies cholesterol prior to diagnosis. Methods We conducted a prospective cohort study of 12,926 men who were enrolled in the Midspan studies between 1970 and 1976 and followed up to 31st December 2007. We used Cox-Proportional Hazards Models to evaluate the association between baseline plasma cholesterol and Gleason grade-specific prostate cancer incidence. We excluded cancers detected within at least 5 years of cholesterol assay. Results 650 men developed prostate cancer in up to 37 years' follow-up. Baseline plasma cholesterol was positively associated with hazard of high grade (Gleason score≥8) prostate cancer incidence (n = 119). The association was greatest among men in the 2nd highest quintile for cholesterol, 6.1 to < 6.69 mmol/l, Hazard Ratio 2.28, 95% CI 1.27 to 4.10, compared with the baseline of < 5.05 mmol/l. This association remained significant after adjustment for body mass index, smoking and socioeconomic status. Conclusions Men with higher cholesterol are at greater risk of developing high-grade prostate cancer but not overall risk of prostate cancer. Interventions to minimise metabolic risk factors may have a role in reducing incidence of aggressive prostate cancer. PMID:22260413

  2. Edwin I. Hatch nuclear plant implementation of improved technical specifications

    SciTech Connect

    Mahler, S.R.; Pendry, D.

    1994-12-31

    Edwin I. Hatch nuclear plant consists of two General Electric boiling water reactor/4 units, with a common control room and a common refueling floor. In March 1993, Hatch began conversion of both units` technical specifications utilizing NUREG 1433. The technical specifications amendment request was submitted February 25, 1994. Issuance is scheduled for October 21, 1994, with implementation on March 15, 1994. The current unit-1 technical specifications are in the {open_quotes}custom{close_quotes} format, and the unit-2 technical specifications are in the old standard format. Hatch previously relocated the fire protection and radiological technical specifications requirements. The Hatch conversion will provide consistency between the two units, to the extent practicable.

  3. Prostate-specific antigen doubling time predicts clinical outcome and survival in prostate cancer patients treated with combined radiation and hormone therapy

    SciTech Connect

    Lee, Andrew K. . E-mail: aklee@mdanderson.org; Levy, Larry B.; Cheung, Rex; Kuban, Deborah

    2005-10-01

    Purpose: To determine whether prostate-specific antigen (PSA) doubling time predicts clinical outcomes in patients with prostate cancer that has been treated with combined radiation and hormone therapy. Methods and Materials: We reviewed the medical records of 621 men with nonmetastatic prostate cancer treated with radiation therapy and hormone therapy between 1989 and 2003. 'Any' clinical failure was defined as any distant, nodal, or local failure, or the use of salvage therapy. 'True' clinical failure was defined as any distant, nodal, or local failure. PSA doubling time was calculated by using the log PSA values from patients with a PSA failure as defined by the American Society of Therapeutic Radiology Oncology consensus statement. One hundred thirty-seven men were at intermediate risk for PSA failure (as determined by T2b, Gleason score of 7, or PSA 10.1-0 ng/mL) and 484 men were at high risk for failure (T2c-4; Gleason 8-10; or PSA >20 ng/mL). Pretreatment PSA value, Gleason score, tumor stage, timing and duration of hormone therapy, radiation therapy dose, and PSA doubling time were analyzed for any associations with time to clinical failure by using Cox regression analysis. Estimates of survival were calculated by using the Kaplan-Meier method. Pairwise comparisons were made by using the log-rank test. Results: Sixty-two men experienced any clinical failure, and 22 men experienced true clinical failure. Multivariate analysis revealed that pretreatment PSA (p = 0.013), Gleason score (p = 0.0019), and a PSA doubling time (PSADT) {<=}8 months (p < 0.001) were independently associated with time to any clinical failure. Tumor stage, hormone therapy timing, hormone therapy duration, and radiation therapy dose were not statistically significant on multivariate or univariate analysis. Only hormone therapy duration (p 0.008) and PSADT {<=}8 months (<0.001) were significantly associated with time to true clinical failure. The estimated 5-year rate of any clinical

  4. ERAP140, a conserved tissue-specific nuclear receptor coactivator.

    PubMed

    Shao, Wenlin; Halachmi, Shlomit; Brown, Myles

    2002-05-01

    We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ER alpha-interacting proteins using the ER alpha ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ER alpha, ERAP140 also binds ER beta, TR beta, PPAR gamma, and RAR alpha. ERAP140 interacts with ER alpha via a noncanonical interaction motif. The ER alpha-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ER alpha on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ER alpha to the promoter region of endogenous ER alpha target genes. Furthermore, the E(2)-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues. PMID:11971969

  5. The Effect of Testosterone Replacement Therapy on Prostate-Specific Antigen (PSA) Levels in Men Being Treated for Hypogonadism

    PubMed Central

    Kang, De-Ying; Li, Hong-Jun

    2015-01-01

    Abstract Testosterone replacement therapy is used for the treatment of age-related male hypogonadism, and prostate-specific antigen (PSA) is a primary screening tool for prostate cancer. The systematic review and meta-analysis aimed to determine the effect of testosterone replacement therapy on PSA levels. Medline, Cochrane Library, EMBASE, and Google Scholar databases were searched until February 28, 2014, and inclusion criteria were as follows: randomized controlled trial; intervention group received testosterone/androgen replacement therapy; control group did not receive treatment; and no history of prostate cancer. The primary outcome was change of PSA level between before and after treatment. Secondary outcomes were elevated PSA level after treatment, and the number of patients who developed prostate cancer. After initially identifying 511 articles, 15 studies with a total of 739 patients that received testosterone replacement and 385 controls were included. The duration of treatment ranged from 3 to 12 months. Patients treated with testosterone tended to have higher PSA levels, and thus a greater change than those that received control treatments (difference in means of PSA levels = 0.154, 95% confidence interval [CI] 0.069 to 0.238, P < 0.001). The difference in means of PSA levels were significant higher for patients that received testosterone intramuscularly (IM) than controls (difference in means of PSA levels = 0.271, 95% CI 0.117–0.425, P = 0.001). Elevated PSA levels after treatment were similar between patients that received treatment and controls (odds ratio [OR] = 1.02, 95% CI 0.48–2.20, P = 0.953). Only 3 studies provided data with respect to the development of prostate cancer, and rates were similar between those that received treatment and controls. Testosterone replacement therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given IM and even the increase with IM administration

  6. Can a Gleason 6 or Less Microfocus of Prostate Cancer in One Biopsy and Prostate-Specific Antigen Level <10 ng/mL Be Defined as the Archetype of Low-Risk Prostate Disease?

    PubMed

    Taverna, Gianluigi; Benecchi, Luigi; Grizzi, Fabio; Seveso, Mauro; Giusti, Guido; Piccinelli, Alessandro; Benetti, Alessio; Colombo, Piergiuseppe; Minuti, Francesco; Graziotti, Pierpaolo

    2012-01-01

    Prostate cancer (PC) remains a cause of death worldwide. Here we investigate whether a single microfocus of PC at the biopsy (graded as Gleason 6 or less, ≤5% occupancy) and the PSA <10 ng/mL can define the archetype of low-risk prostate disease. 4500 consecutive patients were enrolled. Among them, 134 patients with a single micro-focus of PC were followed up, and the parameters influencing the biochemical relapse (BR) were analysed. Out of 134 patients, 94 had clinically significant disease, specifically in 74.26% of the patients with PSA <10 ng/mL. Positive surgical margins and the extracapsular invasion were found in 29.1% and 51.4% patients, respectively. BR was observed in 29.6% of the patients. Cox regression evidenced a correlation between the BR and Gleason grade at the retropubic radical prostatectomy (RRP), capsular invasion, and the presence of positive surgical margins. Multivariate regression analysis showed a statistically significant correlation between the presence of surgical margins at the RRP and BR. Considering a single micro-focus of PC at the biopsy and PSA serum level <10 ng/mL, clinically significant disease was found in 74.26% patients and only positive surgical margins are useful for predicting the BR.

  7. Effective specific impulse of external nuclear pulse propulsion systems

    NASA Technical Reports Server (NTRS)

    Reynolds, T. W.

    1972-01-01

    An investigation of a simple self-similar flow model for an external nuclear pulse propulsion system indicates that to achieve the high effective specific impulse of such a system three principal factors are required. The are (1) attaining pulses of optimum energy, (2) attaining good propellant collimation, and (3) using an ablative material for the pusher surface which has high absorptivity for radiant energy at the propellant stagnation temperature.

  8. Detection of prostate specific antigen based on electrocatalytic platinum nanoparticles conjugated to a recombinant scFv antibody.

    PubMed

    Spain, Elaine; Gilgunn, Sarah; Sharma, Shikha; Adamson, Kellie; Carthy, Eadaoin; O'Kennedy, Richard; Forster, Robert J

    2016-03-15

    Highly sensitive and label free detection of prostate specific antigen (PSA) still remains a challenge in prostate cancer diagnosis. In this paper, we propose a sensitive electrochemical immunosensor based on electrocatalytic platinum nanoparticles conjugated to a recombinant scFv antibody. Gold disc electrodes functionalised with a l-Cysteine (Cys) self-assembled monolayer (SAM) were used to covalently bind PSA specific monoclonal antibody (anti-PSA) using N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (EDC/NHS) chemistry. Immunosensing was completed using sandwich-type immunoreaction of the PSA-antigen (1-30 ng/mL) between anti-PSA immobilized on the l-Cys modified electrode using label free electrochemical impedance (EIS) technique. Furthermore, highly specific in-house generated scFv fragments as receptor proteins were utilised for one step site-directed immobilisation on the surface of platinum nanoparticles (PtNPs). To improve the sensitivity of the immunoassay, these scFV labelled electrocatalytic PtNPs were then used for covalent hybridisation to the PSA modified electrode and then applied in a hybridisation assay to determine the concentration of the PSA by measuring the faradaic current associated with reduction of peroxide in solution. Semi-log plots of the PSA concentration vs. faradaic current are linear from 1 to 30 ng/mL and pM concentrations can be detected without the need for molecular, e.g., PCR or NASBA, amplification. PMID:26513282

  9. Is Serum Prostate-specific Antigen a Diagnostic Marker for Benign and Malignant Breast Tumors in Women?

    PubMed Central

    Razavi, Seyed Hasan Emami; Ghajarzadeh, Mahsa; Abdollahi, Alireza; Shoar, Saeed; Omranipour, Ramesh

    2015-01-01

    Background: Breast cancer is the most common cancer in women. Prostate-specific antigen (PSA) is a marker of prostate gland malignancy, which has been considered in cases with breast cancer in recent years. The goal of this study was to determine total and free PSA levels in cases with malignant and benign breast lesions. Methods: In this case–control study, ninety women with histological proved malignant breast masses and 90 with benign breast masses were enrolled. Total and free PSA levels along with Histological grade and conditions of vascular and perinural invasion, status of hormonal tumor receptors, immune-histo-chemistry markers recorded for all cases. Total and free PSA levels were assessed after treatment in cases with malignant masses. Results: Total and free PSA levels were significantly higher in cases with malignant masses. The best cut-off point for total PSA to differentiate benign and malignant masses was 0.31 with sensitivity and specificity of 100%, 100% (area under the curve [AUC] =1, P < 0.001) and the best cut-off point for free PSA to differentiate benign and malignant masses was 0.19 with sensitivity and specificity of 100% and 100% (AUC = 1, P < 0.001). After treatment, mean free PSA level was significantly lower than free PSA before treatment (0.23 ± 0.1 vs. 0.3 ± 0.08, P < 0.001). Conclusions: Serum PSA level could be applied for differentiating benign and malignant breast masses. PMID:25789147

  10. Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis

    PubMed Central

    Breser, Maria L.; Lino, Andreia C.; Motrich, Ruben D.; Godoy, Gloria J.; Demengeot, Jocelyne; Rivero, Virginia E.

    2016-01-01

    Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence. PMID:27624792

  11. Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis.

    PubMed

    Breser, Maria L; Lino, Andreia C; Motrich, Ruben D; Godoy, Gloria J; Demengeot, Jocelyne; Rivero, Virginia E

    2016-01-01

    Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence. PMID:27624792

  12. Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis.

    PubMed

    Breser, Maria L; Lino, Andreia C; Motrich, Ruben D; Godoy, Gloria J; Demengeot, Jocelyne; Rivero, Virginia E

    2016-09-14

    Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence.

  13. Sci—Fri PM: Dosimetry—06: Commissioning of a 3D patient specific QA system for hypofractionated prostate treatments

    SciTech Connect

    Rivest, R; Venkataraman, S; McCurdy, B

    2014-08-15

    The objective of this work is to commission the 6MV-SRS beam model in COMPASS (v2.1, IBA-Dosimetry) and validate its use for patient specific QA of hypofractionated prostate treatments. The COMPASS system consists of a 2D ion chamber array (MatriXX{sup Evolution}), an independent gantry angle sensor and associated software. The system can either directly calculate or reconstruct (using measured detector responses) a 3D dose distribution on the patient CT dataset for plan verification. Beam models are developed and commissioned in the same manner as a beam model is commissioned in a standard treatment planning system. Model validation was initially performed by comparing both COMPASS calculations and reconstructions to measured open field beam data. Next, 10 hypofractionated prostate RapidArc plans were delivered to both the COMPASS system and a phantom with ion chamber and film inserted. COMPASS dose distributions calculated and reconstructed on the phantom CT dataset were compared to the chamber and film measurements. The mean (± standard deviation) difference between COMPASS reconstructed dose and ion chamber measurement was 1.4 ± 1.0%. The maximum discrepancy was 2.6%. Corresponding values for COMPASS calculation were 0.9 ± 0.9% and 2.6%, respectively. The average gamma agreement index (3%/3mm) for COMPAS reconstruction and film was 96.7% and 95.3% when using 70% and 20% dose thresholds, respectively. The corresponding values for COMPASS calculation were 97.1% and 97.1%, respectively. Based on our results, COMPASS can be used for the patient specific QA of hypofractionated prostate treatments delivered with the 6MV-SRS beam.

  14. The Practicality of Targeted Prostate Biopsy Procedures on the Dominant Side of the Tumor Determined by Magnetic Resonance Imaging in Elderly Patients with High Serum Levels of Prostate-Specific Antigen

    PubMed Central

    Huh, Jung Sik; Kim, Bong Soo; Kim, Young Joo; Kim, Sung Dae

    2015-01-01

    Purpose To examine the possibility of reducing the number of cores per prostate biopsy in elderly patients with high levels of prostate-specific antigen (PSA) without significantly lowering the detection rate of prostate cancer. Materials and Methods Two hundreds sixteen men with PSA levels >20 ng/mL who underwent prostate biopsies from May 2009 to April 2013 were retrospectively reviewed. With the help of magnetic resonance imaging (MRI), the laterality of the dominant tumor burden in patients was determined. The results of targeted biopsies were compared with those of conventional biopsy procedures. Results The mean age and PSA level were 79.5 years and 81.3 ng/mL, respectively, and the overall diagnostic rate of sextant biopsies was 81.9% (177/216). MRI was able to show the tumor burden in 189 of the 216 patients. The detection rate of transrectal ultrasonography (TRUS)-guided targeted biopsies was 87.3% (165/189). Detection rates were comparable with conventional biopsies (81.9% [177/216]) (p=0.23). Of the 177 men in whom the results of the sextant biopsy were positive, 12 men (6.8%) with PSA levels <29 ng/mL did not have any cancer cells according to targeted biopsies. However, all other patients were diagnosed with prostate cancer using the abovementioned techniques. Conclusions We believe that TRUS-guided targeted biopsies of the prostate in elderly men with high PSA levels could reduce the number of unnecessary cores per biopsy. However, a risk of detection loss remains. Therefore, we recommend that at least a sextant biopsy should be performed, even in elderly patients, in order to detect prostate cancer. PMID:26770939

  15. HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer

    PubMed Central

    Ai, Junkui; Wang, Yujuan; Dar, Javid A.; Liu, June; Liu, Lingqi; Nelson, Joel B.; Wang, Zhou

    2009-01-01

    The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa. PMID:19855091

  16. HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.

    PubMed

    Ai, Junkui; Wang, Yujuan; Dar, Javid A; Liu, June; Liu, Lingqi; Nelson, Joel B; Wang, Zhou

    2009-12-01

    The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa.

  17. High-Dose Conformal Radiotherapy Reduces Prostate Cancer-Specific Mortality: Results of a Meta-analysis

    SciTech Connect

    Viani, Gustavo Arruda; Godoi Bernardes da Silva, Lucas; Stefano, Eduardo Jose

    2012-08-01

    Purpose: To determine in a meta-analysis whether prostate cancer-specific mortality (PCSM), biochemical or clinical failure (BCF), and overall mortality (OM) in men with localized prostate cancer treated with conformal high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT). Methods and Materials: The MEDLINE, Embase, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing conformal HDRT with CDRT for localized prostate cancer. Results: Five randomized, controlled trials (2508 patients) that met the study criteria were identified. Pooled results from these randomized, controlled trials showed a significant reduction in the incidence of PCSM and BCF rates at 5 years in patients treated with HDRT (p = 0.04 and p < 0.0001, respectively), with an absolute risk reduction (ARR) of PCSM and BCF at 5 years of 1.7% and 12.6%, respectively. Two trials evaluated PCSM with 10 years of follow up. The pooled results from these trials showed a statistical benefit for HDRT in terms of PCSM (p = 0.03). In the subgroup analysis, trials that used androgen deprivation therapy (ADT) showed an ARR for BCF of 12.9% (number needed to treat = 7.7, p < 0.00001), whereas trials without ADT had an ARR of 13.6% (number needed to treat = 7, p < 0.00001). There was no difference in the OM rate at 5 and 10 years (p = 0.99 and p = 0.11, respectively) between the groups receiving HDRT and CDRT. Conclusions: This meta-analysis is the first study to show that HDRT is superior to CDRT in preventing disease progression and prostate cancer-specific death in trials that used conformational technique to increase the total dose. Despite the limitations of our study in evaluating the role of ADT and HDRT, our data show no benefit for HDRT arms in terms of BCF in trials with or without ADT.

  18. Biomarkers for prostate cancer.

    PubMed

    Makarov, Danil V; Loeb, Stacy; Getzenberg, Robert H; Partin, Alan W

    2009-01-01

    The development of biomarkers for prostate cancer screening, detection, and prognostication has revolutionized the management of this disease. Prostate-specific antigen (PSA) is a useful, though not specific, biomarker for detecting prostate cancer. We review the literature on prostate cancer biomarkers, including serum markers (PAP, tPSA, fPSA, proPSA, PSAD, PSAV, PSADT, EPCA, and EPCA-2), tissue markers (AMACR, methylated GSTP1, and the TMPRSS2-ETS gene rearrangement), and a urine marker (DD3PCA3/UPM-3). Future research should focus on validation of already existing biomarkers and the discovery of new markers to identify men with aggressive prostate cancer.

  19. A Prospective Randomized Trial of Two Different Prostate Biopsy Schemes

    ClinicalTrials.gov

    2016-07-03

    Prostate Cancer; Local Anesthesia; Prostate-Specific Antigen/Blood; Biopsy/Methods; Image-guided Biopsy/Methods; Prostatic Neoplasms/Diagnosis; Prostate/Pathology; Prospective Studies; Humans; Male; Ultrasonography, Interventional/Methods

  20. Reference Ranges of Age-Related Prostate-Specific Antigen in Men without Cancer from Beijing Area

    PubMed Central

    Liu, Xin; Wang, Jie; Zhang, Shun-Xin; Lin, Qian

    2013-01-01

    Abstract Background To determine the normal ranges of serum age-related prostate-specific antigen (PSA) level in men from Beijing area without cancer. Methods In this cross sectional study, form April 2010 to October 2011, 1611 healthy men undergoing a routine health check-up in our hospital and all men received three examinations including serum PSA test, digital rectal ex-amination and transrectal ultrasound. Men with any two abnormal results of the three examinations were undergone a prostate biopsy. Men with any two normal results of the three examinations or with negative biopsy were defined as men without cancer. Men with a prior history of prostate cancer/surgery or with urinary tract infection/obstruction were excluded. 1572 men without cancer were recruited into the study finally and were stratified into 10-year age groups: 40 to 49, 50 to 59, 60 to 69, 70 to 79, and older than 80. Results The median PSA value (95th percentile range) was 0.506(1.565), 1.04(2.920), 1.16(4.113), 1.34(5.561)and 2.975 (7.285) for each age group respectively, and the 25th percentile to 75 percentile was 0.343 to 0.923, 0.663 to 1.580, 0.693 to 2.203, 0.789 to 2.368 and 1.188 to 4.295 respectively. The serum PSA value is directly correlated with age (r=0.314, P<0.001). Conclusions Use the age-related range for PSA increases the sensitivity in younger men and decreases the biopsy rate in older patients. PMID:26171333

  1. Impact of capillary conditioning and background electrolyte composition on capillary electrophoresis analysis of prostate specific antigen isoforms.

    PubMed

    Farina-Gomez, Noemi; Puerta, Angel; Gonzalez, Monica; Diez-Masa, Jose Carlos; de Frutos, Mercedes

    2016-04-22

    Glycoproteins expressed in the human body can experience modifications as result of pathological situations. Detection of those changes can be useful as disease biomarkers. As a result of these modifications, size and/or electrical charge of the glycoprotein can be altered. Migration in capillary zone electrophoresis (CZE) is governed by the size to charge ratio of the analyte and therefore this separation technique can be used to monitor those modifications. At its turn, the alteration of the electrophoretical pattern of a given glycoprotein could be used as disease biomarker. To this aim, high repeatability for separation of a large number of peaks for a given glycoprotein is desirable. For prostate cancer, new markers are needed to decrease the high number of false positive results provided by the biomarkers currently used in clinics. In this sense, CZE methods for analysis of the several prostate specific antigen (PSA) peaks which this glycoprotein exhibit, called isoforms and containing one or more glycoforms, could be useful to study the PSA pattern as prostate cancer marker. In this study two complementary strategies to achieve both lot-to-lot capillary repeatability and high resolution of a large number of PSA isoforms are developed. Better performance and precision have been obtained for capillaries conditioned with HCl than for those conditioned with NaOH. Optimization of the background electrolyte (BGE) pH value to 8.0 and inclusion of 3M urea on its composition were the two factors of highest impact for enhancing resolution of the highest number of PSA peaks. Under the optimized conditions for capillary conditioning and BGE pH and composition, long-term resolution of 10 isoforms of PSA was achieved. Inter-day (n=3) %RSD was 0.55 for the ratio tm/tEOF, 1.15 for μeff, and 5.02 for % Acorr of the PSA peaks. PMID:27018191

  2. Specific probe selection from landscape phage display library and its application in enzyme-linked immunosorbent assay of free prostate-specific antigen.

    PubMed

    Lang, Qiaolin; Wang, Fei; Yin, Long; Liu, Mingjun; Petrenko, Valery A; Liu, Aihua

    2014-03-01

    Probes against targets can be selected from the landscape phage library f8/8, displaying random octapeptides on the pVIII coat protein of the phage fd-tet and demonstrating many excellent features including multivalency, stability, and high structural homogeneity. Prostate-specific antigen (PSA) is usually determined by immunoassay, by which antibodies are frequently used as the specific probes. Herein we found that more advanced probes against free prostate-specific antigen (f-PSA) can be screened from the landscape phage library. Four phage monoclones were selected and identified by the specificity array. One phage clone displaying the fusion peptide ERNSVSPS showed good specificity and affinity to f-PSA and was used as a PSA capture probe in a sandwich enzyme-linked immunosorbent assay (ELISA) array. An anti-human PSA monoclonal antibody (anti-PSA mAb) was used to recognize the captured antigen, followed by horseradish peroxidase-conjugated antibody (HRP-IgG) and o-phenylenediamine, which were successively added to develop plate color. The ELISA conditions such as effect of blocking agent, coating buffer pH, phage concentration, antigen incubation time, and anti-PSA mAb dilution for phage ELISA were optimized. On the basis of the optimal phage ELISA conditions, the absorbance taken at 492 nm on a microplate reader was linear with f-PSA concentration within 0.825-165 ng/mL with a low limit of detection of 0.16 ng/mL. Thus, the landscape phage is an attractive biomolecular probe in bioanalysis.

  3. Ultrasensitive electrochemical detection of prostate-specific antigen by using antibodies anchored on a DNA nanostructural scaffold.

    PubMed

    Chen, Xiaoqing; Zhou, Guobao; Song, Ping; Wang, Jingjing; Gao, Jimin; Lu, Jianxin; Fan, Chunhai; Zuo, Xiaolei

    2014-08-01

    The high occurrence of prostate cancer in men makes the prostate-specific antigen (PSA) screening test really important. More importantly, the recurrence rate after radical prostatectomy is high, whereas the traditional PSA immunoassay does not possess the sufficient high sensitivity for post-treatment PSA detection. In these assays, uncontrolled and random orientation of capture antibodies on the surface largely reduces their activity. Here, by exploiting the rapidly emerging DNA nanotechnology, we developed a DNA nanostructure based scaffold to precisely control the assembly of antibody monolayer. We demonstrated that the detection sensitivity was critically dependent on the nanoscale-spacing (nanospacing) of immobilized antibodies. In addition to the controlled assembly, we further amplified the sensing signal by using the gold nanoparticles, resulting in extremely high sensitivity and a low detection limit of 1 pg/mL. To test the real-world applicability of our nanoengineered electrochemical sensor, we evaluated the performance with 11 patients' serum samples and obtained consistent results with the "gold-standard" assays.

  4. Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men.

    PubMed

    Sun, Xian Liang; Kido, Teruhiko; Honma, Seijiro; Okamoto, Rie; Manh, Ho Dung; Maruzeni, Shoko; Nishijo, Muneko; Nakagawa, Hideaki; Nakano, Takeshi; Koh, Eitetsu; Takasuga, Takumi; Nhu, Dang Duc; Hung, Nguyen Ngoc; Son, Le Ke

    2016-04-01

    Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009-2011, we collected blood samples from 97 men who had resided in a "dioxin hotspot" and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions. PMID:26758301

  5. Evaluation of prostate-specific antigen (PSA) membrane test assays for the forensic identification of seminal fluid.

    PubMed

    Hochmeister, M N; Budowle, B; Rudin, O; Gehrig, C; Borer, U; Thali, M; Dirnhofer, R

    1999-09-01

    Prostate specific antigen (PSA, also known as p30), a glycoprotein produced by the prostatic gland and secreted into seminal plasma, is a marker used for demonstrating the presence of seminal fluid. Methods for the detection of PSA include Ouchterlony double diffusion, crossover electrophoresis, rocket immuno-electrophoresis, radial immunodiffusion, and ELISA. The extremely sensitive ELISA technique can detect PSA in concentrations as low as approximately 4 ng/mL. However, all these techniques are cumbersome and time consuming to perform in forensic laboratories, especially when only a few samples per week are processed. Various membrane tests are currently used in clinical settings to screen a patient's serum for the presence of PSA at levels greater than 4 ng/mL. In this study we evaluated three immunochromatographic PSA membrane tests by analyzing semen stains stored at room temperature for up to 30 years, post-coital vaginal swabs taken at different time after intercourse, semen-free vaginal swabs, and various female and male body fluids, including urine. The data demonstrate that PSA membrane test assays offer the same sensitivity as ELISA-based tests and provide a rapid approach for the forensic identification of seminal fluid. Furthermore, when the supernatant from a DNA extraction is used for the assay, there is essentially no DNA consumption for determining the presence of PSA in a forensic sample.

  6. A microfluidic immunoassay platform for the detection of free prostate specific antigen: a systematic and quantitative approach.

    PubMed

    Madaboosi, Narayanan; Soares, Ruben R G; Chu, Virginia; Conde, João Pedro

    2015-07-01

    As a leading cause of cancer-related deaths in men globally, prostate cancer (PCa) demands immense attention for theranostic purposes. There is an increasing need for the development of rapid, sensitive, economical, miniaturized and multiplexable assays. Towards this goal, we present a systematic approach for the optimisation of a microfluidic sandwich immunoassay, which can be applied as a generic biosensor platform for PCa detection. Prostate specific antigen (PSA) was used as the model biomarker, and its free form was captured using commercially available antibodies and detected using chemiluminescence, both in spiked buffer and matrix solutions. Along with the optimisation of surface chemistry and microfluidic parameters, we report a bio-affinity amplification strategy based on biotin-streptavidin chemistry to bring the limits of detection for free-PSA from 21.4 ng mL(-1) down to 2.7 ng mL(-1), within the clinically relevant range. An estimate of the surface coverage and simulations of the interactions taking place in the microfluidic biosensor during the assay are also presented. This novel platform using a simple passive adsorption-based bio-affinity strategy, when coupled with multiplexing and integrated detection, can serve as a promising point-of-care diagnostic tool for PCa. PMID:25988197

  7. Transcription of Nrdp1 by the androgen receptor is regulated by nuclear Filamin A in prostate cancer

    PubMed Central

    Savoy, Rosalinda M.; Chen, Liqun; Siddiqui, Salma; Melgoza, Frank U.; Durbin-Johnson, Blythe; Drake, Christiana; Jathal, Maitreyee K.; Bose, Swagata; Steele, Thomas M.; Mooso, Benjamin A.; D’Abronzo, Leandro S.; Fry, William H.; Carraway, Kermit L.; Mudryj, Maria; Ghosh, Paramita M.

    2015-01-01

    Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, patients undergoing androgen deprivation therapy (ADT) for disseminated PCa eventually develop castration resistant PCa (CRPC). Studies showed that AR, a transcription factor, occupies distinct genomic loci in CRPC compared to hormone-naïve PCa; however, the cause for this distinction was unknown. The E3 ubiquitin ligase Nrdp1 is a model AR target modulated by androgens in hormone-naïve PCa but not in CRPC. Using Nrdp1, we investigated how AR switches transcription programs during CRPC progression. The proximal Nrdp1 promoter contains an androgen response element (ARE); we demonstrated AR binding to this ARE in androgen-sensitive PCa. Analysis of hormone-naive human prostatectomy specimens revealed correlation between Nrdp1 and AR expression, supporting AR regulation of Nrdp1 levels in androgen-sensitive tissue. However, despite sustained AR levels, AR binding to the Nrdp1 promoter and Nrdp1 expression were suppressed in CRPC. Elucidation of the suppression mechanism demonstrated correlation of Nrdp1 levels with nuclear localization of the scaffolding protein Filamin A (FlnA) which, as we previously showed, is itself repressed following ADT in many CRPC tumors. Restoration of nuclear FlnA in CRPC stimulated AR binding to Nrdp1 ARE, increased its transcription, and augmented Nrdp1 protein expression and responsiveness to ADT, indicating that nuclear FlnA controls AR-mediated androgen-sensitive Nrdp1 transcription. Expressions of other AR-regulated genes lost in CRPC were also re-established by nuclear FlnA. Thus our data demonstrate that nuclear FlnA promotes androgen-dependent AR-regulated transcription in PCa, while loss of nuclear FlnA in CRPC alters the AR-regulated transcription program. PMID:25759396

  8. Metformin is not associated with improved biochemical free survival or cause-specific survival in men with prostate cancer treated with permanent interstitial brachytherapy

    PubMed Central

    Taira, Al V.; Galbreath, Robert W.; Morris, Mallory; Butler, Wayne M.; Adamovich, Edward

    2014-01-01

    Purpose Several recent studies have suggested improved clinical outcomes in diabetic men with prostate cancer who also use metformin. We explore whether metformin use is associated with improved outcomes specifically in men undergoing prostate brachytherapy. Material and methods 2,298 consecutive patients underwent permanent interstitial brachytherapy by a single brachytherapist (GSM). The cohort included 2028 non-diabetic men, 144 men with diabetes who were not taking metformin, and 126 men with diabetes who were taking metformin. Median follow up was 8.3 years. Differences in biochemical free survival, cause specific survival, and overall survival between men taking metformin and those not taking metformin were compared using Kaplan-Meier curves and log rank tests. Results Fifteen year biochemical failure rate, cause specific mortality and overall mortality for non-diabetic men was 4.6%, 1.5%, 47.0%, respectively; for diabetic men taking metformin 4.8%, 2.0%, 37.2%; and for diabetic men not taking metformin was 2.8%, 0%, 72.7%, respectively. Metformin use was not predictive in multivariate analysis of biochemical failure or prostate cancer specific mortality. However, diabetic men not taking metformin had higher overall mortality than non-diabetic men. Conclusions Metformin use was not associated with improved biochemical survival or cancer specific survival in this cohort of men treated with prostate brachytherapy. PMID:25337126

  9. The importance of non-nuclear AR signaling in prostate cancer progression and therapeutic resistance.

    PubMed

    Zarif, Jelani C; Miranti, Cindy K

    2016-05-01

    The androgen receptor (AR) remains the major oncogenic driver of prostate cancer, as evidenced by the efficacy of androgen deprivation therapy (ADT) in naïve patients, and the continued effectiveness of second generation ADTs in castration resistant disease. However, current ADTs are limited to interfering with AR ligand binding, either through suppression of androgen production or the use of competitive antagonists. Recent studies demonstrate 1) the expression of constitutively active AR splice variants that no longer depend on androgen, and 2) the ability of AR to signal in the cytoplasm independently of its transcriptional activity (non-genomic); thus highlighting the need to consider other ways to target AR. Herein, we review canonical AR signaling, but focus on AR non-genomic signaling, some of its downstream targets and how these effectors contribute to prostate cancer cell behavior. The goals of this review are to 1) re-highlight the continued importance of AR in prostate cancer as the primary driver, 2) discuss the limitations in continuing to use ligand binding as the sole targeting mechanism, 3) discuss the implications of AR non-genomic signaling in cancer progression and therapeutic resistance, and 4) address the need to consider non-genomic AR signaling mechanisms and pathways as a viable targeting strategy in combination with current therapies.

  10. Prostate Cancer

    MedlinePlus

    ... version of this page please turn Javascript on. Prostate Cancer What is Prostate Cancer? How Tumors Form The body is made up ... the Escape (Esc) button on your keyboard.) How Prostate Cancer Occurs Prostate cancer occurs when a tumor forms ...

  11. Nuclear Technology Series. Course 16: Mechanical Component Characteristics and Specifications.

    ERIC Educational Resources Information Center

    Center for Occupational Research and Development, Inc., Waco, TX.

    This technical specialty course is one of thirty-five courses designed for use by two-year postsecondary institutions in five nuclear technician curriculum areas: (1) radiation protection technician, (2) nuclear instrumentation and control technician, (3) nuclear materials processing technician, (4) nuclear quality-assurance/quality-control…

  12. Patient specific modeling of palpation-based prostate cancer diagnosis: effects of pelvic cavity anatomy and intrabladder pressure.

    PubMed

    Palacio-Torralba, Javier; Jiménez Aguilar, Elizabeth; Good, Daniel W; Hammer, Steven; McNeill, S Alan; Stewart, Grant D; Reuben, Robert L; Chen, Yuhang

    2016-01-01

    Computational modeling has become a successful tool for scientific advances including understanding the behavior of biological and biomedical systems as well as improving clinical practice. In most cases, only general models are used without taking into account patient-specific features. However, patient specificity has proven to be crucial in guiding clinical practice because of disastrous consequences that can arise should the model be inaccurate. This paper proposes a framework for the computational modeling applied to the example of the male pelvic cavity for the purpose of prostate cancer diagnostics using palpation. The effects of patient specific structural features on palpation response are studied in three selected patients with very different pathophysiological conditions whose pelvic cavities are reconstructed from MRI scans. In particular, the role of intrabladder pressure in the outcome of digital rectal examination is investigated with the objective of providing guidelines to practitioners to enhance the effectiveness of diagnosis. Furthermore, the presence of the pelvic bone in the model is assessed to determine the pathophysiological conditions in which it has to be modeled. The conclusions and suggestions of this work have potential use not only in clinical practice and also for biomechanical modeling where structural patient-specificity needs to be considered. © 2015 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.

  13. SU-D-BRB-02: Patient-Specific Rectal Toxicity Predictor Based Plan Quality Control for Prostate Stereotactic Body Radiation Therapy (SBRT)

    SciTech Connect

    Song, T; Zhou, L; Li, Y; Jiang, S; Gu, X

    2015-06-15

    Purpose: To develop a patient-specific rectal toxicity predictor guided plan quality control tool for prostate SBRT plans. Methods: For prostate SBRT cases, four segments of rectal walls including peri-prostatic anterior rectal wall, peri-prostatic lateral rectal walls, peri-prostatic posterior rectal wall and rectum superior to prostate are identified as organs at risk and the circumference of rectal wall receiving more than 39 Gy (CRW39) and 24 Gy (CRW24) are rectal toxicity predictors. In this new geometry-dosimetry model, a patient geometry descriptor, differential circumference of rectal wall (dCRW) is used as model input geometry parameters and plan dosimetric endpoints CRW39 and CRW24 are output dosimetric parameters. Linear models are built to correlate dCRW to both CRW39 and CRW24 and established with both a linear regression method and a modified bagging ensemble machine learning method. 27 SBRT prostate cases are retrospectively studied from a dose-escalated clinical trial research. 20 prescribed 50 Gy SBRT cases are recruited to train the model and the other rescaled 7 cases are used to evaluated model feasibility and accuracy. Results: Each solved linear coefficient sequence related to CRW39 or CRW24 is a one-dimensional decreasing function of the distance from the PTV boundary, indicating that the different locations of each rectal circumference have different contributions to each particular dosimetric endpoint. The fitting errors for those trained 20 prostate SBRT cases are small with mean values of 2.39%, 2.45% relative to the endpoint values for SBRT rectal toxicity predictor CRW39 and CRW24 respectively. 1 out of 7 evaluation plans is identified as poor quality plan. After re-planning, the CRW39 and CRW24 can be reduced by 3.34% and 3%, without sacrificing PTV coverage. Conclusion: The proposed patient geometry-plan toxicity predictor model for SBRT plans can be successfully applied to plan quality control for prostate SBRT cases.

  14. Monocyte-Induced Prostate Cancer Cell Invasion is Mediated by Chemokine ligand 2 and Nuclear Factor-κB Activity

    PubMed Central

    Lindholm, Paul F; Sivapurapu, Neela; Jovanovic, Borko; Kajdacsy-Balla, André

    2015-01-01

    Study Background The tumor microenvironment contains inflammatory cells which can influence cancer growth and progression; however the mediators of these effects vary with different cancer types. The mechanisms by which prostate cancer cells communicate with monocytes to promote cancer progression are incompletely understood. This study tested prostate cancer cell and monocyte interactions that lead to increased prostate cancer cell invasion. Methods We analyzed the prostate cancer cell invasion and NF-κB activity and cytokine expression during interaction with monocyte-lineage cells in co-cultures. The roles of monocyte chemotactic factor (MCP-1/CCL2) and NF-κB activity for co-culture induced prostate cancer invasion were tested. Clinical prostate cancer NF-κB expression was analyzed by immunohistochemistry. Results In co-cultures of prostate cancer cell lines with monocyte-lineage cells, (C-C motif) ligand 2 (CCL2) levels were significantly increased when compared with monocytes or cancer cells cultured alone. Prostate cancer cell invasion was induced by recombinant CCL2 in a dose dependent manner, similar to co-cultures with monocytes. The monocyte-induced prostate cancer cell invasion was inhibited by CCL2 neutralizing antibodies and by the CCR2 inhibitor, RS102895. Prostate cancer cell invasion and CCL2 expression induced in the co-cultures was inhibited by Lactacystin and Bay11-7082 NF-κB inhibitors. Prostate cancer cell NF-κB DNA binding activity depended on CCL2 dose and was inhibited by CCL2 neutralizing antibodies. Clinical prostate cancer NF-κB expression correlated with tumor grade. Conclusions Co-cultures with monocyte-lineage cell lines stimulated increased prostate cancer cell invasion through increased CCL2 expression and increased prostate cancer cell NF-κB activity. CCL2 and NF-κB may be useful therapeutic targets to interfere with inflammation-induced prostate cancer invasion. PMID:26317041

  15. Twitter Response to the United States Preventive Services Task Force Recommendations against Screening with Prostate Specific Antigen

    PubMed Central

    Prabhu, Vinay; Lee, Ted; Loeb, Stacy; Holmes, John H.; Gold, Heather T.; Lepor, Herbert; Penson, David F.; Makarov, Danil V.

    2014-01-01

    Objective To examine public and media response to the United States Preventive Services Task Force’s (USPSTF) draft (October 2011) and finalized (May 2012) recommendations against prostate-specific antigen (PSA) testing using Twitter, a popular social network with over 200 million active users. Materials and Methods We used a mixed methods design to analyze posts on Twitter, called “tweets.” Using the search term “prostate cancer,” we archived tweets in the 24 hour periods following the release of the USPSTF draft and finalized recommendations. We recorded tweet rate per hour and developed a coding system to assess type of user and sentiment expressed in tweets and linked articles. Results After the draft and finalized recommendations, 2042 and 5357 tweets focused on the USPSTF report, respectively. Tweet rate nearly doubled within two hours of both announcements. Fewer than 10% of tweets expressed an opinion about screening, and the majority of these were pro-screening during both periods. In contrast, anti-screening articles were tweeted more frequently in both draft and finalized study periods. From the draft to the finalized recommendations, the proportion of anti-screening tweets and anti-screening article links increased (p = 0.03 and p<0.01, respectively). Conclusions There was increased Twitter activity surrounding the USPSTF draft and finalized recommendations. The percentage of anti-screening tweets and articles appeared to increase, perhaps due to the interval public comment period. Despite this, most tweets did not express an opinion, suggesting a missed opportunity in this important arena for advocacy. PMID:24661474

  16. Anti-Tumor Effect of the Alphavirus-based Virus-like Particle Vector Expressing Prostate-Specific Antigen in a HLA-DR Transgenic Mouse Model of Prostate Cancer

    PubMed Central

    Riabov, V.; Tretyakova, I.; Alexander, R. B.; Pushko, P.; Klyushnenkova, E. N.

    2015-01-01

    The goal of this study was to determine if an alphavirus-based vaccine encoding human Prostate-Specific Antigen (PSA) could generate an effective anti-tumor immune response in a stringent mouse model of prostate cancer. DR2bxPSA F1 male mice expressing human PSA and HLA-DRB1*1501 transgenes were vaccinated with virus-like particle vector encoding PSA (VLPV-PSA) followed by the challenge with Transgenic Adenocarcinoma of Mouse Prostate cells engineered to express PSA (TRAMP-PSA). PSA-specific cellular and humoral immune responses were measured before and after tumor challenge. PSA and CD8 reactivity in the tumors was detected by immunohistochemistry. Tumor growth was compared in vaccinated and control groups. We found that VLPV-PSA could infect mouse dendritic cells in vitro and induce a robust PSA-specific immune response in vivo. A substantial proportion of splenic CD8+ T cells (19.6±7.4%) produced IFNγ in response to the immunodominant peptide PSA65–73. In the blood of vaccinated mice, 18.4±4.1% of CD8+ T cells were PSA-specific as determined by the staining with H-2Db/PSA65–73 dextramers. VLPV-PSA vaccination also strongly stimulated production of IgG2a/b anti-PSA antibodies. Tumors in vaccinated mice showed low levels of PSA expression and significant CD8 T cell infiltration. Tumor growth in VLPV-PSA vaccinated mice was significantly delayed at early time points (p=0.002, Gehan-Breslow test). Our data suggest that TC-83-based VLPV-PSA vaccine can efficiently overcome immune tolerance to PSA, mediate rapid clearance of PSA-expressing tumor cells and delay tumor growth. The VLPV-PSA vaccine will undergo further testing for the immunotherapy of prostate cancer. PMID:26319744

  17. Relationship of spermatoscopy, prostatic acid phosphatase activity and prostate-specific antigen (p30) assays with further DNA typing in forensic samples from rape cases.

    PubMed

    Romero-Montoya, Lydia; Martínez-Rodríguez, Hugo; Pérez, Miguel Antonio; Argüello-García, Raúl

    2011-03-20

    In the forensic laboratory the biological analyses for rape investigation commonly include vaginal swabs as sample material combined to biochemical tests including sperm cytology (SC) and detection of acid phosphatase activity (AP) and prostate-specific antigen (PSA, p30) for the conclusive identification of semen components. Most reports comparing these tests relied on analysis of semen samples or donor swabs taken under controlled conditions; however their individual or combined efficacy under real live sampling conditions in different laboratories is largely unknown. We carried out SC, APA and PSA analyses in vaginal swabs collected from casework rapes submitted to Mexican Forensic Laboratories at Texcoco and Toluca. On the basis of positive and negative results from each assay and sample, data were classified into eight categories (I-VIII) and compared with those obtained in the two only similar studies reported in Toronto, Canada and Hong Kong, China. SC and APA assays had the higher overall positivity in Toluca and Texcoco samples respectively and otherwise PSA had a lower but very similar positivity between these two laboratories. When compared to the previous studies some similarities were found, namely similar frequencies (at a ratio of approximately 1 out of 3) of samples being positive or negative by all techniques (Categories I and VI respectively) and a comparable overall positivity of APA and SC but higher than that of PSA. Indeed the combined results of using SC, APA and PSA tests was considered as conclusive for semen detection from approximately 1 out of 3 cases (Category I) to approximately 1 out of 2 cases in a scenario where at least SC is positive, strongly presumptive in 2 out of 3 cases (with at least one test positive) and the remainder 1 out of 3 cases (Category VI) suggested absence of semen. By determining Y-STR polymorphisms (12-loci) in additional samples obtained at Toluca laboratory, complete DNA profiles were determined from all

  18. NUCLEAR SCIENCE CURRICULUM PROJECT, PROJECT I, INSTRUCTIONAL SPECIFICATIONS.

    ERIC Educational Resources Information Center

    CAMAREN, JAMES

    ON THE PREMISE THAT A KNOWLEDGE OF NUCLEAR SCIENCE IS ESSENTIAL FOR INTELLIGENT DECISION-MAKING REGARDING ITS USES, THE NUCLEAR SCIENCE CURRICULUM PROJECT WAS DEVELOPED. ITS OBJECTIVE IS TO PROVIDE A PROGRAM THAT CAN BE EFFECTIVELY USED IN SCIENCE CLASSES TO PROVIDE AN UNDERSTANDING OF NUCLEAR SCIENCE AND ITS IMPACT ON SOCIETY. THOUGH TEACHER…

  19. Polymorphisms at the Microseminoprotein-beta (MSMB) Locus Associated With Physiological Variation in Beta-Microseminoprotein (β-MSP) and Prostate Specific Antigen (PSA) Levels

    PubMed Central

    Xu, Xing; Valtonen-André, Camilla; Sävblom, Charlotta; Halldén, Christer; Lilja, Hans; Klein, Robert J.

    2010-01-01

    Background rs10993994, a single nucleotide polymorphism (SNP) at the genetic locus encoding ß-microseminoprotein (β-MSP), is associated with both prostate cancer risk and levels of blood prostate-specific antigen (PSA), a biomarker used in prostate cancer screening. Therefore, we wished to determine the association between SNPs at MSMB, the gene encoding β-MSP, and levels of the prostate-produced biomarkers β-MSP, PSA, and human kallikrein 2 (hK2) in blood and semen. Methods Blood and semen from 304 healthy young Swedish men (aged 18-21) were assayed for β-MSP, PSA and hK2. SNPs around MSMB were genotyped from matched DNA and analyzed for quantitative association with biomarker levels. Empirical p-values were multiple test corrected and independence of each SNP’s effect was determined. Results rs10993994 is significantly associated with blood and semen levels of β-MSP (both p<1.0×10−7) and PSA (p=0.00014 and p=0.0019), and semen levels of hK2 (p=0.00027). Additional copies of the prostate cancer risk allele resulted in lower β-MSP but higher PSA levels, and singly explained 23% and 5% of the variation seen in semen β-MSP and PSA. Additional SNPs at MSMB are associated with β-MSP and PSA independently of rs10993994. Conclusions SNPs at MSMB correlate with physiological variation in β-MSP and PSA levels in the blood and semen of healthy young Swedish men. In particular, rs10993994 has a strong effect on β-MSP levels. Impact Our results suggest a mechanism by which rs10993994 may predispose to prostate cancer and raise the possibility that genetic variation may need to be considered in interpreting levels of these biomarkers. PMID:20696662

  20. 10 CFR 50.36a - Technical specifications on effluents from nuclear power reactors.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Technical specifications on effluents from nuclear power reactors. 50.36a Section 50.36a Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF PRODUCTION AND...; Ineligibility of Certain Applicants § 50.36a Technical specifications on effluents from nuclear power...

  1. 10 CFR 50.36a - Technical specifications on effluents from nuclear power reactors.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Technical specifications on effluents from nuclear power reactors. 50.36a Section 50.36a Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF PRODUCTION AND...; Ineligibility of Certain Applicants § 50.36a Technical specifications on effluents from nuclear power...

  2. High-throughput transcriptomic analysis nominates proteasomal genes as age-specific biomarkers and therapeutic targets in prostate cancer

    PubMed Central

    Zhao, S G; Jackson, W C; Kothari, V; Schipper, M J; Erho, N; Evans, J R; Speers, C; Hamstra, D A; Niknafs, Y S; Nguyen, P L; Schaeffer, E M; Ross, A E; Den, R B; Klein, E A; Jenkins, R B; Davicioni, E; Feng, F Y

    2015-01-01

    Background: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. Methods: The high-density Affymetrix GeneChip platform, encompassing >1 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (age<65) versus older (age⩾65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated age-specific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. Results: Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. Conclusions: Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do

  3. [Development of a biochip for quantitative determination of two forms of prostate specific antigen using internal calibration curve].

    PubMed

    Konovalova, E V; Savvateeva, E N; Dement'eva, E I; Filippova, M A; Turygin, A Iu; Osipova, T V; Riabykh, T P; Rubina, A Iu; Zasedatelev, A S

    2007-01-01

    Three-dimensional gel-based microchip allowing simultaneous quantitative detection of total (PSAtot) and free (PSAfree) forms of prostate specific antigen in human serum (in a format "one patient-one biochip") was developed. A method, which doesn't require preliminary construction of calibration curves when performing an assay, was applied for quantitative determination of PSAtot and PSAfree. Gel elements with immobilized antigen (PSA) in different concentration, forming an internal calibration curve, were included in a structure of the microchip, in addition to the elements with immobilized antibodies specific against PSAtot and PSAfree. The specialized software "ImaGelAssay" was used for data processing and interpretation. The sensitivity of the assay performed on biochips was 0.3 ng/ml for PSAtot and 0.2 ng/ml for PSAfree. Variation coefficient for the measurements inside one series of microchips didn't exceed 10%. Correlation coefficient between the results of measurements in human sera obtained on biochips and by the standard ELISA method was 0.988 for PSAtot and 0.987 for PSAfree.

  4. Gastric adenocarcinoma with prostatic metastasis.

    PubMed

    Roshni, S; Anoop, Tm; Preethi, Tr; Shubanshu, G; Lijeesh, Al

    2014-06-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  5. Gastric Adenocarcinoma with Prostatic Metastasis

    PubMed Central

    Roshni, S; Preethi, TR; Shubanshu, G; Lijeesh, AL

    2014-01-01

    Metastasis of gastric adenocarcinoma to the prostate gland is extremely rare. Herein, we report a case of gastric adenocarcinoma in a 56-year-old man with prostatic metastasis diagnosed through the analysis of biopsy specimens from representative lesions in the stomach and prostate gland. Immunohistochemistry of the prostatic tissue showed positive staining for cytokeratin 7 and negative staining for prostate-specific antigen (PSA), whereas the serum PSA level was normal, confirming the diagnosis of prostatic metastasis from carcinoma of the stomach. PMID:25061542

  6. Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer.

    PubMed

    Pollock, Julie A; Wardell, Suzanne E; Parent, Alexander A; Stagg, David B; Ellison, Stephanie J; Alley, Holly M; Chao, Christina A; Lawrence, Scott A; Stice, James P; Spasojevic, Ivan; Baker, Jennifer G; Kim, Sung Hoon; McDonnell, Donald P; Katzenellenbogen, John A; Norris, John D

    2016-10-01

    Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR-CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC.

  7. Design and preclinical evaluation of a 99mTc-labelled diabody of mAb J591 for SPECT imaging of prostate-specific membrane antigen (PSMA)

    PubMed Central

    2014-01-01

    Background Sensitive and specific detection of nodal status, sites of metastases and low-volume recurrent disease could greatly improve management of patients with advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-established marker for prostate carcinoma with increased levels of expression in high-grade, hormone-refractory and metastatic disease. The monoclonal antibody (mAb) J591 is directed against an extracellular epitope of PSMA and has been shown to efficiently target disseminated disease including metastases in lymph nodes and bone. Its use as a diagnostic imaging agent however is limited due to its slow pharmacokinetics. In this study a diabody derived from mAb J591 was developed as a single photon emission computed tomography (SPECT) tracer with improved pharmacokinetics for the detection of PSMA expression in prostate cancer. Methods A diabody in VH-VL orientation and with a C-terminal cysteine was expressed in HEK293T cells and purified by a combination of metal ion affinity and size exclusion chromatography. Specificity and affinity were determined in cell binding studies. For SPECT imaging, the diabody was site-specifically labelled with [99mTc(CO)3]+ via the C-terminal His tag and evaluated in a subcutaneous DU145/DU145-PSMA prostate carcinoma xenograft model. Results J591C diabody binds to PSMA-expressing cells with low nanomolar affinity (3.3 ± 0.2 nM). SPECT studies allowed imaging of tumour xenografts with high contrast from 4 h post injection (p.i.). Ex vivo biodistribution studies showed peak tumour uptake of the tracer of 12.1% ± 1.7% injected dose (ID)/g at 8 h p.i. with a tumour to blood ratio of 8.0. Uptake in PSMA-negative tumours was significantly lower with 6.3% ± 0.5% at 8 h p.i. (p < 0.001). Conclusion The presented diabody has favourable properties required to warrant its further development for antibody-based imaging of PSMA expression in prostate cancer, including PSMA-specific uptake

  8. NOTE: Adaptation of a 3D prostate cancer atlas for transrectal ultrasound guided target-specific biopsy

    NASA Astrophysics Data System (ADS)

    Narayanan, R.; Werahera, P. N.; Barqawi, A.; Crawford, E. D.; Shinohara, K.; Simoneau, A. R.; Suri, J. S.

    2008-10-01

    Due to lack of imaging modalities to identify prostate cancer in vivo, current TRUS guided prostate biopsies are taken randomly. Consequently, many important cancers are missed during initial biopsies. The purpose of this study was to determine the potential clinical utility of a high-speed registration algorithm for a 3D prostate cancer atlas. This 3D prostate cancer atlas provides voxel-level likelihood of cancer and optimized biopsy locations on a template space (Zhan et al 2007). The atlas was constructed from 158 expert annotated, 3D reconstructed radical prostatectomy specimens outlined for cancers (Shen et al 2004). For successful clinical implementation, the prostate atlas needs to be registered to each patient's TRUS image with high registration accuracy in a time-efficient manner. This is implemented in a two-step procedure, the segmentation of the prostate gland from a patient's TRUS image followed by the registration of the prostate atlas. We have developed a fast registration algorithm suitable for clinical applications of this prostate cancer atlas. The registration algorithm was implemented on a graphical processing unit (GPU) to meet the critical processing speed requirements for atlas guided biopsy. A color overlay of the atlas superposed on the TRUS image was presented to help pick statistically likely regions known to harbor cancer. We validated our fast registration algorithm using computer simulations of two optimized 7- and 12-core biopsy protocols to maximize the overall detection rate. Using a GPU, patient's TRUS image segmentation and atlas registration took less than 12 s. The prostate cancer atlas guided 7- and 12-core biopsy protocols had cancer detection rates of 84.81% and 89.87% respectively when validated on the same set of data. Whereas the sextant biopsy approach without the utility of 3D cancer atlas detected only 70.5% of the cancers using the same histology data. We estimate 10-20% increase in prostate cancer detection rates

  9. Androgen Deprivation Therapy Does Not Impact Cause-Specific or Overall Survival in High-Risk Prostate Cancer Managed With Brachytherapy and Supplemental External Beam

    SciTech Connect

    Merrick, Gregory S. . E-mail: gmerrick@urologicresearchinstitute.org; Butler, Wayne M.; Wallner, Kent E.; Galbreath, Robert W.; Allen, Zachariah A.; Adamovich, Edward; Lief, Jonathan

    2007-05-01

    Purpose: To determine cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) in high-risk prostate cancer patients undergoing brachytherapy with or without supplemental therapies. Methods and Materials: Between April 1995 and July 2002, 204 patients with high-risk prostate cancer (Gleason score {>=}8 or prostate-specific antigen [PSA] >20 ng/mL or clinical stage {>=}T2c) underwent brachytherapy. Median follow-up was 7.0 years. The bPFS was defined by a PSA {<=}0.40 ng/mL after nadir. Multiple clinical, treatment, and dosimetric parameters were evaluated for the impact on survival. Results: The 10-year CSS, bPFS, and OS were 88.9%, 86.6%, and 68.6%, respectively. A statistically significant difference in bPFS was discerned between hormone naive, ADT {<=}6 months, and ADT >6 month cohorts (79.7% vs. 95.% vs. 89.9%, p = 0.032). Androgen deprivation therapy (ADT) did not impact CSS or OS. For bPFS patients, the median posttreatment PSA was <0.04 ng/mL. A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS, whereas percent positive biopsies and duration of ADT best predicted for bPFS. The OS was best predicted by Gleason score and diabetes. Thirty-eight patients have died, with 26 of the deaths from cardiovascular/pulmonary disease or second malignancy. Eleven patients have died of metastatic prostate cancer. Conclusions: The ADT improved 10-year bPFS without statistical impact on CSS or OS. Death as a result of cardiovascular/pulmonary disease and second malignancies were more than twice as common as prostate cancer deaths. Strategies to improve cardiovascular health should positively impact OS.

  10. The urologic epithelial stem cell database (UESC) – a web tool for cell type-specific gene expression and immunohistochemistry images of the prostate and bladder

    PubMed Central

    Pascal, Laura E; Deutsch, Eric W; Campbell, David S; Korb, Martin; True, Lawrence D; Liu, Alvin Y

    2007-01-01

    Background Public databases are crucial for analysis of high-dimensional gene and protein expression data. The Urologic Epithelial Stem Cells (UESC) database is a public database that contains gene and protein information for the major cell types of the prostate, prostate cancer cell lines, and a cancer cell type isolated from a primary tumor. Similarly, such information is available for urinary bladder cell types. Description Two major data types were archived in the database, protein abundance localization data from immunohistochemistry images, and transcript abundance data principally from DNA microarray analysis. Data results were organized in modules that were made to operate independently but built upon a core functionality. Gene array data and immunostaining images for human and mouse prostate and bladder were made available for interrogation. Data analysis capabilities include: (1) CD (cluster designation) cell surface protein data. For each cluster designation molecule, a data summary allows easy retrieval of images (at multiple magnifications). (2) Microarray data. Single gene or batch search can be initiated with Affymetrix Probeset ID, Gene Name, or Accession Number together with options of coalescing probesets and/or replicates. Conclusion Databases are invaluable for biomedical research, and their utility depends on data quality and user friendliness. UESC provides for database queries and tools to examine cell type-specific gene expression (normal vs. cancer), whereas most other databases contain only whole tissue expression datasets. The UESC database provides a valuable tool in the analysis of differential gene expression in prostate cancer genes in cancer progression. PMID:18072977

  11. Improving the Specificity of the Prostate-Specific Antigen Substrate Glutaryl-Hyp-Ala-Ser-Chg-Gln as a Promoiety.

    PubMed

    Aloysius, Herve; Hu, Longqin

    2015-10-01

    To develop PSA peptide substrates with improved specificity and plasma stability from the known substrate sequence glutaryl-Hyp-Ala-Ser-Chg-Gln, systematic replacements of the N-terminal segment with D-retro-inverso-peptides were performed with the incorporation of 7-amino-4-methylcoumarin (7-AMC) after Gln for convenient fluorometric determination and ranking of the PSA substrate activity. The D-retro-inverso-peptide conjugates with P2-P5 D-amino acid substitutions were moderate but poorer PSA substrates as compared to the original peptide, suggesting that inversion of the amide bonds and/or incorporation of the additional atom as in the urea linker adversely affected PSA binding. However, P5 substitution of Hyp with Ser showed significant improvements in PSA cleavage rate; the resulting AMC conjugate, glutaryl-Ser-Ala-Ser-Chg-Gln-AMC (11), exhibited the fastest PSA cleavage rate of 351 pmol/min/100 nmol PSA. In addition, GABA←mGly-Ala-Ser-Chg-Gln-AMC (conjugate 6) was the second best PSA substrate and released 7-AMC at a rate of 225 pmol/min/100 nmol PSA as compared to 171 pmol/min/100 nmol PSA for the control conjugate glutaryl-Hyp-Ala-Ser-Chg-Gln-AMC. Incubations of selected AMC conjugates with mouse and human plasma revealed that GABA←D-Ser-ψ[NH-CO-NH]-Ala-Ser-Chg-Gln-AMC (5) and GABA←mGly-Ala-Ser-Chg-Gln-AMC (6) were most stable to non-PSA-mediated proteolysis. Our results suggest that the PSA specificity of glutaryl-Hyp-Ala-Ser-Chg-Gln is improved with Ser and mGly substitutions of Hyp at the P5.

  12. Investigation of Histone Lysine-Specific Demethylase 5D (KDM5D) Isoform Expression in Prostate Cancer Cell Lines: a System Approach

    PubMed Central

    Jangravi, Zohreh; Najafi, Mohammad; Shabani, Mohammd

    2016-01-01

    Background: It is now well-demonstrated that histone demethylases play an important role in developmental controls, cell-fate decisions, and a variety of diseases such as cancer. Lysine-specific demethylase 5D (KDM5D) is a male-specific histone demethylase that specifically demethylates di- and tri-methyl H3K4 at the start site of active gene. In this light, the aim of this study was to investigate isoform/transcript-specific expression profiles of KDM5D in three prostate cancer cell lines, Du-145, LNCaP, and PC3. Methods: Real-time PCR analysis was performed to determine the expression levels of different KDM5D transcripts in the prostate cell lines. A gene regulatory network was established to analyze the gene expression profile. Results: Significantly different expression levels of both isoforms were found among the three cell lines. Interestingly, isoform I was expressed in three cell lines while isoform III did only in DU-145. The expression levels of both isoforms were higher in DU-145 when compared to other cell lines (P<0.0001). The observed expression profile was determined by using regulatory network analyses. Conclusion: The present study, for the first time, not only showed the expression profiles of KDM5D isoforms in prostate cancer cell lines but also evaluated the effects of the gene regulatory network on the expression profile of this gene. PMID:26728332

  13. A nanoparticle label/immunochromatographic electrochemical biosensor for rapid and sensitive detection of prostate-specific antigen

    SciTech Connect

    Lin, Ying-Ying; Wang, Jun; Liu, Guodong; Wu, Hong; Wai, Chien M.; Lin, Yuehe

    2008-06-15

    We present a nanoparticle (NP) label/immunochromatographic electrochemical biosensor (IEB) for rapid and sensitive detection of prostate-specific antigen (PSA) in human serum. This IEB integrates the immunochromatographic strip with the electrochemical detector for transducing quantitative signals. The NP label, made of CdSe@ZnS, serves as a signal-amplifier vehicle. A sandwich immunoreaction was performed on the immunochromatographic strip. The captured NP labels in the test zone were determined by highly sensitive stripping voltammetric measurement of the dissolved metallic component (cadmium) with a disposable-screen-printed electrode, which is embedded underneath the membrane of the test zone. Experimental parameters (e.g., immunoreaction time, the amount of anti-PSA-NP conjugations applied) and electrochemical detection conditions (e.g., preconcentration potential and time) were optimized using this biosensor for PSA detection. The analytical performance of this biosensor was evaluated with serum PSA samples according to the “figure-of-merits” (e.g., dynamic range, reproducibility, and detection limit). The results were validated with enzyme-linked immunosorbent assay (ELISA) and show high consistency. It is found that this biosensor is very sensitive with the detection limit of 0.02 ng/mL PSA and is quite reproducible. This method is rapid, clinically accurate, and less expensive than other diagnosis tools for PSA; therefore, this IEB coupled with a portable electrochemical analyzer shows great promise for simple, sensitive, quantitative point-of-care testing of disease-related protein biomarkers.

  14. Signal amplification strategy for sensitive immunoassay of prostate specific antigen (PSA) based on ferrocene incorporated polystyrene spheres.

    PubMed

    Ding, Lu; You, Jinmao; Kong, Rongmei; Qu, Fengli

    2013-09-01

    A new kind of signal amplification strategy based on ferrocene (Fc) incorporated polystyrene spheres (PS-Fc) was proposed. The synthesized PS-Fc displayed narrow size distribution and good stability. PS-Fc was applied as label to develop immunosensors for prostate specific antigen (PSA) after the typical sandwich immunoreaction by linking anti-PSA antibody (Ab2) onto PS-Fc. After the fabrication of the immunosensor, tetrahydrofuran (THF) was dropped to dissolve PS and release the contained Fc for the following stripping voltammetric detection. PS-Fc as a new electrochemical label prevented the leakage of Fc and greatly amplified the immunosensor signal. In addition, the good biocompatibility of PS could maintain the bioactivity of the antibodies. The response current was linear to the logarithm of PSA concentration in the range from 0.01 ng mL(-1) to 20 ng mL(-1) with a detection limit of 1 pg mL(-1). The immunosensor results were validated through the detection of PSA in serum samples with satisfactory results.

  15. Arraying prostate specific antigen PSA and Fab anti-PSA using light-assisted molecular immobilization technology

    PubMed Central

    Parracino, Antonietta; Neves-Petersen, Maria Teresa; di Gennaro, Ane Kold; Pettersson, Kim; Lövgren, Timo; Petersen, Steffen B

    2010-01-01

    We here report for the first time the creation of prostate specific antigen (PSA) and Fab anti-PSA biosensor arrays using UV light-assisted molecular immobilization (LAMI), aiming at the detection and quantification of PSA, a cancer marker. The technology involves formation of free, reactive thiol groups upon UV excitation of protein aromatic residues located in spatial proximity of disulphide bridges, a conserved structural feature in both PSA and Fab molecules. The created thiol groups bind onto thiol reactive surfaces leading to oriented covalent protein immobilization. Protein activity was confirmed carrying out immunoassays: immobilized PSA was recognized by Fab anti-PSA in solution and immobilized Fab anti-PSA cross-reacted with PSA in solution. LAMI technology proved successful in immobilizing biomedically relevant molecules while preserving their activity, highlighting that insight into how light interacts with biomolecules may lead to new biophotonic technologies. Our work focused on the application of our new engineering principles to the design, analysis, construction, and manipulation of biological systems, and on the discovery and application of new engineering principles inspired by the properties of biological systems. PMID:20665692

  16. Microfluidic chip-based nanoelectrode array as miniaturized biochemical sensing platform for prostate-specific antigen detection.

    PubMed

    Triroj, Napat; Jaroenapibal, Papot; Shi, Haibin; Yeh, Joanne I; Beresford, Roderic

    2011-02-15

    A microfluidic biosensor chip with an embedded three-electrode configuration is developed for the study of the voltammetric response of a nanoelectrode array with controlled inter-electrode distance in a nanoliter-scale sample volume. The on-chip three-electrode cell consists of a 5 × 5 array of Au working nanoelectrodes with radii between 60 and 120 nm, a Cl(2)-plasma-treated Ag/AgCl reference electrode, and a Au counter electrode. The nanoelectrode array is fabricated by creating high-aspect-ratio pores through an alumina insulating layer using an I(2) gas-assisted focused-ion-beam (FIB) milling, ion beam sculpting, and electrodeposition of Au. The glass substrate with the electrode pattern is assembled with a polydimethylsiloxane (PDMS) microchannel slab giving a volume of 180 nL for each channel. Cyclic voltammetry calibration with a standard redox species exhibits a significant increase of current density by two orders of magnitude compared to that obtained from a microelectrode. On-chip functionalization of the nanoelectrodes with a prostate-specific antigen (PSA) biosensor complex and detection of PSA based on a competitive immunoassay method are performed. The detection limit is approximately 10 pg/mL (∼270 fM), which corresponds to roughly 30,000 copies of PSA in the microchannel test volume.

  17. Ethnic differences and predictors of colonoscopy, prostate-specific antigen, and mammography screening participation in the multiethnic cohort

    PubMed Central

    Harmon, Brook E.; Little, Melissa A.; Woekel, Erica D.; Ettienne, Reynolette; Long, Camonia R.; Wilkens, Lynne R.; Le Marchand, Loic; Henderson, Brian E.; Kolonel, Laurence N.; Maskarinec, Gertraud

    2014-01-01

    Purpose Given the relation between screening and improved cancer outcomes and the persistence of ethnic disparities in cancer mortality, we explored ethnic differences in colonoscopy, prostate-specific antigen (PSA), and mammography screening in the Multiethnic Cohort Study. Methods Logistic regression was applied to examine the influence of ethnicity as well as demographics, lifestyle factors, comorbidities, family history of cancer, and previous screening history on self-reported screening participation collected in 1999–2002. Results The analysis included 140,398 participants who identified as white, African American, Native Hawaiian, Japanese American, US born-Latino, or Mexican born-Latino. The screening prevalences overall were mammography: 88% of women, PSA: 45% of men, and colonoscopy: 35% of men and women. All minority groups reported 10–40% lower screening utilization than whites, but Mexican-born Latinos and Native Hawaiian were lowest. Men were nearly twice as likely to have a colonoscopy (OR = 1.94, 95% CI = 1.89–1.99) as women. A personal screening history, presence of comorbidities, and family history of cancer predicted higher screening utilization across modalities, but to different degrees across ethnic groups. Conclusions This study confirms previously reported sex differences in colorectal cancer screening and ethnic disparities in screening participation. The findings suggest it may be useful to include personal screening history and family history of cancer into counseling patients about screening participation. PMID:24667037

  18. Variation in Prostate-Specific Antigen Screening in Men Aged 80 and Older in Fee-for-Service Medicare

    PubMed Central

    Bynum, Julie; Song, Yunjie; Fisher, Elliott

    2010-01-01

    OBJECTIVES To determine the rate of prostate-specific antigen (PSA) screening in men aged 80 and older in Medicare and to examine geographic variation in screening rates across the U.S. DESIGN Retrospective cohort study of variation across hospital referral regions using administrative data. SETTING National random sample in fee-for-service Medicare. PARTICIPANTS Medicare beneficiaries aged 80 and older in 2003. MEASUREMENTS Percentage of men aged 80 and older screened using the PSA test. RESULTS The national rate of PSA screening in men aged 80 and older was 17.2%, but there was wide variation across regions (<2–38%). Higher PSA screening in a region was positively associated with greater total costs (correlation coefficient (r) = 0.49, P<.001), greater intensive care unit use at the end of life (r = 0.46, P<.001), and greater number of unique physicians seen (r = 0.36, P<.001). PSA screening was negatively associated with proportion of beneficiaries using a primary care physician as opposed to a medical subspecialist for the predominance of ambulatory care (r = −0.38, P<.001). CONCLUSION PSA screening in men aged 80 and older is common practice, although its frequency is highly variable across the United States. Its association with fragmented physician care and aggressive end-of-life care may reflect less reliance on primary care and consequent difficulty informing patients of the potential harms and low likelihood of benefit of this procedure. PMID:20345867

  19. Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation

    SciTech Connect

    Buyyounouski, Mark K.; Hanlon, Alexandra L.; Horwitz, Eric M.; Uzzo, Robert G.; Pollack, Alan . E-mail: alan.pollack@fccc.edu

    2005-04-01

    Purpose: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Methods and Materials: Between December 1, 1991 and April 30, 1998, 688 men with T1c-T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n = 586) or in combination with either short-term (STAD: 3 to 12 months, n = 82) or long-term (LTAD: 12 to 36 months, n = 20) AD. Follow-up, calculated from the end of all treatment, was {>=}48 months. The mean posttreatment PSA was calculated in 3-month intervals. Results: The median posttreatment clinical follow-up period was 76 months (range, 48-152 months). The posttreatment PSA values from the end of all treatment for the RT+STAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RT+STAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RT+STAD-NBF profile, the RT+LTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RT+LTAD-BF profile rose continuously but at a slower rate over time. Nine RT+STAD-NBF patients (22%) and 2 RT+LTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RT+LTAD-BF profile rose constantly and steadily with a doubling

  20. Long-term follow-up of {sup 111}In-capromab pendetide (ProstaScint) scan as pretreatment assessment in patients who undergo salvage radiotherapy for rising prostate-specific antigen after radical prostatectomy for prostate cancer

    SciTech Connect

    Nagda, Suneel N. . E-mail: snagda@gmail.com; Mohideen, Najeeb; Lo, Simon S.; Khan, Usman B.S.; Dillehay, Gary; Wagner, Robert; Campbell, Steven; Flanigan, Robert

    2007-03-01

    Purpose: To evaluate the long-term failure patterns in patients who underwent an {sup 111}In-capromab pendetide (ProstaScint) scan as part of their pretreatment assessment for a rising prostate-specific antigen (PSA) level after prostatectomy and subsequently received local radiotherapy (RT) to the prostate bed. Methods: Fifty-eight patients were referred for evaluation of a rising PSA level after radical prostatectomy. All patients had negative findings for metastatic disease after abdominal/pelvis imaging with CT and isotope bone scans. All patients underwent a capromab pendetide scan, and the sites of uptake were noted. All patients were treated with local prostate bed RT (median dose 66.6 Gy). Results: Of the 58 patients, 20 had biochemical failure (post-RT PSA level >0.2 ng/mL or a rise to greater than the nadir PSA), including 6 patients with positive uptake outside the bed (positive elsewhere). The 4-year biochemical relapse-free survival (bRFS) rates for patients with negative (53%), positive in the prostate bed alone (45%), or positive elsewhere (74%) scan findings did not differ significantly (p = 0.51). The positive predictive value of the capromab pendetide scan in detecting disease outside the bed was 27%. The capromab pendetide scan status had no effect on bRFS. Those with a pre-RT PSA level of <1 ng/mL had improved bRFS (p = 0.003). Conclusion: The capromab pendetide scan has a low positive predictive value in patients with positive elsewhere uptake and the 4-year bRFS was similar to that for those who did not exhibit positive elsewhere uptake. Therefore, patients with a postprostatectomy rising PSA level should considered for local RT on the basis of clinicopathologic factors.

  1. Comparison of Prostate-Specific Membrane Antigen–Based 18F-DCFBC PET/CT to Conventional Imaging Modalities for Detection of Hormone-Naïve and Castration-Resistant Metastatic Prostate Cancer

    PubMed Central

    Rowe, Steven P.; Macura, Katarzyna J.; Ciarallo, Anthony; Mena, Esther; Blackford, Amanda; Nadal, Rosa; Antonarakis, Emmanuel S.; Eisenberger, Mario A.; Carducci, Michael A.; Ross, Ashley E.; Kantoff, Philip W.; Holt, Daniel P.; Dannals, Robert F.; Mease, Ronnie C.; Pomper, Martin G.; Cho, Steve Y.

    2016-01-01

    Conventional imaging modalities (CIMs) have limited sensitivity and specificity for detection of metastatic prostate cancer. We examined the potential of a first-in-class radiofluorinated small-molecule inhibitor of prostate-specific membrane antigen (PSMA), N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC), to detect metastatic hormone-naïve (HNPC) and castration-resistant prostate cancer (CRPC). Methods Seventeen patients were prospectively enrolled (9 HNPC and 8 CRPC); 16 had CIM evidence of new or progressive metastatic prostate cancer and 1 had high clinical suspicion of metastatic disease. 18F-DCFBC PET/CT imaging was obtained with 2 successive PET scans starting at 2 h after injection. Patients were imaged with CIM at approximately the time of PET. A lesion-by-lesion analysis of PET to CIM was performed in the context of either HNPC or CRPC. The patients were followed with available clinical imaging as a reference standard to determine the true nature of identified lesions on PET and CIM. Results On the lesion-by-lesion analysis, 18F-DCFBC PET was able to detect a larger number of lesions (592 positive with 63 equivocal) than CIM (520 positive with 61 equivocal) overall, in both HNPC and CRPC patients. 18F-DCFBC PET detection of lymph nodes, bone lesions, and visceral lesions was superior to CIM. When intrapatient clustering effects were considered, 18F-DCFBC PET was estimated to be positive in a large proportion of lesions that would be negative or equivocal on CIM (0.45). On follow-up, the sensitivity of 18F-DCFBC PET (0.92) was superior to CIM (0.71). 18F-DCFBC tumor uptake was increased at the later PET time point (∼2.5 h after injection), with background uptake showing a decreasing trend on later PET. Conclusion PET imaging with 18F-DCFBC, a small-molecule PSMA-targeted radiotracer, detected more lesions than CIM and promises to diagnose and stage patients with metastatic prostate cancer more accurately than current

  2. Prostate brachytherapy

    MedlinePlus

    Implant therapy - prostate cancer; Radioactive seed placement; Internal radiation therapy - prostate; High dose radiation (HDR) ... plan and then place the seeds that deliver radiation into your prostate. The seeds are placed with ...

  3. 10 CFR 50.36a - Technical specifications on effluents from nuclear power reactors.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... reactors. 50.36a Section 50.36a Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF PRODUCTION AND...; Ineligibility of Certain Applicants § 50.36a Technical specifications on effluents from nuclear power reactors..., including expected occurrences, as low as is reasonably achievable, each licensee of a nuclear power...

  4. 10 CFR 50.36a - Technical specifications on effluents from nuclear power reactors.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... reactors. 50.36a Section 50.36a Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF PRODUCTION AND...; Ineligibility of Certain Applicants § 50.36a Technical specifications on effluents from nuclear power reactors..., including expected occurrences, as low as is reasonably achievable, each licensee of a nuclear power...

  5. 10 CFR 50.36a - Technical specifications on effluents from nuclear power reactors.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... reactors. 50.36a Section 50.36a Energy NUCLEAR REGULATORY COMMISSION DOMESTIC LICENSING OF PRODUCTION AND...; Ineligibility of Certain Applicants § 50.36a Technical specifications on effluents from nuclear power reactors..., including expected occurrences, as low as is reasonably achievable, each licensee of a nuclear power...

  6. Measuring disease-specific health status in men with benign prostatic hyperplasia. Measurement Committee of The American Urological Association.

    PubMed

    Barry, M J; Fowler, F J; O'Leary, M P; Bruskewitz, R C; Holtgrewe, H L; Mebust, W K

    1995-04-01

    In preparation for an outcomes study of benign prostatic hyperplasia (BPH), two measures of disease-specific health status were developed to supplement a symptom score and overall health status measures. The symptom problem index (SPI) captures how troublesome patients find their urinary symptoms. The BPH impact index (BII) measures how much their urinary problems affect various domains of health. A prospective revalidation of the refined instruments (N = 108 BPH patients and 50 controls) documented that both indices had good internal consistency (Cronbach's alpha = 0.88 and 0.79, respectively) and test-retest (r = 0.88 for both) reliabilities, correlated strongly with symptom scores (r = 0.86 and 0.77), and discriminated between BPH and control subjects (receiver-operating characteristic areas = 0.87 and 0.85, respectively). These indices were nearly as responsive as symptom scores in 50 men actively treated for BPH, and much more responsive than a non-disease-specific General Health Index (GHI), a Mental Health Index (MHI), and an Activity Index (AI). Finally, these measures capture most of the health status significance of BPH symptoms. In linear regression models constructed to predict scores on the GHI, MHI, and AI, symptom scores added little explanatory power to the SPI and, particularly, to the BII. These measures help clarify how BPH affects overall health status and function. Such measures have an important role to play in studies of the outcomes of treatment for BPH, and probably for other conditions that interfere with health status and function.

  7. MHC class II tetramer analyses in AE37-vaccinated prostate cancer patients reveal vaccine-specific polyfunctional and long-lasting CD4(+) T-cells.

    PubMed

    Anastasopoulou, Eleftheria A; Voutsas, Ioannis F; Papamichail, Michael; Baxevanis, Constantin N; Perez, Sonia A

    2016-07-01

    Realizing the basis for generating long-lasting clinical responses in cancer patients after therapeutic vaccinations provides the means to further ameliorate clinical efficacy. Peptide cancer vaccines stimulating CD4(+) T helper cells are often promising for inducing immunological memory and persistent CD8(+) cytotoxic T cell responses. Recent reports from our clinical trial with the AE37 vaccine, which is a HER2 hybrid polypeptide, documented its efficacy to induce CD4(+) T cell immunity, which was associated with clinical improvements preferentially among HLA-DRB1*11(+) prostate cancer patients. Here, we performed in-depth investigation of the CD4(+) T cell response against the AE37 vaccine. We used the DR11/AE37 tetramer in combination with multicolor flow cytometry to identify and characterize AE37-specific CD4(+) T cells regarding memory and Tregs phenotype in HLA-DRB1*11(+) vaccinated patients. To verify vaccine-specific immunological memory in vivo, we also assessed AE37-specific CD4(+) T cells in defined CD4(+) memory subsets by cell sorting. Finally, vaccine-induced AE37-specific CD4(+) T cells were assessed regarding their functional profile. AE37-specific memory CD4(+) T cells could be detected in peptide-stimulated cultures from prostate cancer patients following vaccination even 4 y post-vaccination. The vast majority of vaccine-induced AE37-specific CD4(+) T cells exhibited a multifunctional, mostly Th1 cytokine signature, with the potential of granzyme B production. In contrast, we found relatively low frequencies of Tregs among AE37-specific CD4(+) T cells. This is the first report on the identification of vaccine-induced HER2-specific multifunctional long-lasting CD4(+) T cells in vaccinated prostate cancer patients. PMID:27622033

  8. MHC class II tetramer analyses in AE37-vaccinated prostate cancer patients reveal vaccine-specific polyfunctional and long-lasting CD4(+) T-cells.

    PubMed

    Anastasopoulou, Eleftheria A; Voutsas, Ioannis F; Papamichail, Michael; Baxevanis, Constantin N; Perez, Sonia A

    2016-07-01

    Realizing the basis for generating long-lasting clinical responses in cancer patients after therapeutic vaccinations provides the means to further ameliorate clinical efficacy. Peptide cancer vaccines stimulating CD4(+) T helper cells are often promising for inducing immunological memory and persistent CD8(+) cytotoxic T cell responses. Recent reports from our clinical trial with the AE37 vaccine, which is a HER2 hybrid polypeptide, documented its efficacy to induce CD4(+) T cell immunity, which was associated with clinical improvements preferentially among HLA-DRB1*11(+) prostate cancer patients. Here, we performed in-depth investigation of the CD4(+) T cell response against the AE37 vaccine. We used the DR11/AE37 tetramer in combination with multicolor flow cytometry to identify and characterize AE37-specific CD4(+) T cells regarding memory and Tregs phenotype in HLA-DRB1*11(+) vaccinated patients. To verify vaccine-specific immunological memory in vivo, we also assessed AE37-specific CD4(+) T cells in defined CD4(+) memory subsets by cell sorting. Finally, vaccine-induced AE37-specific CD4(+) T cells were assessed regarding their functional profile. AE37-specific memory CD4(+) T cells could be detected in peptide-stimulated cultures from prostate cancer patients following vaccination even 4 y post-vaccination. The vast majority of vaccine-induced AE37-specific CD4(+) T cells exhibited a multifunctional, mostly Th1 cytokine signature, with the potential of granzyme B production. In contrast, we found relatively low frequencies of Tregs among AE37-specific CD4(+) T cells. This is the first report on the identification of vaccine-induced HER2-specific multifunctional long-lasting CD4(+) T cells in vaccinated prostate cancer patients.

  9. Soy milk digestion extract inhibits progression of prostate cancer cell growth via regulation of prostate cancer‑specific antigen and cell cycle-regulatory genes in human LNCaP cancer cells.

    PubMed

    Kang, Nam-Hee; Shin, Hee-Chang; Oh, Seunghyun; Lee, Kyun-Hee; Lee, Yoon-Bok; Choi, Kyung-Chul

    2016-08-01

    Soy milk, which is produced from whole soybeans, contains a variety of biologically active components. Isoflavones are a class of soy-derived phytoestrogens with beneficial effects, among which genistein (GEN) has been previously indicated to reduce the risk of prostate cancer. The present study evaluated the effects of soy milk digestion extract (SMD) on the progression of prostate cancer via the estrogen receptor (ER)β in human LNCaP prostate cancer cells. To evaluate the effects of SMD (daizein, 1.988 mg/100g, glycitein, 23.537 mg/100 g and GEN, 0.685 mg/100g) on cell proliferation, LNCaP cells were cultured in media containing vehicle (0.1% dimethyl sulfoxide), 17β‑estradiol (E2; 2.7x10‑7 mg/ml), GEN (2.7x10-2 mg/ml) of SMD (total aglycon concentration, 0.79 mg/ml), after which the cell viability was examined using an MTT assay. The cell viability was significantly elevated by E2 (by 45±0.18%), while it was markedly reduced by GEN (73.2±0.03%) or SMD (74.8±0.09%). Semi‑quantitative reverse transcription polymerase chain reaction analysis was performed to assess the mRNA expression levels of target genes, including ERβ, prostate cancer‑specific antigen (PSA) and cell cycle regulators p21, Cyclin D1 and cyclin-dependent kinase (CDK)4. The expression of ERβ was almost completely diminished by E2, whereas it was significantly elevated by SMD. In addition, the expression levels of PSA were considerably reduced by SMD. The expression of p21 was significantly elevated by SMD, while it was markedly reduced by E2. Of note, the expression levels of Cyclin D1 and CDK4 were considerably elevated by E2, while being significantly reduced by GEN and SMD. All of these results indicated that SMD may inhibit the proliferation of human prostate cancer cells via regulating the expression of ERβ, PSA, p21, Cyclin D1 and CDK4 in an ER-dependent manner.

  10. Electrochemical assay of active prostate-specific antigen (PSA) using ferrocene-functionalized peptide probes

    SciTech Connect

    Zhao, Ning; He, Yuqing; Mao, Xun; Sun, Yuhan; Zhang, Xibao; Li, Chen-Zhong; Lin, Yuehe; Liu, Guodong

    2010-03-24

    This paper presents a novel approach to electrochemically determine enzymatically active PSA using ferrocene-functionalized helix peptide (CHSSLKQK). The principle of electrochemical measurement is based on the specific proteolytic cleavage events of the FC-peptide on the gold electrode surface in the presence of PSA, resulting the change of the current signal of the electrode. The percentage of the decreased current is linear with the concentration of active PSA at the range of 0.5-40 ng/mL with a detection limit of 0.2 ng/mL. The direct transduction of peptide cleavage events into an electrical signal provides a simple, sensitive method for detecting the enzymatic activity of PSA and determining the active PSA concentration.

  11. Attachment and health care utilization among middle-aged and older African-descent men: dismissiveness predicts less frequent digital rectal examination and prostate-specific antigen screening.

    PubMed

    Consedine, Nathan S; Tuck, Natalie L; Fiori, Katherine L

    2013-09-01

    Although health care utilization occurs in interpersonal contexts, little is known regarding how interpersonal preferences or styles among patients may be relevant. A small body of work has identified links between attachment-a dispositional style of relating to others-and patterns of health care use. The current report examined how attachment characteristics predicted the frequency of digital rectal exam and prostate-specific antigen testing in a sample of African-descent men. Four hundred and fourteen African-descent men aged 45 to 70 years completed measures of prostate screening and attachment, together with measures of traditional predictors of screening (demographics, insurance, family history, physician variables, knowledge, perceived risk, and accessibility). Consistent with predictions, dismissiveness-the most common relational style among older men-predicted less frequent prostate-specific antigen testing and digital rectal examination. However, attachment security-a comfort with intimate relationships-also predicted lower screening frequency. Identifying the interpersonal characteristics predicting screening may help identify men at risk of suboptimal health care use and guide the development of interventions suited to the normative relational preferences of current cohorts of older, African-descent men.

  12. Fear, knowledge, and efficacy beliefs differentially predict the frequency of digital rectal examination versus prostate specific antigen screening in ethnically diverse samples of older men.

    PubMed

    Consedine, Nathan S; Horton, David; Ungar, Tracey; Joe, Andrew K; Ramirez, Paul; Borrell, Luisa

    2007-03-01

    Emotional and cognitive characteristics have been studied in the context of women's cancer screening but have received scant attention in the study of men's screening behavior. Researchers know little about how such factors interact to predict screening or whether digital rectal examination (DRE) and prostate specific antigen (PSA) screens are predicted by the same characteristics. This study examines the relevance of emotional and cognitive characteristics to DRE and PSA screening among 180 U.S.-born African American, U.S.- born European American, and immigrant Jamaican men. The study identifies the expected effects in which fear is negatively related and efficacy beliefs positively related to DRE and PSA screening. Greater efficacy and (marginally) knowledge appear to "offset" the negative impact of fear on screening, and fear appears particularly relevant to DRE frequency. Results are discussed in terms of their implications for the development of health belief and self-regulatory models in the context of prostate cancer screening among minority men.

  13. Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies

    PubMed Central

    Gittelman, Marc C; Marks, Leonard S; Hill, Lawrence A; Volinn, Weining; Hoel, Gary

    2011-01-01

    Purpose Pooled results from 2 randomized, placebo-controlled, US phase III studies (NCT00224107, NCT00224120) showed that silodosin, a uroselective α-blocker, significantly improved International Prostate Symptom Scores (IPSS) in men with symptomatic benign prostatic hyperplasia (BPH). This analysis evaluated the effect of silodosin on each symptom assessed by IPSS questionnaire. Materials and methods Study participants (N = 923) were men aged ≥50 years with IPSS ≥13 and Qmax 4–15 mL/s. They received silodosin 8 mg or placebo once daily for 12 weeks. Patient responses to 7 IPSS questions were collected at weeks 0 (baseline), 0.5, 1, 2, 4, and 12 and scored on a 6-point scale. Efficacy of silodosin versus placebo was assessed by analysis of covariance. Results For each symptom, the 2 treatment groups had similar mean baseline scores. Decrease in score from baseline (mean ± standard deviation) to last observation was significantly greater with silodosin than with placebo for all symptoms (P < 0.005); symptom improvement with silodosin (versus placebo) was greatest for weak stream (silodosin, −1.1 ± 1.4 versus placebo, −0.5 ± 1.2; P < 0.0001) and smallest for nocturia (silodosin, −0.6 ± 1.1 versus placebo, −0.4 ± 1.2; P = 0.0037). Compared with placebo, silodosin significantly improved nocturia within 1 week (silodosin, −0.5 ± 1.07 versus placebo, −0.3 ± 1.05; P = 0.009) and all other symptoms within 3 to 4 days (P < 0.01). Conclusions Silodosin significantly improved all BPH-associated symptoms assessed by IPSS questionnaire within the first week of treatment. All improvements were maintained over the 12-week study period. PMID:24198629

  14. Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer

    PubMed Central

    Foekens, J A; Diamandis, E P; Yu, H; Look, M P; Gelder, M E Meijer-van; Klijn, J G M

    1999-01-01

    Prostate-specific antigen (PSA) is a serine protease which may play a role in a variety of cancer types, including breast cancer. In the present study, we evaluated whether the level of PSA in breast tumour cytosol could be associated with prognosis in primary breast cancer, or with response to tamoxifen therapy in recurrent disease. PSA levels were determined by enzyme-linked immunosorbent assay (ELISA) in breast tumour cytosols, and were correlated with prognosis in 1516 patients with primary breast cancer and with response to first-line tamoxifen therapy in 434 patients with recurrent disease. Relating the levels of PSA with classical prognostic factors, low levels were more often found in larger tumours, tumours of older and post-menopausal patients, and in steroid hormone receptor-negative tumours. There was no significant association between the levels of PSA with grade of differentiation or the number of involved lymph nodes. In patients with primary breast cancer, PSA was not significantly related to the rate of relapse, and a positive association of PSA with an improved survival could be attributed to its relationship to age. In patients with recurrent breast cancer, a high level of PSA was significantly related to a poor response to tamoxifen therapy, and a short progression-free and overall survival after start of treatment for recurrent disease. In Cox multivariate analyses for response to therapy and for (progression-free) survival, corrected for age/menopausal status, disease-free interval, site of relapse and steroid hormone receptor status, PSA was an independent variable of poor prognosis. It is concluded that the level of PSA in cytosols of primary breast tumours might be a marker to select breast cancer patients who may benefit from systemic tamoxifen therapy. © 1999 Cancer Research Campaign PMID:10070886

  15. Long Distance Bicycle Riding Causes Prostate-Specific Antigen to Increase in Men Aged 50 Years and Over

    PubMed Central

    Mejak, Sandra L.; Bayliss, Julianne; Hanks, Shayne D.

    2013-01-01

    Objectives To investigate whether bicycle riding alters total prostate-specific antigen (tPSA) serum concentrations in healthy older men. Methods 129 male participants, ranging in age from 50 to 71 years (mean 55 years), rode in a recreational group bicycle ride of between 55 and 160 kilometers. Blood samples for tPSA analysis were drawn within 60 minutes before starting, and within 5 minutes after completing the ride. The pre-cycling and post-cycling tPSA values were log transformed for normality and compared using paired t-tests. Linear regression was used to assess the relationship between changes in tPSA with age and distance cycled. Results Bicycle riding caused tPSA to increase by an average of 9.5% (95% CI = 6.1–12.9; p<0.001) or 0.23 ng/ml. The number of participants with an elevated tPSA (using the standard PSA normal range cut-off of 4.0 ng/ml) increased from two pre-cycle to six post-cycle (or from five to eight when using age-based normal ranges). Univariate linear regression analysis revealed that the change in tPSA was positively correlated with age and the distance cycled. Conclusions Cycling causes an average 9.5% increase in tPSA, in healthy male cyclists ≥50 years old, when measured within 5 minutes post cycling. We considered the increase clinically significant as the number of participants with an elevated PSA, according to established cut-offs, increased post-ride. Based on the research published to date, the authors suggest a 24–48 hour period of abstinence from cycling and ejaculation before a PSA test, to avoid spurious results. PMID:23418500

  16. Circulating testosterone and prostate-specific antigen in nipple aspirate fluid and tissue are associated with breast cancer.

    PubMed Central

    Sauter, Edward R; Tichansky, David S; Chervoneva, Inna; Diamandis, Eleftherios P

    2002-01-01

    Preliminary evidence has associated testosterone and prostate-specific antigen (PSA) with breast cancer. Our objective was to determine whether a) testosterone levels in nipple aspirate fluid (NAF), serum, or breast tissue are associated with breast cancer; b) testosterone levels in serum are associated with levels in NAF; c) PSA in NAF, serum, or breast tissue is associated with breast cancer; and d) serum PSA is associated with NAF PSA levels. We obtained 342 NAF specimens from 171 women by means of a modified breast pump. Additionally, we collected 201 blood samples from 99 women and 51 tissue samples from 41 subjects who underwent surgical resection for suspected disease. Women currently using birth control pills or hormone replacement therapy were excluded from the study. Controlling for age and menopausal status, serum testosterone was significantly increased in women with breast cancer (p = 0.002). NAF and serum testosterone levels were not associated. Neither NAF nor tissue testosterone was associated with breast cancer. Controlling for menopausal status and age, NAF PSA was significantly decreased in women with breast cancer (p < 0.001). We did not find serum PSA to be associated with breast cancer, although we found an indication that, in postmenopausal women, its levels were lower in women with cancer. Serum PSA was associated with NAF PSA in postmenopausal women (p < 0.001). PSA levels in cancerous tissue were significantly lower than in benign breast specimens from subjects without cancer (p = 0.011), whereas levels of PSA in histologically benign specimens from subjects with cancer were intermediate. Our results suggest that serum testosterone is increased and NAF PSA is decreased in women with breast cancer, with PSA expression being higher in normal than in cancerous breast tissues. NAF and serum PSA levels in postmenopausal women are correlated, suggesting that as laboratory assessment of PSA becomes more sensitive, serum PSA may become useful in

  17. Whole Milk Intake Is Associated with Prostate Cancer-Specific Mortality among U.S. Male Physicians1234

    PubMed Central

    Song, Yan; Chavarro, Jorge E.; Cao, Yin; Qiu, Weiliang; Mucci, Lorelei; Sesso, Howard D.; Stampfer, Meir J.; Giovannucci, Edward; Pollak, Michael; Liu, Simin; Ma, Jing

    2013-01-01

    Previous studies have associated higher milk intake with greater prostate cancer (PCa) incidence, but little data are available concerning milk types and the relation between milk intake and risk of fatal PCa. We investigated the association between intake of dairy products and the incidence and survival of PCa during a 28-y follow-up. We conducted a cohort study in the Physicians’ Health Study (n = 21,660) and a survival analysis among the incident PCa cases (n = 2806). Information on dairy product consumption was collected at baseline. PCa cases and deaths (n = 305) were confirmed during follow-up. The intake of total dairy products was associated with increased PCa incidence [HR = 1.12 (95% CI: 0.93, 1.35); >2.5 servings/d vs. ≤0.5 servings/d]. Skim/low-fat milk intake was positively associated with risk of low-grade, early stage, and screen-detected cancers, whereas whole milk intake was associated only with fatal PCa [HR = 1.49 (95% CI: 0.97, 2.28); ≥237 mL/d (1 serving/d) vs. rarely consumed]. In the survival analysis, whole milk intake remained associated with risk of progression to fatal disease after diagnosis [HR = 2.17 (95% CI: 1.34, 3.51)]. In this prospective cohort, higher intake of skim/low-fat milk was associated with a greater risk of nonaggressive PCa. Most importantly, only whole milk was consistently associated with higher incidence of fatal PCa in the entire cohort and higher PCa-specific mortality among cases. These findings add further evidence to suggest the potential role of dairy products in the development and prognosis of PCa. PMID:23256145

  18. VIP induces NF-κB1-nuclear localisation through different signalling pathways in human tumour and non-tumour prostate cells.

    PubMed

    Fernández-Martínez, Ana B; Carmena, María J; Bajo, Ana M; Vacas, Eva; Sánchez-Chapado, Manuel; Prieto, Juan C

    2015-02-01

    The nuclear factor κB (NF-κB) is a powerful activator of angiogenesis, invasion and metastasis. Transactivation and nuclear localisation of NF-κB is an index of recurrence in prostate cancer. Vasoactive intestinal peptide (VIP) exerts similar effects in prostate cancer models involving increased expression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) which are related to NF-κB transactivation. Here we studied differential mechanisms of VIP-induced NF-κB transactivation in non-tumour RWPE-1 and tumour LNCaP and PC3 human prostate epithelial cells. Immunofluorescence studies showed that VIP increases translocation of the p50 subunit of NF-κB1 to the nucleus, an effect that was inhibited by curcumin. The signalling transduction pathways involved are different depending on cell transformation degree. In control cells (RWPE1), the effect is mediated by protein kinase A (PKA) activation and does not implicate extracellular signal-regulated kinase (ERK) or phosphoinositide 3-kinase (PI3-K) pathways whereas the opposite is true in tumour LNCaP and PC3 cells. Exchange protein directly activated by cAMP (EPAC) pathway is involved in transformed cells but not in control cells. Curcumin blocks the activating effect of VIP on COX-2 promoter/prostaglandin E2 (PGE2) production and VEGF expression and secretion. The study incorporates direct observation on COX-2 promoter and suggests that VIP effect on VEGF may be indirectly mediated by PGE2 after being synthesised by COX-2, thus amplifying the initial signal. We show that the signalling involved in VIP effects on VEGF is cAMP/PKA in non-tumour cells and cAMP/EPAC/ERK/PI3K in tumour cells which coincides with pathways mediating p50 nuclear translocation. Thus, VIP appears to use different pathways for NF-κB1 (p50) transactivation in prostate epithelial cells depending on whether they are transformed or not. Transformed cells depend on pro-survival and pro-proliferative signalling pathways

  19. The simultaneous detection of free and total prostate antigen in serum samples with high sensitivity and specificity by using the dual-channel surface plasmon resonance.

    PubMed

    Jiang, Zhongxiu; Qin, Yun; Peng, Zhen; Chen, Shenghua; Chen, Shu; Deng, Chunyan; Xiang, Juan

    2014-12-15

    Free/total prostate antigen (f/t-PSA) ratio in serum as a promising parameter has been used to improve the differentiation of benign and malignant prostate disease. In order to obtain the accurate and reliable f/t-PSA ratio, the simultaneous detection of f-PSA and t-PSA with high sensitivity and specificity is required. In this work, the dual-channel surface plasmon resonance (SPR) has been employed to meet the requirement. In one channel, t-PSA was directly measured with a linear range from 1.0 to 20.0 ng/mL. In another channel, due to the low concentration of f-PSA in serum, the asynchronous competitive inhibition immunoassay with f-PSA@Au nanoparticles (AuNPs) was developed. As expected, the detection sensitivity of f-PSA was greatly enhanced, and a linear correlation with wider linear range from 0.010 to 0.40 ng/mL was also achieved. On the other hand, a simple method was explored for significantly reducing the non-specific adsorption of co-existing proteins. On basis of this, the f/t-PSA ratios in serum samples from prostate cancer (PCa) or benign prostatic hyperplasia (BPH) patients were measured. And it was found that there was significant difference between the distributions of f/t-PSA ratio in BPH patients (16.44±1.77%) and those in PCa patients (24.53±4.97%). This present work provides an effective method for distinguishing PCa from BPH, which lays a potential foundation for the early diagnosis of PCa.

  20. A Phase 1 Study of a Vaccine Targeting Preferentially Expressed Antigen in Melanoma and Prostate-specific Membrane Antigen in Patients With Advanced Solid Tumors

    PubMed Central

    Weber, Jeffrey S.; Vogelzang, Nicholas J.; Ernstoff, Marc S.; Goodman, Oscar B.; Cranmer, Lee D.; Marshall, John L.; Miles, Sabrina; Rosario, Dar; Diamond, David C.; Qiu, Zhiyong; Obrocea, Mihail; Bot, Adrian

    2013-01-01

    Summary Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications. PMID:21760528

  1. Inhibition of Stat5a/b enhances proteasomal degradation of androgen receptor liganded by antiandrogens in prostate cancer

    PubMed Central

    Hoang, David T.; Gu, Lei; Liao, Zhiyong; Talati, Pooja G.; Shen, Feng; Koptyra, Mateusz; Tan, Shyh-Han; Ellsworth, Elyse; Gupta, Shilpa; Montie, Heather; Dagvadorj, Ayush; Savolainen, Saija; Leiby, Benjamin; Mirtti, Tuomas; Merry, Diane E.; Nevalainen, Marja T.

    2015-01-01

    Although poorly understood, androgen receptor (AR) signaling is sustained despite treatment of prostate cancer with antiandrogens and potentially underlies development of incurable castrate-resistant prostate cancer. However, therapies targeting the AR signaling axis eventually fail when prostate cancer progresses to the castrate-resistant stage. Stat5a/b, a candidate therapeutic target protein in prostate cancer, synergizes with AR to reciprocally enhance signaling of both proteins. In this work, we demonstrate that Stat5a/b sequesters antiandrogen-liganded (MDV3100, Bicalutamide, Flutamide) AR in prostate cancer cells and protects it against proteasomal degradation in prostate cancer. Active Stat5a/b increased nuclear levels of both unliganded and antiandrogen-liganded AR, as demonstrated in prostate cancer cell lines, xenograft tumors and clinical patient-derived prostate cancer samples. Physical interaction between Stat5a/b and AR in prostate cancer cells was mediated by the DNA-binding domain of Stat5a/b and the N-terminal domain of AR. Moreover, active Stat5a/b increased AR occupancy of the Prostate Specific Antigen promoter and AR-regulated gene expression in prostate cancer cells. Mechanistically, both Stat5a/b genetic knockdown and antiandrogen treatment induced proteasomal degradation of AR in prostate cancer cells, with combined inhibition of Stat5a/b and AR leading to maximal loss of AR protein and prostate cancer cell viability. Our results indicate that therapeutic targeting of AR in prostate cancer using antiandrogens may be substantially improved by targeting of Stat5a/b. PMID:25552366

  2. Preclinical Evaluation of 86Y-Labeled Inhibitors of Prostate-Specific Membrane Antigen for Dosimetry Estimates

    PubMed Central

    Banerjee, Sangeeta Ray; Foss, Catherine A.; Pullambhatla, Mrudula; Wang, Yuchuan; Srinivasan, Senthamizhchelvan; Hobbs, Robert F.; Baidoo, Kwamena E.; Brechbiel, Martin W.; Nimmagadda, Sridhar; Mease, Ronnie C.; Sgouros, George; Pomper, Martin G.

    2016-01-01

    86Y (half-life = 14.74 h, 33% β+) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low-molecular-weight compounds labeled with 86Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding 90Y-labeled radiotherapeutics. Methods Multistep syntheses were used in preparing 86Y-4–6. PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for 86Y-4–6 and by biodistribution studies of 86Y-4 and 86Y-6 out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using 86Y-6. Results Compounds 86Y-4–6 were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/µmol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that 86Y-4–6 had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound 86Y-6 demonstrated the highest tumor uptake and retention, with 32.17 ± 7.99 and 15.79 ± 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of 86Y-6. Conclusion Compound 86Y-6 is a promising

  3. Ultrasensitive Prostate Specific Antigen Assay Following Laparoscopic Radical Prostatectomy – An Outcome Measure for Defining the Learning Curve

    PubMed Central

    Viney, R; Gommersall, L; Zeif, J; Hayne, D; Shah, ZH; Doherty, A

    2009-01-01

    INTRODUCTION Radical retropubic prostatectomy (RRP) performed laparoscopically is a popular treatment with curative intent for organ-confined prostate cancer. After surgery, prostate specific antigen (PSA) levels drop to low levels which can be measured with ultrasensitive assays. This has been described in the literature for open RRP but not for laparoscopic RRP. This paper describes PSA changes in the first 300 consecutive patients undergoing non-robotic laparoscopic RRP by a single surgeon. OBJECTIVES To use ultrasensitive PSA (uPSA) assays to measure a PSA nadir in patients having laparoscopic radical prostatectomy below levels recorded by standard assays. The aim was to use uPSA nadir at 3 months' post-prostatectomy as an early surrogate end-point of oncological outcome. In so doing, laparoscopic oncological outcomes could then be compared with published results from other open radical prostatectomy series with similar end-points. Furthermore, this end-point could be used in the assessment of the surgeon's learning curve. PATIENTS AND METHODS Prospective, comprehensive, demographic, clinical, biochemical and operative data were collected from all patients undergoing non-robotic laparoscopic RRP. We present data from the first 300 consecutive patients undergoing laparoscopic RRP by a single surgeon. uPSA was measured every 3 months post surgery. RESULTS Median follow-up was 29 months (minimum 3 months). The likelihood of reaching a uPSA of ≤ 0.01 ng/ml at 3 months is 73% for the first 100 patients. This is statistically lower when compared with 83% (P < 0.05) for the second 100 patients and 80% for the third 100 patients (P < 0.05). Overall, 84% of patients with pT2 disease and 66% patients with pT3 disease had a uPSA of ≤ 0.01 ng/ml at 3 months. Pre-operative PSA, PSA density and Gleason score were not correlated with outcome as determined by a uPSA of ≤ 0.01 ng/ml at 3 months. Positive margins correlate with outcome as determined by a uPSA of ≤ 0

  4. Tissue-specific expression and androgen regulation of different genes encoding rat prostatic 22-kilodalton glycoproteins homologous to human and rat cystatin.

    PubMed

    Winderickx, J; Hemschoote, K; De Clercq, N; Van Dijck, P; Peeters, B; Rombauts, W; Verhoeven, G; Heyns, W

    1990-04-01

    22-Kilodalton (kDa) protein cDNA clones were isolated from a rat prostatic library. Nucleotide sequence analysis revealed three different cDNA sequences encoding two somewhat different open reading frames of 176 amino acids. The N-terminal 24 amino acids of these sequences show the typical characteristics of signal peptides of secretory proteins. The C-terminal end of the derived protein sequences displays sequence similarity to a number of cysteine proteinase inhibitors, called cystatins, suggesting a common physiological function. Upon Northern blotting with a labeled cDNA fragment, three different 22-kDa protein mRNAs, i.e. 950 nucleotides (nt), 920 nt and 860 nt, could be detected in the rat ventral prostate and the lacrymal gland. In both tissues these messengers were regulated by androgens showing the most rapid androgen response for the 950 nt mRNA form. Administration of cycloheximide nearly completely abolished the observed androgen effect suggesting that a short-living protein is required for the full induction of the 22-kDa protein genes. Hybridization experiments with specific oligonucleotides which distinguish between the mRNAs encoding both 22-kDa protein variants indicate that one protein form is less androgen dependent in the ventral prostate and not expressed in the lacrymal gland.

  5. [Alternative tests to PSA for prostate cancer diagnosis].

    PubMed

    Defilippi, Elio; Zitella, Andrea; Tizzani, Alessandro

    2011-01-01

    Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis.

  6. Improving Patient Prostate Cancer Risk Assessment: Moving From Static, Globally-Applied to Dynamic, Practice-Specific Cancer Risk Calculators

    PubMed Central

    Strobl, Andreas N.; Vickers, Andrew J.; Van Calster, Ben; Steyerberg, Ewout; Leach, Robin J.; Thompson, Ian M.; Ankerst, Donna P.

    2015-01-01

    Clinical risk calculators are now widely available but have generally been implemented in a static and one-size-fits-all fashion. The objective of this study was to challenge these notions and show via a case study concerning risk-based screening for prostate cancer how calculators can be dynamically and locally tailored to improve on-site patient accuracy. Yearly data from five international prostate biopsy cohorts (3 in the US, 1 in Austria, 1 in England) were used to compare 6 methods for annual risk prediction: static use of the online US-developed Prostate Cancer Prevention Trial Risk Calculator (PCPTRC); recalibration of the PCPTRC; revision of the PCPTRC; building a new model each year using logistic regression, Bayesian prior-to-posterior updating, or random forests. All methods performed similarly with respect to discrimination, except for random forests, which were worse. All methods except for random forests greatly improved calibration over the static PCPTRC in all cohorts except for Austria, where the PCPTRC had the best calibration followed closely by recalibration. The case study shows that a simple annual recalibration of a general online risk tool for prostate cancer can improve its accuracy with respect to the local patient practice at hand. PMID:25989018

  7. Biopsy Quantitative Patohistology and Seral Values of Prostate Specific Antigen-Alpha (1) Antichymotrypsine Complex in Prediction of Adverse Pathology Findings after Radical Prostatectomy.

    PubMed

    Tomasković, Igor; Milicić, Valerija; Tomić, Miroslav; Ruzić, Boris; Ulamec, Monika

    2015-09-01

    In this prospective study we examined the utility of parameters obtained on prostate needle biopsy and prostate specific antigen-alpha(1)-antichymotripsine complex (PSA-ACT) to predict adverse pathologic findings after radical prostatectomy. 45 consecutive patients assigned for radical prostatectomy due to clinically localized prostate cancer were included in the study. Prostate biopsy parameters such as number of positive cores, the greatest percentage of tumor in the positive cores, Gleason score, perineural invasion, unilaterality or bilaterality of the tumor were recorded. PSA-ACT was determined using sandwich immunoassay chemiluminiscent method (Bayer, Tarrytown, New York). We analyzed relationship of preoperative PSA, PSA-ACTand quantitative biopsy parameters with final pathology after prostatectomy. Adverse findings were considered when extracapsular extension of cancer (pT3) was noted. Postoperatively, 29 (64.4%) patients were diagnosed with pT2 disease and 16 (35.6%) with pT3 disease. There was a significant difference in localized vs. locally advanced disease in number of positive biopsy cores (p<0.001), greatest percentage of tumor in the core (p=0.008), localization of the tumor (p=0.003) and perineural invasion (p=0.004). Logistic regression was used to develop a model on the multivariate level. It included number of positive cores and PSA-ACT and was significant on our cohort with the reliability of 82.22%. The combination of PSA-ACT and a large scale of biopsy parameters could be used in prediction of adverse pathologic findings after radical prostatectomy. Clinical decisions and patients counselling could be influenced by these predictors but further confirmation on a larger population is necessary. PMID:26898067

  8. Changes in Estrogen Receptor ERβ (ESR2) Expression without Changes in the Estradiol Levels in the Prostate of Aging Rats

    PubMed Central

    Morais-Santos, Mônica; Nunes, Aryane E. B.; Oliveira, André G.; Moura-Cordeiro, Júnia Dayrell; Mahecha, Germán A. B.; Avellar, Maria Christina W.; Oliveira, Cleida A.

    2015-01-01

    Although the prostate is androgen-dependent, it is also influenced by estrogens, which act via the estrogen receptors ERα and ERβ. In the prostate, ERβ is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation. Evidence shows that ERβ is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. Despite the relationship between reductions in ERβ and abnormal growth of the gland, little is known about the age-dependent variation of this receptor. Therefore, we aimed to investigate ERβ expression in the prostatic lobes of aging Wistar rats (3 to 24 months). Histopathological alterations, including hyperplasia, intraluminal concretions, nuclear atypia and prostate intraepithelial neoplasias (PIN), were observed in the prostates of aging rats. Epithelial proliferation led to cribriform architecture in some acini, especially in the ventral prostate (VP). In the VP, areas of epithelial atrophy were also observed. Furthermore, in the lateral prostate, there was frequent prostatitis. Immunohistochemistry revealed that the expression of ERβ is reduced in specific areas related to PIN, atrophic abnormalities and cellular atypia in the prostate epithelium of senile rats. Corroborating the involvement of the receptor with proliferative activity, the punctual reduction in ERβ paralleled the increase in cell proliferation especially in areas of PIN and nuclear atypies. The decrease in ERβ reactivity occurred in a hormonal milieu characterized by a constant concentration of estradiol and decreased plasmatic and tissue DHT. This paper is a pioneering study that reveals focal ERβ reduction in the prostate of aging rats and indicates a potential disorder in the ERβ pathway. These data corroborate previous data from humans and dogs that silencing of this receptor may be associated with premalignant or malignant conditions in the prostate. PMID:26147849

  9. PSA, PSA derivatives, proPSA and prostate health index in the diagnosis of prostate cancer

    PubMed Central

    Ayyıldız, Sema Nur; Ayyıldız, Ali

    2014-01-01

    Currently, prostate- specific antigen (PSA) is the most common oncological marker used for prostate cancer screening. However, high levels of PSA in benign prostatic hyperplasia and prostatitis decrease the specificity of PSA as a cancer marker. To increase the specificity of PSA, PSA derivatives and PSA kinetics have been used. However, these new techniques were not able to increase the diagnostic specificity for prostate cancer. Therefore, the search for new molecules and derivatives of PSA continues. With the aim of increasing the specificity of prostate cancer diagnosis, proPSA and the Prostate Health Index have been introduced. In this review, the roles of PSA, PSA derivatives, proPSA and the Prostate Health Index in Prostate Cancer diagnosis are examined. PMID:26328156

  10. Opium consumption is negatively associated with serum prostate-specific antigen (PSA), free PSA, and percentage of free PSA levels.

    PubMed

    Safarinejad, Mohammad Reza; Asgari, Seyyed Alaeddin; Farshi, Alireza; Iravani, Shahrokh; Khoshdel, Alireza; Shekarchi, Babak

    2013-01-01

    Addiction to opium continues to be a major worldwide medical and social problem. The study addressing the association between opium consumption and serum prostate-specific antigen (PSA) level is lacking. We determined the effects of opium consumption on serum PSA levels in opium-addict men. Our study subjects comprised 438 opium-addict men with a mean age of 52.2 ± 6.4 years (group 1). We compared these men with 446 men who did not indicate current or past opium use (group 2). Serum total PSA (tPSA), free PSA (fPSA), % fPSA, and sex hormones were compared between the 2 groups. The mean serum tPSA level was significantly lower in group 1 (1.05 ng/mL) than in controls (1.45 ng/mL) (P = 0.001). Opium consumption was also associated with lower fPSA (P = 0.001) and % fPSA (P = 0.001). Serum free testosterone level in opium-addict patients (132.5 ± 42 pg/mL) was significantly lower than that in controls (156.2 ± 43 pg/mL) (P = 0.03). However, no significant correlation existed between tPSA and free testosterone levels (r = 0.28, 95% CI, -0.036 to 0.51, P = 0.34). Among the patients with cancer in group 1, 35% were found to have high-grade tumor (Gleason score ≥ 7) compared with 26.7% in group 2 (P = 0.02). Total PSA and fPSA were strongly correlated with duration of opium use (r = -0.06, 95% CI, -0.04 to -0.08, P = 0.0001; and r = -0.05, 95% CI, -0.03 to -0.07, P = 0.0001, respectively). Opium consumption is independently and negatively associated with serum tPSA, fPSA, and % fPSA levels.

  11. Comparison of the Effects of Testosterone Gels, Injections, and Pellets on Serum Hormones, Erythrocytosis, Lipids, and Prostate-Specific Antigen

    PubMed Central

    Pastuszak, Alexander W; Gomez, Lissette P; Scovell, Jason M; Khera, Mohit; Lamb, Dolores J; Lipshultz, Larry I

    2015-01-01

    Introduction Numerous testosterone (T) formulations are available, each with differing effects on serum parameters. Aim The aim of this study was to compare the long-term effects of topical, injectable, and implantable pellet T formulations in hypogonadal men. Methods Retrospective review of hypogonadal men treated with a single T formulation was performed: 47 men on T gels, 57 on injectable T, and 74 on T pellets were identified. Total T (TT), calculated free T (FT), estradiol (E), hemoglobin (Hgb), hematocrit (Hct), prostate-specific antigen (PSA), total cholesterol (Tchol), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were evaluated at baseline and every 3–6 months for 3 years. Serum parameters were compared using a mixed model linear regression for repeated measures. Main Outcome Measures Effects of topical, injectable, and pellet T formulations on serum hormone levels, Hgb, Hct, lipid parameters and PSA. Results Men in the injectable T group were younger (42.5 ± 12.3 years) than in the gel (54.1 ± 9.8 years) or pellet groups (53.8 ± 13.0 years), and baseline FT, Hgb, and Hct were higher in the injectable T group than in gel or pellet groups. Increases in TT and FT were observed throughout follow-up in all groups. Increases in E were observed at in all T groups and throughout follow-up in injectable and gel groups. No PSA increases were observed. Erythrocytosis (Hct > 50%) was more common with injectable T (66.7%) than with T gels (12.8%) or pellets (35.1%, P < 0.0001). Transient changes in cholesterol, TG, and LDL were observed, and no significant changes were seen in HDL for any group. Conclusions All T formulations increase serum T and FT. More significant increases in E occur with injectable T and T gels. Changes in Hgb and Hct are most significant with injectable T, and effects on lipids are variable and inconsistent. Selection of T formulations must account for individual

  12. The effect of testosterone replacement therapy on prostate-specific antigen (PSA) levels in men being treated for hypogonadism: a systematic review and meta-analysis.

    PubMed

    Kang, De-Ying; Li, Hong-Jun

    2015-01-01

    Testosterone replacement therapy is used for the treatment of age-related male hypogonadism, and prostate-specific antigen (PSA) is a primary screening tool for prostate cancer. The systematic review and meta-analysis aimed to determine the effect of testosterone replacement therapy on PSA levels.Medline, Cochrane Library, EMBASE, and Google Scholar databases were searched until February 28, 2014, and inclusion criteria were as follows: randomized controlled trial; intervention group received testosterone/androgen replacement therapy; control group did not receive treatment; and no history of prostate cancer. The primary outcome was change of PSA level between before and after treatment. Secondary outcomes were elevated PSA level after treatment, and the number of patients who developed prostate cancer.After initially identifying 511 articles, 15 studies with a total of 739 patients that received testosterone replacement and 385 controls were included. The duration of treatment ranged from 3 to 12 months. Patients treated with testosterone tended to have higher PSA levels, and thus a greater change than those that received control treatments (difference in means of PSA levels = 0.154, 95% confidence interval [CI] 0.069 to 0.238, P < 0.001). The difference in means of PSA levels were significant higher for patients that received testosterone intramuscularly (IM) than controls (difference in means of PSA levels = 0.271, 95% CI 0.117-0.425, P = 0.001). Elevated PSA levels after treatment were similar between patients that received treatment and controls (odds ratio [OR] = 1.02, 95% CI 0.48-2.20, P = 0.953). Only 3 studies provided data with respect to the development of prostate cancer, and rates were similar between those that received treatment and controls.Testosterone replacement therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given IM and even the increase with IM administration is minimal

  13. Body Composition and Serum Prostate Specific Antigen: A Review and Findings from the Flint Men’s Health Study

    PubMed Central

    Beebe-Dimmer, Jennifer L.; Faerber, Gary J.; Morgenstern, Hal; Werny, David; Wojno, Kirk; Halstead-Nussloch, Bronwen; Cooney, Kathleen A.

    2008-01-01

    Recent studies suggest obesity is associated with lower serum PSA, perhaps influencing recommendation for prostate biopsy, potentially explaining part of the observed poorer prognosis among obese men. African American men have the highest rates of prostate cancer and are more likely to die of the disease making early detection a priority in this group. We present findings from the Flint Men’s Health Study, a study in African American men, which are consistent with most studies suggesting that overweight men have PSA levels 0.15–0.30 ng/mL lower than those who are not overweight. We have coupled our results with a systematic review of publications in this area. PMID:18308373

  14. Effect of metallothionein 2A gene polymorphism on allele-specific gene expression and metal content in prostate cancer

    SciTech Connect

    Krześlak, Anna; Forma, Ewa; Jóźwiak, Paweł; Szymczyk, Agnieszka; Bryś, Magdalena

    2013-05-01

    Metallothioneins (MTs) are highly conserved, small molecular weight, cysteine rich proteins. The major physiological functions of metallothioneins include homeostasis of essential metals Zn and Cu and protection against cytotoxicity of heavy metals. The aim of this study was to determine whether there is an association between the − 5 A/G single nucleotide polymorphism (SNP; rs28366003) in core promoter region and expression of metallothionein 2A (MT2A) gene and metal concentration in prostate cancer tissues. MT2A polymorphism was determined by the polymerase chain reaction–restriction fragment length polymorphism technique (PCR–RFLP) using 412 prostate cancer tissue samples. MT2A gene expression analysis was performed by real-time RT-PCR method. A significant association between rs28366003 genotype and MT2A expression level was found. The average mRNA level was found to be lower among minor allele carriers (the risk allele) than average expression among homozygotes for the major allele. Metal levels were analyzed by flamed atomic absorption spectrometer system. Highly statistically significant associations were detected between the SNP and Cd, Zn, Cu and Pb levels. The results of Spearman's rank correlation showed that the expressions of MT2A and Cu, Pb and Ni concentrations were negatively correlated. On the basis of the results obtained in this study, we suggest that SNP polymorphism may affect the MT2A gene expression in prostate and this is associated with some metal accumulation. - Highlights: • MT2A gene expression and metal content in prostate cancer tissues • Association between SNP (rs28366003) and expression of MT2A • Significant associations between the SNP and Cd, Zn, Cu and Pb levels • Negative correlation between MT2A gene expression and Cu, Pb and Ni levels.

  15. Sex steroid receptor expression and localization in benign prostatic hyperplasia varies with tissue compartment.

    PubMed

    Nicholson, Tristan M; Sehgal, Priyanka D; Drew, Sally A; Huang, Wei; Ricke, William A

    2013-01-01

    Androgens and estrogens, acting via their respective receptors, are important in benign prostatic hyperplasia (BPH). The goals of this study were to quantitatively characterize the tissue distribution and staining intensity of androgen receptor (AR) and estrogen receptor-alpha (ERα), and assess cells expressing both AR and ERα, in human BPH compared to normal prostate. A tissue microarray composed of normal prostate and BPH tissue was used and multiplexed immunohistochemistry was performed to detect AR and ERα. We used a multispectral imaging platform for automated scanning, tissue and cell segmentation and marker quantification. BPH specimens had an increased number of epithelial and stromal cells and increased percentage of epithelium. In both stroma and epithelium, the mean nuclear area was decreased in BPH relative to normal prostate. AR expression and staining intensity in epithelial and stromal cells was significantly increased in BPH compared to normal prostate. ERα expression was increased in BPH epithelium. However, stromal ERα expression and staining intensity was decreased in BPH compared to normal prostate. Double positive (AR and ERα) epithelial cells were more prevalent in BPH, and fewer double negative (AR and ERα) stromal and epithelial negative cells were observed in BPH. These data underscore the importance of tissue layer localization and expression of steroid hormone receptors in the prostate. Understanding the tissue-specific hormone action of androgens and estrogens will lead to a better understanding of mechanisms of pathogenesis in the prostate and may lead to better treatment for BPH.

  16. Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

    PubMed Central

    Stoyanova, Tanya; Riedinger, Mireille; Lin, Shu; Faltermeier, Claire M.; Smith, Bryan A.; Zhang, Kelvin X.; Going, Catherine C.; Goldstein, Andrew S.; Lee, John K.; Drake, Justin M.; Rice, Meghan A.; Hsu, En-Chi; Nowroozizadeh, Behdokht; Castor, Brandon; Orellana, Sandra Y.; Blum, Steven M.; Cheng, Donghui; Pienta, Kenneth J.; Reiter, Robert E.; Pitteri, Sharon J.; Huang, Jiaoti; Witte, Owen N.

    2016-01-01

    Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer. PMID:27694579

  17. Prospective Evaluation of Operating Characteristics of Prostate Cancer Detection Biomarkers

    PubMed Central

    Liang, Yuanyuan; Ankerst, Donna P.; Ketchum, Norma S.; Ercole, Barbara; Shah, Girish; Shaughnessy, John D.; Leach, Robin J.; Thompson, Ian M.

    2016-01-01

    Purpose We assessed the independent predictive values of the serum markers free prostate specific antigen, proenzyme prostate specific antigen, neuroendocrine marker and Dickkopf-1 compared to serum prostate specific antigen and other standard risk factors for early prostate cancer detection. Materials and Methods From the prospectively collected SABOR cohort 250 prostate cancer cases, and 250 mean age matched and proportion of African-American race/ethnicity matched controls were selected who had a prior available prostate specific antigen and digital rectal examination. Serum samples were obtained, and free prostate specific antigen, [−2]proenzyme prostate specific antigen, Dickkopf-1 and neuroendocrine marker were measured. AUC, sensitivities and specificities were calculated, and multivariable logistic regression was used to assess the independent predictive value compared to prostate specific antigen, digital rectal examination, family history, prior biopsy history, race/ethnicity and age. Results The AUCs (95% CI) were 0.76 (0.71, 0.8) for free prostate specific antigen, 0.72 (0.67, 0.76) for [−2]proenzyme prostate specific antigen, 0.76 (0.72, 0.8) for %free prostate specific antigen, 0.61 (0.56, 0.66) for %[−2]proenzyme prostate specific antigen, 0.73 (0.68, 0.77) for prostate health index, 0.53 (0.48, 0.58) for Dickkopf-1 and 0.53 (0.48, 0.59) for neuroendocrine marker. In the 2 to 10 ng/ml prostate specific antigen range the AUCs (95% CI) were 0.58 (0.49, 0.67) for free prostate specific antigen, 0.53 (0.44, 0.62) for [−2]proenzyme prostate specific antigen, 0.67 (0.59, 0.75) for %free prostate specific antigen, 0.57 (0.49, 0.65) for %[−2]proenzyme prostate specific antigen and 0.59 (0.51, 0.67) for phi. Only %free prostate specific antigen retained independent predictive value compared to the traditional risk factors. Conclusions Free prostate specific antigen retained independent diagnostic usefulness for prostate cancers detected through

  18. Prostate Cancer

    MedlinePlus

    ... man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  19. [(18)F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA).

    PubMed

    Yang, Xing; Mease, Ronnie C; Pullambhatla, Mrudula; Lisok, Ala; Chen, Ying; Foss, Catherine A; Wang, Yuchuan; Shallal, Hassan; Edelman, Hannah; Hoye, Adam T; Attardo, Giorgio; Nimmagadda, Sridhar; Pomper, Martin G

    2016-01-14

    Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four (18)F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[(18)F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [(18)F]23 and 4-iodo-2-[(18)F]fluorobenzoyllysine OPA carbamate [(18)F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [(18)F]23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [(18)F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues. PMID:26629713

  20. The Number of High-Risk Factors and the Risk of Prostate Cancer-Specific Mortality After Brachytherapy: Implications for Treatment Selection

    SciTech Connect

    Wattson, Daniel A.; Chen Minghui; Moul, Judd W.; Moran, Brian J.; Dosoretz, Daniel E.; Robertson, Cary N.; Polascik, Thomas J.; Braccioforte, Michelle H.; Salenius, Sharon A.; D'Amico, Anthony V.

    2012-04-01

    Purpose: To determine whether an increasing number of high-risk factors is associated with higher prostate cancer-specific mortality (PCSM) among men treated with brachytherapy (BT)-based treatment, and whether supplemental therapy has an impact on this risk. Methods and Materials: We analyzed the cases of 2234 men with localized prostate cancer treated between 1991 and 2007 with low-dose rate BT monotherapy (n = 457) or BT with supplemental external-beam radiotherapy (EBRT, n = 229), androgen suppression therapy (AST, n = 424), or both (n = 1124). All men had at least one high-risk factor (prostate-specific antigen >20 ng/mL, biopsy Gleason score 8-10, or clinical stage {>=}T2c). Competing-risks multivariable regressions were performed to determine whether the presence of at least two high-risk factors was associated with an increased risk of PCSM, with adjustment for age, comorbidity, and the type of supplemental treatment. Results: The median follow-up time was 4.3 years. The number of men with at least two high-risk factors was highest in the group treated with BT, EBRT, and AST (21%), followed by BT plus EBRT or AST (13%), and BT alone (8%) (p{sub trend} < 0.001). The adjusted hazard ratio (AHR) for PCSM for those with at least two high-risk factors (as compared with one) was 4.8 (95% confidence interval [CI], 2.8-8.0; p < 0.001). The use of both supplemental EBRT and AST was associated with a decreased risk of PCSM (AHR 0.5; 95% CI, 0.2-0.9; p = 0.03) compared with BT alone. When the high-risk factors were analyzed separately, Gleason score 8-10 was most significantly associated with increased PCSM (AHR 6.2; 95% CI, 3.5-11.2; p < 0.001). Conclusions: Men with high-risk prostate adenocarcinoma treated with BT have decreased PCSM if they receive trimodailty therapy that includes EBRT and AST. This benefit is likely most important in men with multiple determinants of high risk.

  1. Initial specifications for nuclear waste package external dimensions and materials

    SciTech Connect

    Gregg, D.W.; O`Neal, W.C.

    1983-09-01

    Initial specifications of external dimensions and materials for waste package conceptual designs are given for Defense High Level Waste (DHLW), Commercial High Level Waste (CHLW) and Spent Fuel (SF). The designs have been developed for use in a high-level waste repository sited in a tuff media in the unsaturated zone. Drawings for reference and alternative package conceptual designs are presented for each waste form for both vertical and horizontal emplacement configurations. Four metal alloys: 304L SS, 321 SS, 316L SS and Incoloy 825 are considered for the canister or overpack; 1020 carbon steel was selected for horizontal borehole liners, and a preliminary packing material selection is either compressed tuff or compressed tuff containing iron bearing smectite clay as a binder.

  2. Specific nuclear envelope transmembrane proteins can promote the location of chromosomes to and from the nuclear periphery

    PubMed Central

    2013-01-01

    Background Different cell types have distinctive patterns of chromosome positioning in the nucleus. Although ectopic affinity-tethering of specific loci can be used to relocate chromosomes to the nuclear periphery, endogenous nuclear envelope proteins that control such a mechanism in mammalian cells have yet to be widely identified. Results To search for such proteins, 23 nuclear envelope transmembrane proteins were screened for their ability to promote peripheral localization of human chromosomes in HT1080 fibroblasts. Five of these proteins had strong effects on chromosome 5, but individual proteins affected different subsets of chromosomes. The repositioning effects were reversible and the proteins with effects all exhibited highly tissue-restricted patterns of expression. Depletion of two nuclear envelope transmembrane proteins that were preferentially expressed in liver each reduced the normal peripheral positioning of chromosome 5 in liver cells. Conclusions The discovery of nuclear envelope transmembrane proteins that can modulate chromosome position and have restricted patterns of expression may enable dissection of the functional relevance of tissue-specific patterns of radial chromosome positioning. PMID:23414781

  3. Prostate Diseases

    MedlinePlus

    The prostate is a gland in men. It helps make semen, the fluid that contains sperm. The prostate surrounds the tube that carries urine away from ... and out of the body. A young man's prostate is about the size of a walnut. It ...

  4. Identification and characterization of a tumor infiltrating CD56(+)/CD16 (-) NK cell subset with specificity for pancreatic and prostate cancer cell lines.

    PubMed

    Frankel, Timothy L; Burns, William; Riley, John; Morgan, Richard A; Davis, Jeremy L; Hanada, Kenichi; Quezado, Martha; Rosenberg, Steven A; Royal, Richard E

    2010-12-01

    In a recent clinical trial, a patient exhibited regression of several pancreatic cancer metastases following the administration of the immune modulator Ipilimumab (anti-CTLA-4 antibody). We sought to characterize the immune cells responsible for this regression. Tumor infiltrating lymphocytes (TIL-2742) and an autologous tumor line (TC-2742) were expanded from a regressing metastatic lesion excised from this patient. Natural killer (NK) cells predominated in the TIL (92% CD56(+)) with few T cells (12% CD3(+)). A majority (88%) of the NK cells were CD56(bright)CD16(-). TIL-2742 secreted IFN-γ and GM-CSF following co-culture with TC-2742 and major histocompatibility complex mismatched pancreatic tumor lines. After sorting TIL-2742, the purified CD56(+)CD16(-)CD3(-) subset showed reactivity similar to TIL-2742 while the CD56(-)CD16(-)CD3(+) cells exhibited no tumor recognition. In co-culture assays, TIL-2742 and the NK subset expressed high reactivity to several pancreatic and prostate cancer cell lines and could lyse the autologous tumor as well as pancreas and prostate cancer lines. Reactivity was partially abrogated by blockade of TRAIL. We thus identified a unique subset of NK cells (CD56(bright)CD16(dim)) isolated from a regressing metastatic pancreatic cancer in a patient responding to Ipilimumab. This represents the first report of CD56(+)CD16(-) NK cells with apparent specificity for pancreatic and prostate cancer cell lines and associated with tumor regression following the treatment with an immune modulating agent. PMID:20734041

  5. Exposure to Agent Orange is a significant predictor of prostate-specific antigen (PSA)-based recurrence and a rapid PSA doubling time after radical prostatectomy

    PubMed Central

    Shah, Sagar R.; Freedland, Stephen J.; Aronson, William J.; Kane, Christopher J.; Presti, Joseph C.; Amling, Christopher L.; Terris, Martha K.

    2011-01-01

    OBJECTIVE To investigate and report the clinicopathological characteristics and outcomes after radical prostatectomy (RP) in patients with prostate cancer and previous exposure to Agent Orange (AO), particularly in relationship to race. PATIENTS AND METHODS In 1495 veterans who had undergone RP the clinicopathological characteristics, biochemical progression rates, and prostate-specific antigen (PSA) doubling time (DT) after recurrence between AO-exposed and unexposed men were compared using logistic and linear regression and Cox proportional hazards analyses, and stratified by race. RESULTS The 206 (14%) men with AO exposure were more likely to be black (P = 0.001), younger (P < 0.001), treated more recently (P < 0.001), have a higher body mass index (P = 0.001), have clinical stage T1 disease (P < 0.001), and have lower preoperative PSA levels (P = 0.001). After adjusting for several clinical characteristics, AO exposure was not significantly related to adverse pathological features but was significantly associated with biochemical progression risk (relative risk 1.55, 95% confidence interval 1.15–2.09, P = 0.004) and shorter PSADT (P < 0.001) after recurrence (8.2 vs 18.6 months). When stratified by race, these associations were present and similar in both races, with no significant interaction between race and AO exposure for predicting biochemical recurrence or mean adjusted PSADT (P interaction >0.20). CONCLUSIONS Patients with AO exposure and treated with RP were more likely to be black, present with lower risk features, have an increased risk of biochemical progression, and shorter PSADT after recurrence. When stratified by race, the association between AO exposure and poor outcomes was present in both races. These findings suggest that among selected men who choose RP, AO exposure might be associated with more aggressive prostate cancer. PMID:19298411

  6. Synthesis and SAR of ⁹⁹mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates.

    PubMed

    Lu, Genliang; Maresca, Kevin P; Hillier, Shawn M; Zimmerman, Craig N; Eckelman, William C; Joyal, John L; Babich, John W

    2013-03-01

    Prostate specific membrane antigen (PSMA) is recognized as an attractive molecular target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel (99m)Tc/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC(50) values ranged from 3.8 ± 2 to >2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compounds, 23b (IC(50)=4.8 ± 2.7 nM), was radiolabeled with technetium tricarbonyl ({(99m)Tc(CO)(3)}(+)) to afford the {(99m)Tc(CO)(3)}(+) complex in excellent yield and high purity. This effort has led to the identification of a diverse series of promising high affinity {(99m)Tc(CO)(3)}(+) radiolabeled PSMA inhibitors. PMID:23333070

  7. Specific heat of matter formed in relativistic nuclear collisions

    NASA Astrophysics Data System (ADS)

    Basu, Sumit; Chatterjee, Sandeep; Chatterjee, Rupa; Nayak, Tapan K.; Nandi, Basanta K.

    2016-10-01

    We report the excitation energy dependence of specific heat (cv) of hadronic matter at freeze-out in Au+Au and Cu+Cu collisions at the BNL Relativistic Heavy Ion Collider energies by analyzing the published data on event-by-event mean transverse momentum ( ) distributions. The distributions in finite pT ranges are converted to distributions of effective temperatures, and dynamical fluctuations in temperature are extracted by subtracting widths of the corresponding mixed event distributions. The heat capacity per particle at the kinetic freeze-out surface is presented as a function of collision energy, which shows a sharp rise in cv below √{sN N}=62.4 GeV. We employ the hadron resonance gas (HRG) model to estimate cv at the chemical and kinetic freeze-out surfaces. The experimental results are compared to the HRG and other theoretical model calculations. HRG results show good agreement with data. Model predictions for cv at the CERN Large Hadron Collider energy are presented.

  8. Silencing by nuclear matrix attachment distinguishes cell-type specificity: association with increased proliferation capacity

    PubMed Central

    Linnemann, Amelia K.; Krawetz, Stephen A.

    2009-01-01

    DNA loop organization by nuclear scaffold/matrix attachment is a key regulator of gene expression that may provide a means to modulate phenotype. We have previously shown that attachment of genes to the NaCl-isolated nuclear matrix correlates with their silencing in HeLa cells. In contrast, expressed genes were associated with the lithium 3,5-diiodosalicylate (LIS)-isolated nuclear scaffold. To define their role in determining phenotype matrix attached regions (MARs) on human chromosomes 14–18 were identified as a function of expression in a primary cell line. The locations of MARs in aortic adventitial fibroblast (AoAF) cells were very stable (r = 0.909) and 96% of genes attached at MARs are silent (P < 0.001). Approximately one-third of the genes uniquely expressed in AoAF cells were associated with the HeLa cell nuclear matrix and silenced. Comparatively, 81% were associated with the AoAF cell nuclear scaffold (P < 0.001) and expressed. This suggests that nuclear scaffold/matrix association mediates a portion of cell type-specific gene expression thereby modulating phenotype. Interestingly, nuclear matrix attachment and thus silencing of specific genes that regulate proliferation and maintain the integrity of the HeLa cell genome suggests that transformation may at least in part be achieved through aberrant nuclear matrix attachment. PMID:19276204

  9. Targeted hyperthermia in prostate with an MR-guided endorectal ultrasound phased array: patient specific modeling and preliminary experiments

    NASA Astrophysics Data System (ADS)

    Salgaonkar, Vasant A.; Prakash, Punit; Plata, Juan; Holbrook, Andrew; Rieke, Viola; Kurhanewicz, John; Hsu, I.-C.; Diederich, Chris J.

    2013-02-01

    Feasibility of hyperthermia delivery to the prostate with a commercially available MR-guided endorectal ultrasound (ERUS) phased array ablation system (ExAblate 2100, Insightec, LTD) was assessed through computer simulations and ex vivo experiments. The simulations included a 3D FEM-based biothermal model, and acoustic field calculations for the ExAblate phased array (2.3 MHz, 2.3x4.0 cm2) using the rectangular radiator method. Array beamforming strategies were investigated to deliver 30-min hyperthermia (<41 °C) to focal regions of prostate cancer, identified from MR images in representative patient cases. Constraints on power densities, sonication durations and switching speeds imposed by ExAblate hardware and software were incorporated in the models. T<41 °C was calculated in 14-19 cm3 for sonications with planar or diverging beam patterns at 0.9-1.2 W/cm2, and in 3-10 cm3 for curvilinear (cylindrical) or multifocus beam patterns at 1.5-3.3 W/cm2, potentially useful for treating focal disease in a single posterior quadrant. Preliminary experiments included beamformed sonications in tissue mimicking phantom material under MRI-based temperature monitoring at 3T (GRE TE=7.0 ms, TR=15 ms, BW=10.5 kHz, FOV=15 cm, matrix 128x128, FA=40°). MR-temperature rises of 2-6 °C were induced in a phantom with the ExAblate array, consistent with calculated values and lower power settings (~0.86 W/cm2, 3 min.). Conformable hyperthermia may be delivered by tailoring power deposition along the array length and angular expanse. MRgERUS HIFU systems can be controlled for continuous hyperthermia in prostate to augment radiotherapy and drug delivery. [FUS Foundation, NIH R01 122276, 111981].

  10. Socioeconomic determinants of prostate-specific antigen testing and estimation of the prevalence of undiagnosed prostate cancer in an elderly Polish population based on the PolSenior study

    PubMed Central

    Prajsner, Andrzej; Szybalska, Aleksandra; Piotrowicz, Karolina; Zejda, Jan; Więcek, Andrzej

    2016-01-01

    Introduction Socioeconomic determinants of prostate-specific antigen (PSA) testing and prevalence of undiagnosed prostate cancer (PCa) in the Polish population are poorly understood. The aim of this study was to identify factors associated with PSA testing in elderly Polish men, and estimate the size of the population at risk of PCa related to PSA non-testing. Material and methods We analyzed questionnaire-derived data concerning PSA testing, obtained in 2567 elderly and 332 younger (age: 55–59) participants of the population-based PolSenior study. Additionally, PSA was measured in 2414 subjects. Results The PSA had previously been tested in 41.2% of elderly and in 24.8% of younger participants. Non-smoking status (OR = 2.06, p < 0.001), higher personal income (OR = 1.56, p < 0.001), better education (OR = 1.49, p = 0.001), previous white-collar work (OR = 1.37, p = 0.005), alcohol abstinence (OR = 1.28, p = 0.02), married status (OR = 1.24, p = 0.04), dependence in Instrumental Activities of Daily Living (IADL) but not in Activities of Daily Living (ADL) (OR = 0.65, p < 0.001), and dependence in ADL (OR = 0.55, p < 0.001) were independent predictors of previous PSA testing in elderly participants. There were 31 elderly previously treated for PCa (calculated standardized prevalence: 935 per 100,000 elderly population). The PSA levels > 4 ng/ml were found in 12.8% of 65–74-year-old and 4.5% of 55–59-year-old previously non-tested participants. We calculated the standardized prevalence rate of undiagnosed PCa as approximately 1370 and 2352 cases per 100,000 population aged 55–59 and 65–74 years, respectively. Conclusions In Poland, 58.8% of elderly men have never had PSA tested. These were less likely to be functionally independent, married, better educated, non-smokers or to have previous office employment or higher than average personal income. Our data suggest substantial underdiagnosis of prostate cancer among Polish men. PMID:27695494

  11. Quantifying Post- Laser Ablation Prostate Therapy Changes on MRI via a Domain-Specific Biomechanical Model: Preliminary Findings

    PubMed Central

    Toth, Robert; Sperling, Dan; Madabhushi, Anant

    2016-01-01

    Focal laser ablation destroys cancerous cells via thermal destruction of tissue by a laser. Heat is absorbed, causing thermal necrosis of the target region. It combines the aggressive benefits of radiation treatment (destroying cancer cells) without the harmful side effects (due to its precise localization). MRI is typically used pre-treatment to determine the targeted area, and post-treatment to determine efficacy by detecting necrotic tissue, or tumor recurrence. However, no system exists to quantitatively evaluate the post-treatment effects on the morphology and structure via MRI. To quantify these changes, the pre- and post-treatment MR images must first be spatially aligned. The goal is to quantify (a) laser-induced shape-based changes, and (b) changes in MRI parameters post-treatment. The shape-based changes may be correlated with treatment efficacy, and the quantitative effects of laser treatment over time is currently poorly understood. This work attempts to model changes in gland morphology following laser treatment due to (1) patient alignment, (2) changes due to surrounding organs such as the bladder and rectum, and (3) changes due to the treatment itself. To isolate the treatment-induced shape-based changes, the changes from (1) and (2) are first modeled and removed using a finite element model (FEM). A FEM models the physical properties of tissue. The use of a physical biomechanical model is important since a stated goal of this work is to determine the physical shape-based changes to the prostate from the treatment, and therefore only physical real deformations are to be allowed. A second FEM is then used to isolate the physical, shape-based, treatment-induced changes. We applied and evaluated our model in capturing the laser induced changes to the prostate morphology on eight patients with 3.0 Tesla, T2-weighted MRI, acquired approximately six months following treatment. Our results suggest the laser treatment causes a decrease in prostate volume

  12. Quantifying Post- Laser Ablation Prostate Therapy Changes on MRI via a Domain-Specific Biomechanical Model: Preliminary Findings.

    PubMed

    Toth, Robert; Sperling, Dan; Madabhushi, Anant

    2016-01-01

    Focal laser ablation destroys cancerous cells via thermal destruction of tissue by a laser. Heat is absorbed, causing thermal necrosis of the target region. It combines the aggressive benefits of radiation treatment (destroying cancer cells) without the harmful side effects (due to its precise localization). MRI is typically used pre-treatment to determine the targeted area, and post-treatment to determine efficacy by detecting necrotic tissue, or tumor recurrence. However, no system exists to quantitatively evaluate the post-treatment effects on the morphology and structure via MRI. To quantify these changes, the pre- and post-treatment MR images must first be spatially aligned. The goal is to quantify (a) laser-induced shape-based changes, and (b) changes in MRI parameters post-treatment. The shape-based changes may be correlated with treatment efficacy, and the quantitative effects of laser treatment over time is currently poorly understood. This work attempts to model changes in gland morphology following laser treatment due to (1) patient alignment, (2) changes due to surrounding organs such as the bladder and rectum, and (3) changes due to the treatment itself. To isolate the treatment-induced shape-based changes, the changes from (1) and (2) are first modeled and removed using a finite element model (FEM). A FEM models the physical properties of tissue. The use of a physical biomechanical model is important since a stated goal of this work is to determine the physical shape-based changes to the prostate from the treatment, and therefore only physical real deformations are to be allowed. A second FEM is then used to isolate the physical, shape-based, treatment-induced changes. We applied and evaluated our model in capturing the laser induced changes to the prostate morphology on eight patients with 3.0 Tesla, T2-weighted MRI, acquired approximately six months following treatment. Our results suggest the laser treatment causes a decrease in prostate volume

  13. Direct Energy Conversion for Nuclear Propulsion at Low Specific Mass

    NASA Technical Reports Server (NTRS)

    Scott, John H.

    2014-01-01

    The project will continue the FY13 JSC IR&D (October-2012 to September-2013) effort in Travelling Wave Direct Energy Conversion (TWDEC) in order to demonstrate its potential as the core of a high potential, game-changing, in-space propulsion technology. The TWDEC concept converts particle beam energy into radio frequency (RF) alternating current electrical power, such as can be used to heat the propellant in a plasma thruster. In a more advanced concept (explored in the Phase 1 NIAC project), the TWDEC could also be utilized to condition the particle beam such that it may transfer directed kinetic energy to a target propellant plasma for the purpose of increasing thrust and optimizing the specific impulse. The overall scope of the FY13 first-year effort was to build on both the 2012 Phase 1 NIAC research and the analysis and test results produced by Japanese researchers over the past twenty years to assess the potential for spacecraft propulsion applications. The primary objective of the FY13 effort was to create particle-in-cell computer simulations of a TWDEC. Other objectives included construction of a breadboard TWDEC test article, preliminary test calibration of the simulations, and construction of first order power system models to feed into mission architecture analyses with COPERNICUS tools. Due to funding cuts resulting from the FY13 sequestration, only the computer simulations and assembly of the breadboard test article were completed. The simulations, however, are of unprecedented flexibility and precision and were presented at the 2013 AIAA Joint Propulsion Conference. Also, the assembled test article will provide an ion current density two orders of magnitude above that available in previous Japanese experiments, thus enabling the first direct measurements of power generation from a TWDEC for FY14. The proposed FY14 effort will use the test article for experimental validation of the computer simulations and thus complete to a greater fidelity the

  14. Contributions of mitogen-activated protein kinase and nuclear factor kappa B to N-(4-hydroxyphenyl)retinamide-induced apoptosis in prostate cancer cells.

    PubMed

    Shimada, Keiji; Nakamura, Mitsutoshi; Ishida, Eiwa; Kishi, Munehiro; Yonehara, Shin; Konishi, Noboru

    2002-11-01

    The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) has been shown to induce apoptosis in various types of tumors, including prostate cancer. We sought to examine the key mechanisms affecting the resistance to 4-HPR-induced apoptosis in three human prostate cancer cell lines, PC-3, DU145, and LNCaP. Concentrations of more than 40 microM 4-HPR produced apoptosis to almost the same extent in all cell lines; however, only the LNCaP line remained highly sensitive to concentrations less than 10 microM. These differing sensitivities at low concentrations correlated well with the level of constitutive activation of nuclear factor kappa B (NFkappaB) in the individual cell lines. We found that NFkappaB activation inhibited c-jun NH(2)-terminal kinase and caspase 3 activation induced by 4-HPR and that NFkappaB inhibition by the I kappa B alpha phosphorylation inhibitor compound Bay 117082 resulted in increasing sensitization of both PC-3 and DU145 lines to apoptosis induced by 4-HPR at low concentrations. Furthermore, we found that inhibition of extracellular signal-regulated kinase (ERK) enhanced the suppression of NFkappaB by 4-HPR and also resulted in sensitization to apoptosis in the DU145 cell line, in which ERK is activated constitutively. It thus appears that mitogen-activated protein kinase associated with the activity of NFkappaB plays an important role in the degree of resistance to 4-HPR-induced apoptosis in human prostate cancer cells.

  15. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    PubMed

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells. PMID:27681649

  16. Fifteen-Year Biochemical Relapse-Free Survival, Cause-Specific Survival, and Overall Survival Following I{sup 125} Prostate Brachytherapy in Clinically Localized Prostate Cancer: Seattle Experience

    SciTech Connect

    Sylvester, John E.; Grimm, Peter D.; Wong, Jason; Galbreath, Robert W.; Merrick, Gregory; Blasko, John C.

    2011-10-01

    Purpose: To report 15-year biochemical relapse-free survival (BRFS), cause-specific survival (CSS), and overall survival (OS) outcomes of patients treated with I{sup 125} brachytherapy monotherapy for clinically localized prostate cancer early in the Seattle experience. Methods and Materials: Two hundred fifteen patients with clinically localized prostate cancer were consecutively treated from 1988 to 1992 with I{sup 125} monotherapy. They were prospectively followed as a tight cohort. They were evaluated for BRFS, CSS, and OS. Multivariate analysis was used to evaluate outcomes by pretreatment clinical prognostic factors. BRFS was analyzed by the Phoenix (nadir + 2 ng/mL) definition. CSS and OS were evaluated by chart review, death certificates, and referring physician follow-up notes. Gleason scoring was performed by general pathologists at a community hospital in Seattle. Time to biochemical failure (BF) was calculated and compared by Kaplan-Meier plots. Results: Fifteen-year BRFS for the entire cohort was 80.4%. BRFS by D'Amico risk group classification cohort analysis was 85.9%, 79.9%, and 62.2% for low, intermediate, and high-risk patients, respectively. Follow-up ranged from 3.6 to 18.4 years; median follow-up was 15.4 years for biochemically free of disease patients. Overall median follow-up was 11.7 years. The median time to BF in those who failed was 5.1 years. CSS was 84%. OS was 37.1%. Average age at time of treatment was 70 years. There was no significant difference in BRFS between low and intermediate risk groups. Conclusion: I{sup 125} monotherapy results in excellent 15-year BRFS and CSS, especially when taking into account the era of treatment effect.

  17. Red Maca (Lepidium meyenii) did not affect cell viability despite increased androgen receptor and prostate-specific antigen gene expression in the human prostate cancer cell line LNCaP.

    PubMed

    Díaz, P; Cardenas, H; Orihuela, P A

    2016-10-01

    We examined whether aqueous extract of Lepidium meyenii (red Maca) could inhibit growth, potentiate apoptotic activity of two anticancer drugs Taxol and 2-methoxyestradiol (2ME) or change mRNA expression for the androgen target genes, androgen receptor (Ar) and prostate-specific antigen (Psa) in the human prostate cancer cell line LNCaP. Red Maca aqueous extract at 0, 10, 20, 40 or 80 μg/ml was added to LNCaP cells, and viability was evaluated by the MTS assay at 24 or 48 hr after treatment. Furthermore, LNCaP cells were treated with 80 μg/ml of red Maca plus Taxol or 2ME 5 μM and viability was assessed 48 hr later. Finally, LNCaP cells were treated with red Maca 0, 20, 40 or 80 μg/ml, and 12 hr later, mRNA level for Ar or Psa was assessed by real-time PCR. Treatment with red Maca did not affect viability of LNCaP cells. Apoptotic activity induced by Taxol and 2ME in LNCaP cells was not altered with red Maca treatment. Relative expression of the mRNA for Ar and Psa increased with red Maca 20 and 40 μg/ml, but not at 80 μg/ml. We conclude that red Maca aqueous extract does not have toxic effects, but stimulates androgen signalling in LNCaP cells.

  18. Molecular Imaging of Prostate Cancer.

    PubMed

    Wibmer, Andreas G; Burger, Irene A; Sala, Evis; Hricak, Hedvig; Weber, Wolfgang A; Vargas, Hebert Alberto

    2016-01-01

    Prostate cancer is the most common noncutaneous malignancy among men in the Western world. The natural history and clinical course of prostate cancer are markedly diverse, ranging from small indolent intraprostatic lesions to highly aggressive disseminated disease. An understanding of this biologic heterogeneity is considered a necessary requisite in the quest for the adoption of precise and personalized management strategies. Molecular imaging offers the potential for noninvasive assessment of the biologic interactions underpinning prostate carcinogenesis. Currently, numerous molecular imaging probes are in clinical use or undergoing preclinical or clinical evaluation. These probes can be divided into those that image increased cell metabolism, those that target prostate cancer-specific membrane proteins and receptor molecules, and those that bind to the bone matrix adjacent to metastases to bone. The increased metabolism and vascular changes in prostate cancer cells can be evaluated with radiolabeled analogs of choline, acetate, glucose, amino acids, and nucleotides. The androgen receptor, prostate-specific membrane antigen, and gastrin-releasing peptide receptor (ie, bombesin) are overexpressed in prostate cancer and can be targeted by specific radiolabeled imaging probes. Because metastatic prostate cancer cells induce osteoblastic signaling pathways of adjacent bone tissue, bone-seeking radiotracers are sensitive tools for the detection of metastases to bone. Knowledge about the underlying biologic processes responsible for the phenotypes associated with the different stages of prostate cancer allows an appropriate choice of methods and helps avoid pitfalls. PMID:26587888

  19. [Prostate cancer].

    PubMed

    Morote, Joan; Maldonado, Xavier; Morales-Bárrera, Rafael

    2016-02-01

    The Vall d'Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow-up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity. Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance.

  20. [Prostate cancer].

    PubMed

    Morote, Joan; Maldonado, Xavier; Morales-Bárrera, Rafael

    2016-02-01

    The Vall d'Hebron multidisciplinary prostate cancer (PC) team reviews recent advances in the management of this neoplasm. Screening studies with long follow-up show a reduction in mortality, whereas active surveillance is emerging as a therapeutic approach of non-aggressive cancers. New markers increase the specificity of PSA and also allow targeting suspected aggressive cancers. Multiparametric magnetic resonance (mMRI) has emerged as the most effective method in the selection of patients for biopsy and also for local tumor staging. The paradigm of random prostatic biopsy is changing through the fusion techniques that allow guiding ultrasonography-driven biopsy of suspicious areas detected in mMRI. Radical prostatectomy (RP) and radiotherapy (RT) are curative treatments of localized PC and both have experienced significant technological improvements. RP is highly effective and the incorporation of robotic surgery is reducing morbidity. Modern RT allows the possibility of high tumor dose with minimal adjacent dose reducing its toxicity. Androgen deprivation therapy with LHRH analogues remains the treatment of choice for advanced PC, but should be limited to this indication. The loss of bone mass and adverse metabolic effects increases the frequency of fractures and cardiovascular morbimortality. After castration resistance in metastatic disease, new hormone-based drugs have demonstrated efficacy even after chemotherapy resistance. PMID:25727526

  1. Chemoprevention of prostate cancer.

    PubMed

    Stephenson, Andrew J; Abouassaly, Robert; Klein, Eric A

    2010-02-01

    Prostate cancer is an appropriate target for primary chemoprevention because of its ubiquity, disease-related mortality, treatment-related morbidity, and long latency period. The PCPT and REDUCE trials demonstrate that this cancer can be prevented by a relatively nontoxic oral pharmacologic agent (5alpha-reductase inhibitors). Evidence from the SELECT trial argues against the recommendation of the use of vitamins and micronutrients as chemoprevention of prostate cancer. Dietary modification may substantially alter a man's risk of prostate cancer, but the specific dietary manipulations that are necessary are poorly defined and these may need to be instituted in early adulthood to be successful. 5alpha-reductase inhibitors represent an effective primary prevention strategy, and these agents should be used more liberally for the prevention of prostate cancer, particularly in high-risk patients. PMID:20152515

  2. What is Prostate Cancer?

    MedlinePlus

    ... Topic Key statistics for prostate cancer What is prostate cancer? Cancer starts when cells in the body begin ... through the center of the prostate. Types of prostate cancer Almost all prostate cancers are adenocarcinomas . These cancers ...

  3. Emerging Roles of Human Prostatic Acid Phosphatase

    PubMed Central

    Kong, Hoon Young; Byun, Jonghoe

    2013-01-01

    Prostate cancer is one of the most prevalent non-skin related cancers. It is the second leading cause of cancer deaths among males in most Western countries. If prostate cancer is diagnosed in its early stages, there is a higher probability that it will be completely cured. Prostatic acid phosphatase (PAP) is a non-specific phosphomonoesterase synthesized in prostate epithelial cells and its level proportionally increases with prostate cancer progression. PAP was the biochemical diagnostic mainstay for prostate cancer until the introduction of prostate-specific antigen (PSA) which improved the detection of early-stage prostate cancer and largely displaced PAP. Recently, however, there is a renewed interest in PAP because of its usefulness in prognosticating intermediate to high-risk prostate cancers and its success in the immunotherapy of prostate cancer. Although PAP is believed to be a key regulator of prostate cell growth, its exact role in normal prostate as well as detailed molecular mechanism of PAP regulation is still unclear. Here, many different aspects of PAP in prostate cancer are revisited and its emerging roles in other environment are discussed. PMID:24009853

  4. Prostate cancer markers: An update

    PubMed Central

    PENTYALA, SRINIVAS; WHYARD, TERRY; PENTYALA, SAHANA; MULLER, JOHN; PFAIL, JOHN; PARMAR, SUNJIT; HELGUERO, CARLOS G.; KHAN, SARDAR

    2016-01-01

    As the most common noncutaneous malignancy in American men, prostate cancer currently accounts for 29% of all diagnosed cancers, and ranks second as the cause of cancer fatality in American men. Prostatic cancer is rarely symptomatic early in its course and therefore disease presentation often implies local extension or even metastatic disease. Thus, it is extremely critical to detect and diagnose prostate cancer in its earliest stages, often prior to the presentation of symptoms. Three of the most common techniques used to detect prostate cancer are the digital rectal exam, the transrectal ultrasound, and the use of biomarkers. This review presents an update regarding the field of prostate cancer biomarkers and comments on future biomarkers. Although there is not a lack of research in the field of prostate cancer biomarkers, the discovery of a novel biomarker that may have the advantage of being more specific and effective warrants future scientific inquiry. PMID:26998261

  5. PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.

    PubMed

    Wang, Yin; Wu, Xiaohou; Ou, Liping; Yang, Xue; Wang, Xiaorong; Tang, Min; Chen, E; Luo, Chunli

    2015-06-28

    Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

  6. Nuclear interaction of Smac/DIABLO with Survivin at G2/M arrest prompts docetaxel-induced apoptosis in DU145 prostate cancer cells

    SciTech Connect

    Kim, Ji Young; Chung, Jin-Yong; Lee, Seung Gee; Kim, Yoon-Jae; Park, Ji-Eun; Yoo, Ki Soo; Yoo, Young Hyun; Park, Young Chul; Kim, Byeong Gee; Kim, Jong-Min . E-mail: jmkim7@dau.ac.kr

    2006-12-01

    Smac/DIABLO is released by mitochondria in response to apoptotic stimuli and is thought to antagonize the function of inhibitors of apoptosis proteins. Recently, it has been shown that, like XIAP, Survivin can potentially interact with Smac/DIABLO. However, the precise mechanisms and cellular location of their action have not been determined. We report for the first time that Smac/DIABLO translocates to the nucleus and is colocalized with Survivin at mitotic spindles during apoptosis resulting from G2/M arrest due to docetaxel treatment of DU145 prostate cancer cells. Our data demonstrate that the nuclear interaction of Smac/DIABLO with Survivin is an important step for suppressing the anti-apoptotic function of Survivin in Doc-induced apoptosis. This suggests that the balance between cellular Smac/DIABLO and Survivin levels could be critical for cellular destiny in taxane-treated cancer cells.

  7. Familial prostate cancer: the damage done and lessons learnt

    PubMed Central

    Taherian, Nassim; Hamel, Nancy; Bégin, Louis R.; Bismar, Tarek A.; Goldgar, David E.; Feng, Bing-Jian; Foulkes, William D.

    2014-01-01

    Background A 51-year-old French Canadian man commenced screening for prostate cancer at the request of his family physician given his extensive family history of prostate cancer in five brothers, his father and two paternal uncles. His prostate specific antigen (PSA) level was 4.9ng/ml and a subsequent six-core biopsy revealed the presence of a prostate adenocarcinoma with a Gleason score of 7 (3+4). He was treated with a radical prostatectomy. Repeat PSA tests revealed a gradual rise in PSA levels despite androgen deprivation therapy with bicalutamide and goserelin over the course of 3 years. Genetic evaluation was undertaken in view of his personal and family history. The proband died a year later of widespread metastasis, at the age of 58. Investigations Doppler ultrasound for the proband’s leg, abdominal and pelvic computed tomography (CT) scan with intravenous (IV) and oral contrast as well as chest CT with IV contrast for the assessment of metastatic prostate cancer; genetic counselling and mutation analysis for French Canadian founder mutations in the BRCA1 and BRCA2 genes; mutations specific analysis of the mother’s formalin-fixed, paraffin-embedded (FFPE) breast tissue blocks; examination of loss of heterozygosity at the BRCA2 gene locus; immunohistochemistry to determine the expression of the ERG nuclear oncoprotein in prostate tumours; genotyping with eight selected risk-associated single nucleotide polymorphisms (SNPs); genetic testing for the G84E variant in the HOXB13 gene Diagnosis Early-onset and aggressive prostate cancer associated with a missense French Canadian BRCA2 founder mutation, c.5857G>T (p.Glu1953*). Management Radical prostatectomy, hormone therapy with bicalutamide and goserelin, palliative chemotherapy initially with docetaxel plus prednisone then with mitoxantrone plus prednisone, as well as genetic counselling and testing for the proband and his family members. PMID:23318356

  8. Retrospective Evaluation Reveals That Long-term Androgen Deprivation Therapy Improves Cause-Specific and Overall Survival in the Setting of Dose-Escalated Radiation for High-Risk Prostate Cancer

    SciTech Connect

    Feng, Felix Y.; Blas, Kevin; Olson, Karin; Stenmark, Matthew; Sandler, Howard; Hamstra, Daniel A.

    2013-05-01

    Purpose: To evaluate the role of androgen deprivation therapy (ADT) and duration for high-risk prostate cancer patients treated with dose-escalated radiation therapy (RT). Methods and Materials: A retrospective analysis of high-risk prostate cancer patients treated with dose-escalated RT (minimum 75 Gy) with or without ADT was performed. The relationship between ADT use and duration with biochemical failure (BF), metastatic failure (MF), prostate cancer-specific mortality (PCSM), non-prostate cancer death (NPCD), and overall survival (OS) was assessed as a function of pretreatment characteristics, comorbid medical illness, and treatment using Fine and Gray's cumulative incidence methodology. Results: The median follow-up time was 64 months. In men with National Comprehensive Cancer Network defined high-risk prostate cancer treated with dose-escalated RT, on univariate analysis, both metastasis (P<.0001; hazard ratio 0.34; 95% confidence interval 0.18-0.67; cumulative incidence at 60 months 13% vs 35%) and PCSM (P=.015; hazard ratio 0.41; 95% confidence interval 0.2-1.0; cumulative incidence at 60 months 6% vs 11%) were improved with the use of ADT. On multivariate analysis for all high-risk patients, Gleason score was the strongest negative prognostic factor, and long-term ADT (LTAD) improved MF (P=.002), PCSM (P=.034), and OS (P=.001). In men with prostate cancer and Gleason scores 8 to 10, on multivariate analysis after adjustment for other risk features, there was a duration-dependent improvement in BF, metastasis, PCSM, and OS, all favoring LTAD in comparison with STAD or RT alone. Conclusion: For men with high-risk prostate cancer treated with dose-escalated EBRT, this retrospective study suggests that the combination of LTAD and RT provided a significant improvement in clinical outcome, which was especially true for those with Gleason scores of 8 to 10.

  9. SU-E-T-77: Comparison of 2D and 3D Gamma Analysis in Patient-Specific QA for Prostate VMAT Plans

    SciTech Connect

    Clemente, F; Perez, C

    2014-06-01

    Purpose: Patient-specific QA procedures for IMRT and VMAT are traditionally performed by comparing TPS calculations with measured single point values and plane dose distributions by means of gamma analysis. New QA devices permit us to calculate 3D dose distributions on patient anatomy as redundant secondary check and reconstruct it from measurements taken with 2D and 3D detector arrays. 3D dose calculations allow us to perform DVH-based comparisons with clinical relevance, as well as 3D gamma analysis. One of these systems (Compass, IBA Dosimetry) combines traditional 2D with new anatomical-based 3D gamma analysis. This work shows the ability of this system by comparing 2D and 3D gamma analysis in pre-treatment QA for several VMAT prostate plans. Methods: Compass is capable of calculating dose as secondary check from DICOM TPS data and reconstructing it from measurements taken by a 2D ion chamber array (MatriXX Evolution, IBA Dosimetry). Both 2D and 3D gamma tests are available to compare calculated and reconstructed dose in Compass with TPS RT Dose. Results: 15 VMAT prostate plans have been measured with Compass. Dose is reconstructed with Compass for these plans. 2D gamma comparisons can be done for any plane from dose matrix. Mean gamma passing rates for isocenter planes (axial, coronal, sagittal) are (99.7±0.2)%, (99.9±0.1)%, (99.9±0.1)% for reconstructed dose planes. 3D mean gamma passing rates are (98.5±1.7)% for PTVs, (99.1±1.5)% for rectum, (100.0±0.0)% for bladder, (99.6±0.7)% for femoral heads and (98.1±4.1)% for penile bulb. Conclusion: Compass is a powerful tool to perform a complete pre-treatment QA analysis, from 2D techniques to 3D DVH-based techniques with clinical relevance. All reported values for VMAT prostate plans are in good agreement with TPS values. This system permits us to ensure the accuracy in the delivery of VMAT treatments completing a full patient-specific QA program.

  10. Long-Term Follow-Up and Risk of Cancer Death After Radiation for Post-Prostatectomy Rising Prostate-Specific Antigen

    SciTech Connect

    Swanson, Gregory P.; Du, Fei; Michalek, Joel E.; Hermans, Michael

    2011-05-01

    Purpose: The results of salvage radiation therapy for rising prostate-specific antigen (PSA) levels after radical prostatectomy appear favorable, but the ultimate outcome is uncertain, given the relatively short follow-up in most studies. We report on a group of patients at a median follow-up of 13.9 years after salvage radiation therapy. Methods and Materials: From 1990 to 1995, 92 patients were referred postoperatively for radiation for a rising PSA level. PSA level at the time of referral ranged from 0.1 to 30.5 ng/ml (median, 1.5 ng/ml). The median time from surgery to radiation was 2.1 years (range,, 0.3-7.4 years). Radiation was directed to the prostatic fossa only with a median dose of 6,500 cGy (range, 6,000-7,000 cGy). Results: Eighty-five patients experienced a PSA drop after radiation, as predicted by Gleason score and PSA level at the start of radiation. Five- and 10-year biochemical failure free survival (BFFS) was 35% and 26%, respectively, and overall survival was 86% and 67%, respectively. Median survival was 12.0 years, and median BFF was 2.3 years. The presurgery PSA level was not predictive, but the PSA level at the start of radiation predicted a response. Patients with Gleason 8 to 9 cancers had a significantly higher progression rate than those with lower Gleason scores. There were no significant differences in outcomes based on pathology findings (none vs. positive margins vs. positive seminal vesicles). Overall, 22 (24%) patients died directly from prostate cancer, resulting in a 10-year cancer-specific survival rate of 82%. Multivariate analysis risk factors for dying of cancer were Gleason's score (8 to 9) and PSA at the start of radiation therapy (>1.0 ng/ml). Conclusions: Patients have a good response to salvage radiation therapy. A small but durable subgroup appears to have permanent control. In those for whom therapy fails, radiation delays the need for other salvage therapy, indicating at least a transient benefit to most patients.

  11. Regulation of Phosphatidylinositol-specific Phospholipase C at the Nuclear Envelope in Cardiac Myocytes

    PubMed Central

    Smrcka, Alan V.

    2014-01-01

    Phosphatidylinositol 4,5 bisphosphate hydrolysis at the plasma membrane by phospholipase C is one of the major hormone regulated intracellular signaling systems. The system generates the diffusible second messenger IP3 and the membrane bound messenger diacylglycerol. Spatial regulation of this system has been thought to be through specific subcellular distributions of the IP3 receptor or PKC. As is becoming increasingly apparent, receptor-stimulated signaling systems are also found at intracellular membranes. As discussed in this issue, GPCRs have been identified at the nuclear envelope implying intracellular localization of the signaling systems that respond to GPCRs. Here we discuss the evidence for the existence of PLC signals that regulate nuclear processes, as well as the evidence for nuclear and nuclear envelope localization of PLC signaling components, and their implications for cardiac physiology and disease. PMID:25658460

  12. Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders.

    PubMed

    Choi, Siwon; Wang, Wei; Ribeiro, Alexandrew J S; Kalinowski, Agnieszka; Gregg, Siobhan Q; Opresko, Patricia L; Niedernhofer, Laura J; Rohde, Gustavo K; Dahl, Kris Noel

    2011-01-01

    Computational image analysis is used in many areas of biological and medical research, but advanced techniques including machine learning remain underutilized. Here, we used automated segmentation and shape analyses, with pre-defined features and with computer generated components, to compare nuclei from various premature aging disorders caused by alterations in nuclear proteins. We considered cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) with an altered nucleoskeletal protein; a mouse model of XFE progeroid syndrome caused by a deficiency of ERCC1-XPF DNA repair nuclease; and patients with Werner syndrome (WS) lacking a functional WRN exonuclease and helicase protein. Using feature space analysis, including circularity, eccentricity, and solidity, we found that XFE nuclei were larger and significantly more elongated than control nuclei. HGPS nuclei were smaller and rounder than the control nuclei with features suggesting small bumps. WS nuclei did not show any significant shape changes from control. We also performed principle component analysis (PCA) and a geometric, contour based metric. PCA allowed direct visualization of morphological changes in diseased nuclei, whereas standard, feature-based approaches required pre-defined parameters and indirect interpretation of multiple parameters. Both methods yielded similar results, but PCA proves to be a powerful pre-analysis methodology for unknown systems.

  13. A novel target-specific gene delivery system combining baculovirus and sequence-specific long interspersed nuclear elements.

    PubMed

    Kawashima, Tomoko; Osanai, Mizuko; Futahashi, Ryo; Kojima, Tetsuya; Fujiwara, Haruhiko

    2007-07-01

    Transposable elements are valuable for somatic and germ-line transformation. However, long interspersed nuclear elements (LINEs) have not been used because of poor information on the transposition mechanism. We have developed a novel gene delivery system combining baculovirus AcNPV and two silkworm LINEs, SART1 and R1, which integrate into specific sequences of telomeric repeats and 28S ribosomal DNA, respectively. When two LINEs containing the enhanced green fluorescent protein gene recombined into AcNPV were infected into fifth instar larvae of the silkworm, we observed target-specific retrotransposition of LINEs at 72h post-infection, using polymerase chain reaction amplification and sequencing. Telomere- and 28S rDNA-specific transposition occurred in all nine tissues tested, including the ovary and testis. This is the first demonstration of site-specific gene delivery in living larvae. Insertion efficiencies were dependent on the virus titer for injection and the host strains of Bombyx mori. Using this system, we successfully detected the intergeneration transmission of retrotransposed sequences. In addition, AcNPV-mediated SART1 also transposed into telomere of another lepidopteran, Orgyia recens, suggesting that this system is useful for a wide variety of AcNPV-infectious insects. Site-specific gene delivery by virus-mediated LINE will be a potential gene therapy tool to avoid harmful unexpected insertions.

  14. Ubiquitin-specific protease 12 interacting partners Uaf-1 and WDR20 are potential therapeutic targets in prostate cancer

    PubMed Central

    McClurg, Urszula L.; Harle, Victoria J.; Nabbi, Arash; Batalha-Pereira, Amanda; Walker, Scott; Coffey, Kelly; Gaughan, Luke; McCracken, Stuart RC; Robson, Craig N.

    2015-01-01

    The androgen receptor (AR) is a key transcription factor in the initiation and progression of prostate cancer (PC) and is a major therapeutic target for the treatment of advanced disease. Unfortunately, current therapies are not curative for castration resistant PC and a better understanding of AR regulation could identify novel therapeutic targets and biomarkers to aid treatment of this disease. The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR. We determined that Usp12 deubiquitinates the AR resulting in elevated receptor stability and activity. Furthermore, Usp12 silencing was shown to reduce proliferation of PC cells. Usp12 is known to require the co-factors Uaf-1 and WDR20 for catalytic activity. In this report we focus further on the role of Uaf-1 and WDR20 in Usp12 regulation and investigate if these co-factors are also required for controlling AR activity. Firstly, we confirm the presence of the Usp12/Uaf-1/WDR20 complex in PC cells and demonstrate the importance of Uaf-1 and WDR20 for Usp12 stabilisation. Consequently, we show that individual silencing of either Uaf-1 or WDR20 is sufficient to abrogate the activity of the Usp12 complex and down-regulate AR-mediated transcription via receptor destabilisation resulting in increased apoptosis and decreased colony forming ability of PC cells. Moreover, expression of both Uaf-1 and WDR20 is higher in PC tissue compared to benign controls. Overall these results highlight the potential importance of the Usp12/Uaf-1/WDR20 complex in AR regulation and PC progression. Highlights: Androgen receptor is a key transcriptional regulator in prostate cancerUsp12/Uaf-1/WDR20 complex plays a crucial role in androgen receptor stability and activityDestabilising an individual Usp12/Uaf-1/WDR20 complex member reduces the protein levels of the whole complex and diminishes androgen receptor activity

  15. Biomarkers in localized prostate cancer.

    PubMed

    Ferro, Matteo; Buonerba, Carlo; Terracciano, Daniela; Lucarelli, Giuseppe; Cosimato, Vincenzo; Bottero, Danilo; Deliu, Victor M; Ditonno, Pasquale; Perdonà, Sisto; Autorino, Riccardo; Coman, Ioman; De Placido, Sabino; Di Lorenzo, Giuseppe; De Cobelli, Ottavio

    2016-02-01

    Biomarkers can improve prostate cancer diagnosis and treatment. Accuracy of prostate-specific antigen (PSA) for early diagnosis of prostate cancer is not satisfactory, as it is an organ- but not cancer-specific biomarker, and it can be improved by using models that incorporate PSA along with other test results, such as prostate cancer antigen 3, the molecular forms of PSA (proPSA, benign PSA and intact PSA), as well as kallikreins. Recent reports suggest that new tools may be provided by metabolomic studies as shown by preliminary data on sarcosine. Additional molecular biomarkers have been identified by the use of genomics, proteomics and metabolomics. We review the most relevant biomarkers for early diagnosis and management of localized prostate cancer.

  16. Role of Desumoylation in the Development of Prostate Cancer1

    PubMed Central

    Cheng, Jinke; Bawa, Tasneem; Lee, Peng; Gong, Limin; Yeh, Edward T. H

    2006-01-01

    Abstract SUMO is a novel ubiquitin-like protein that can covalently modify a large number of nuclear proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. Sumoylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and is readily reversed by a family of SUMO-specific proteases (SENPs). Since SUMO was discovered 10 years ago, the biologic contribution of this posttranslational modification has remained unclear. In this review, we report that SENP1, a member of the SENP family, is overexpressed in human prostate cancer specimens. The induction of SENP1 is observed with the chronic exposure of prostate cancer cells to androgen and/or interleukin (IL) 6. SENP1 upregulation modulates the transcriptional activity of androgen receptors (ARs) and c-Jun, as well as cyclin D1 expression. Initial in vivo data from transgenic mice indicate that overexpression of SENP1 in the prostate leads to the development of prostatic intraepithelial neoplasia at an early age. Collectively, these studies indicate that overexpression of SENP1 is associated with prostate cancer development. PMID:16925949

  17. Mitochondrial-Nuclear Interactions Mediate Sex-Specific Transcriptional Profiles in Drosophila

    PubMed Central

    Mossman, Jim A.; Tross, Jennifer G.; Li, Nan; Wu, Zhijin; Rand, David M.

    2016-01-01

    The assembly and function of mitochondria require coordinated expression from two distinct genomes, the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Mutations in either genome can be a source of phenotypic variation, yet their coexpression has been largely overlooked as a source of variation, particularly in the emerging paradigm of mitochondrial replacement therapy. Here we tested how the transcriptome responds to mtDNA and nDNA variation, along with mitonuclear interactions (mtDNA × nDNA) in Drosophila melanogaster. We used two mtDNA haplotypes that differ in a substantial number of single nucleotide polymorphisms, with >100 amino acid differences. We placed each haplotype on each of two D. melanogaster nuclear backgrounds and tested for transcription differences in both sexes. We found that large numbers of transcripts were differentially expressed between nuclear backgrounds, and that mtDNA type altered the expression of nDNA genes, suggesting a retrograde, trans effect of mitochondrial genotype. Females were generally more sensitive to genetic perturbation than males, and males demonstrated an asymmetrical effect of mtDNA in each nuclear background; mtDNA effects were nuclear-background specific. mtDNA-sensitive genes were not enriched in male- or female-limited expression space in either sex. Using a variety of differential expression analyses, we show the responses to mitonuclear covariation to be substantially different between the sexes, yet the mtDNA genes were consistently differentially expressed across nuclear backgrounds and sexes. Our results provide evidence that the main mtDNA effects can be consistent across nuclear backgrounds, but the interactions between mtDNA and nDNA can lead to sex-specific global transcript responses. PMID:27558138

  18. Ki-67 Is an Independent Predictor of Metastasis and Cause-Specific Mortality for Prostate Cancer Patients Treated on Radiation Therapy Oncology Group (RTOG) 94-08

    SciTech Connect

    Verhoven, Bret; Yan, Yan; Ritter, Mark; Khor, Li-Yan; Hammond, Elizabeth; Jones, Christopher; Amin, Mahul; Bahary, Jean-Paul; Zeitzer, Kenneth; Pollack, Alan

    2013-06-01

    Purpose: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. Methods and Materials: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. Results: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. Conclusions: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

  19. Prostate specific antigen testing in family practice: a cross sectional survey of self-reported rates of and reasons for testing participation and risk disclosure

    PubMed Central

    2013-01-01

    Background Despite controversy about the benefits of routine prostate specific antigen (PSA) testing, rates of participation continue to rise. It is important to ensure that men are fully informed about the potential risks associated with this test. Little is known about the processes of shared decision making for PSA testing in the family practice setting. This study aimed to explore men’s experiences of PSA testing participation and risk disclosure for PSA testing. Methods A cross-sectional survey of male family practice attendees aged 40 years or older, with no previous history of prostate cancer, between June 2010 and November 2011. Questions related to whether participants had undertaken PSA testing or discussed this with their doctor over the past 5 years, whether the patient or doctor had initiated the discussion, reasons for undergoing testing, and whether their doctor had discussed particular risks associated with PSA testing. Results Sixty-seven percent (215/320) of men recalled having a PSA test in the past five years. Of the respondents who reported not having a test, 14% had discussed it with their doctor. The main reasons for having a PSA test were doctor recommendation and wanting to keep up to date with health tests. Thirty-eight percent or fewer respondents reported being advised of each potential risk. Conclusions Despite debate over the benefits of routine PSA testing, a high proportion of male family practice attendees report undertaking this test. Risks associated with testing appear to be poorly disclosed by general practitioners. These results suggest the need to improve the quality of informed consent for PSA testing in the family practice setting. PMID:24321004

  20. Intracellular lysyl oxidase: Effect of a specific inhibitor on nuclear mass in proliferating cells

    SciTech Connect

    Saad, Fawzy A.; Torres, Marie; Wang, Hao; Graham, Lila

    2010-06-11

    LOX, the principal enzyme involved in crosslinking of collagen, was the first of several lysyl oxidase isotypes to be characterized. Its active form was believed to be exclusively extracellular. Active LOX was later reported to be present in cell nuclei; its function there is unknown. LOX expression opposes the effect of mutationally activated Ras, which is present in about 30% of human cancers. The mechanism of LOX in countering the action of Ras is also unknown. In the present work, assessment of nuclear protein for possible effects of lysyl oxidase activity led to the discovery that proliferating cells dramatically increase their nuclear protein content when exposed to BAPN ({beta}-aminopropionitrile), a highly specific lysyl oxidase inhibitor that reportedly blocks LOX inhibition of Ras-induced oocyte maturation. In three cell types (PC12 cells, A7r5 smooth muscle cells, and NIH 3T3 fibroblasts), BAPN caused a 1.8-, 1.7-, and 2.1-fold increase in total nuclear protein per cell, respectively, affecting all major components in both nuclear matrix and chromatin fractions. Since nuclear size is correlated with proliferative status, enzyme activity restricting nuclear growth may be involved in the lysyl oxidase tumor suppressive effect. Evidence is also presented for the presence of apparent lysyl oxidase isotype(s) containing a highly conserved LOX active site sequence in the nuclei of PC12 cells, which do not manufacture extracellular lysyl oxidase substrates. Results reported here support the hypothesis that nuclear lysyl oxidase regulates nuclear growth, and thereby modulates cell proliferation.

  1. A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice.

    PubMed

    Zins, Karin; Lucas, Trevor; Reichl, Patrick; Abraham, Dietmar; Aharinejad, Seyedhossein

    2013-01-01

    Deregulated Rho GTPases Rac1 and Cdc42 have been discovered in various tumors, including prostate and Rac protein expression significantly increases in prostate cancer. The Rac and Cdc42 pathways promote the uncontrolled proliferation, invasion and metastatic properties of human cancer cells. We synthesized the novel compound AZA1 based on structural information of the known Rac1 inhibitor NSC23766. In the current study we investigated the effects of inhibition of these pathways by AZA1 on prostate tumorigenicity by performing preclinical studies using a xenograft mouse model of prostate cancer. In androgen-independent prostate cancer cells, AZA1 inhibited both Rac1 and Cdc42 but not RhoA GTPase activity in a dose-dependent manner and blocked cellular migration and proliferation. Cyclin D1 expression significantly decreased following Rac1/Cdc42 inhibition in prostate cancer cells. AZA1 treatment also down-regulated PAK and AKT activity in prostate cancer cells, associated with induction of the pro-apoptotic function of BAD by suppression of serine-112 phosphorylation. Daily systemic administration of AZA1 for 2 weeks reduced growth of human 22Rv1 prostate tumor xenografts in mice and improved the survival of tumor-bearing animals significantly. These data suggest a role of AZA1 in blocking Rac1/Cdc42-dependent cell cycle progression, cancer cell migration and increase of cancer cell apoptosis involving down-regulation of the AKT and PAK signaling pathway in prostate cancer cells. We therefore propose that a small-molecule inhibitor therapy targeting Rac1/Cdc42 Rho GTPase signaling pathways may be used as a novel treatment for patients with advanced prostate cancer.

  2. Characterization of the nuclear protein import mechanism using Ran mutants with altered nucleotide binding specificities.

    PubMed Central

    Weis, K; Dingwall, C; Lamond, A I

    1996-01-01

    The small nuclear GTP binding protein Ran is required for transport of nuclear proteins through the nuclear pore complex (NPC). Although it is known that GTP hydrolysis by Ran is essential for this reaction, it has been unclear whether additional energy-consuming steps are also required. To uncouple the energy requirements for Ran from other nucleoside triphosphatases, we constructed a mutant derivative of Ran that has an altered nucleotide specificity from GTP to xanthosine 5' triphosphate. Using this Ran mutant, we demonstrate that nucleotide hydrolysis by Ran is sufficient to promote efficient nuclear protein import in vitro. Under these conditions, protein import could no longer be inhibited with non-hydrolysable nucleotide analogues, indicating that no Ran-independent energy-requiring steps are essential for the protein translocation reaction through the NPC. We further provide evidence that nuclear protein import requires Ran in the GDP form in the cytoplasm. This suggests that a coordinated exchange reaction from Ran-GDP to Ran-GTP at the pore is necessary for translocation into the nucleus. Images PMID:9003787

  3. Compartment-specific aggregases direct distinct nuclear and cytoplasmic aggregate deposition

    PubMed Central

    Miller, Stephanie BM; Ho, Chi-Ting; Winkler, Juliane; Khokhrina, Maria; Neuner, Annett; Mohamed, Mohamed YH; Guilbride, D Lys; Richter, Karsten; Lisby, Michael; Schiebel, Elmar; Mogk, Axel; Bukau, Bernd

    2015-01-01

    Disruption of the functional protein balance in living cells activates protective quality control systems to repair damaged proteins or sequester potentially cytotoxic misfolded proteins into aggregates. The established model based on Saccharomyces cerevisiae indicates that aggregating proteins in the cytosol of eukaryotic cells partition between cytosolic juxtanuclear (JUNQ) and peripheral deposits. Substrate ubiquitination acts as the sorting principle determining JUNQ deposition and subsequent degradation. Here, we show that JUNQ unexpectedly resides inside the nucleus, defining a new intranuclear quality control compartment, INQ, for the deposition of both nuclear and cytosolic misfolded proteins, irrespective of ubiquitination. Deposition of misfolded cytosolic proteins at INQ involves chaperone-assisted nuclear import via nuclear pores. The compartment-specific aggregases, Btn2 (nuclear) and Hsp42 (cytosolic), direct protein deposition to nuclear INQ and cytosolic (CytoQ) sites, respectively. Intriguingly, Btn2 is transiently induced by both protein folding stress and DNA replication stress, with DNA surveillance proteins accumulating at INQ. Our data therefore reveal a bipartite, inter-compartmental protein quality control system linked to DNA surveillance via INQ and Btn2. PMID:25672362

  4. Detection of prostate cancer with a blood-based assay for early prostate cancer antigen.

    PubMed

    Paul, Barbara; Dhir, Rajiv; Landsittel, Douglas; Hitchens, Moira R; Getzenberg, Robert H

    2005-05-15

    Prostate-specific antigen lacks specificity for prostate cancer, so the identification and characterization of a unique blood-based marker for the disease would provide for a more accurate diagnosis, reducing both unnecessary biopsies and patient uncertainty. We previously identified a novel biomarker for prostate cancer, early prostate cancer antigen (EPCA). EPCA antibodies positively stained the negative biopsies of men who, as much as 5 years later, were diagnosed with prostate cancer. The goal of this study was to determine whether EPCA antibodies could be used in a clinically applicable plasma-based immunoassay to specifically detect prostate cancer. Using an EPCA-based ELISA, the protein was measured in the plasma of 46 individuals, including prostate cancer patients, healthy individuals, other cancer patients, spinal cord injury victims, and patients with prostatitis. With a predetermined cutoff value of 1.7 absorbance at 450 nm, only the prostate cancer population, as a whole, expressed plasma-EPCA levels above the cutoff. Statistical analysis showed a significant difference in EPCA levels between the prostate cancer population and each of the other groups, specifically the healthy donors (P < 0.0001), bladder cancer patients (P = 0.03), and spinal cord injury patients (P = 0.001). Sensitivity of the EPCA assay for prostate cancer patients was 92% whereas the overall specificity was 94%. Specificity for the healthy donors was 100%. Although larger trials are required, this initial study shows the potential of EPCA to serve as a highly specific blood-based marker for prostate cancer. EPCA, when coupled with prostate-specific antigen, may help reduce the number of both unnecessary biopsies and undetected prostate tumors.

  5. 0610009K11Rik, a testis-specific and germ cell nuclear receptor-interacting protein

    SciTech Connect

    Zhang Heng; Denhard, Leslie A.; Zhou Huaxin; Liu Lanhsin; Lan Zijian

    2008-02-22

    Using an in silico approach, a putative nuclear receptor-interacting protein 0610009K11Rik was identified in mouse testis. We named this gene testis-specific nuclear receptor-interacting protein-1 (Tnrip-1). Tnrip-1 was predominantly expressed in the testis of adult mouse tissues. Expression of Tnrip-1 in the testis was regulated during postnatal development, with robust expression in 14-day-old or older testes. In situ hybridization analyses showed that Tnrip-1 is highly expressed in pachytene spermatocytes and spermatids. Consistent with its mRNA expression, Tnrip-1 protein was detected in adult mouse testes. Immunohistochemical studies showed that Tnrip-1 is a nuclear protein and mainly expressed in pachytene spermatocytes and round spermatids. Moreover, co-immunoprecipitation analyses showed that endogenous Tnrip-1 protein can interact with germ cell nuclear receptor (GCNF) in adult mouse testes. Our results suggest that Tnrip-1 is a testis-specific and GCNF-interacting protein which may be involved in the modulation of GCNF-mediated gene transcription in spermatogenic cells within the testis.

  6. Atelocollagen-mediated intravenous siRNA delivery specific to tumor tissues orthotopically xenografted in prostates of nude mice and its anticancer effects.

    PubMed

    Yuan, Yuan; Makita, Naoki; Cao, Dongliang; Mihara, Keichiro; Kadomatsu, Kenji; Takei, Yoshifumi

    2015-04-01

    Successful short interfering RNA (siRNA)-based therapy for cancers depends on functional siRNA delivery specific to tumors. In our previous report, we have shown systemic siRNA delivery specific to human prostate cancer cell line PC-3 subcutaneous tumors in nude mice by atelocollagen, a collagen derivative, for formulating a complex with siRNA. We used an siRNA for human Bcl-xL as a model target. In the present study, we examined the antitumor effect on PC-3 orthotopic tumors in nude mice, as these tumors resemble the human clinical situation. The systemic intravenous administration of the complex (siRNA, 50 μg/shot) significantly reduced Bcl-xL expression and induced apoptosis in the tumors, and suppressed their growth. Liver metastasis was also inhibited in the orthotopic model. We successfully showed tumor-specific accumulation of the siRNA by Cy3-labeled siRNA and the direct quantification of the siRNA via reverse-phase high-performance liquid chromatography. The tumor-specific delivery was achieved by the enhanced permeability and retention effect, which is characteristic of macromolecular drugs. The high expression of vascular endothelial growth factor-A in the tumors provided adequate conditions to promote the permeability in the tumors, and to finally form the enhanced permeability and retention effect. In conclusion, our siRNA delivery is specific to the PC-3 orthotopic tumors in nude mice, and is practically feasible to treat tumors.

  7. Examination of CK2α and NF-κB p65 expression in human benign prostatic hyperplasia and prostate cancer tissues.

    PubMed

    Qaiser, Fatima; Trembley, Janeen H; Sadiq, Sarah; Muhammad, Iqbal; Younis, Rubina; Hashmi, Shoaib Naiyar; Murtaza, Badar; Rector, Thomas S; Naveed, Abdul Khaliq; Ahmed, Khalil

    2016-09-01

    Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression. The expression level and localization of CK2α and NF-κB p65 proteins in PCa and BPH tissue specimens was determined. Nuclear CK2α and NF-κB p65 protein levels are significantly higher in PCa compared with BPH, and these proteins are positively correlated with each other in both diseases. Nuclear NF-κB p65 levels correlated with Ki-67 or with cytoplasmic NF-κB p65 expression in BPH, but not in PCa. The findings provide information that combined analysis of CK2α and NF-κB p65 expression in prostate specimens relates to the disease status. Increased nuclear NF-κB p65 expression levels in PCa specifically related to nuclear CK2α levels, indicating a possible CK2-dependent relationship in malignancy. In contrast, nuclear NF-κB p65 protein levels related to both Ki-67 and cytoplasmic NF-κB p65 levels exclusively in BPH, suggesting a potential separate impact for NF-κB p65 function in proliferation for benign disease as opposed to malignant disease. PMID:27435858

  8. Nanogold-functionalized g-C3N4 nanohybrids for sensitive impedimetric immunoassay of prostate-specific antigen using enzymatic biocatalytic precipitation.

    PubMed

    Ding, Li-Li; Ge, Jing-Ping; Zhou, Wen-Quan; Gao, Jian-Ping; Zhang, Zheng-Yu; Xiong, Ya

    2016-11-15

    This work reports on a new impedimetric immunosensing strategy for sensitive detection of prostate-specific antigen (PSA) in biological fluids. The assay was carried out on monoclonal anti-PSA capture antibody-modified glassy carbon electrode with a sandwich-type detection format. Gold nanoparticles-decorated g-C3N4 nanosheets (AuNP/g-C3N4), synthesized by the wet-chemistry method, were utilized for the labeling of polyclonal anti-PSA detection antibody and horseradish peroxidase (HRP). Upon target PSA introduction, the sandwiched immunocomplex could be formed between capture antibody and detection antibody. Followed by the AuNP/g-C3N4, the labeled HRP could catalyze 4-choloro-1-naphthol into benzo-4-chlorohexadienone. The as-generated insoluble product was coated on the electrode surface, thus increasing the Faradaic impedance of Fe(CN)6(4-/3)(-) indicator between the solution and the base electrode. Under the optimal conditions, the impedance increased with the increasing target PSA in the sample, and exhibited a wide linear range from 10pgmL(-1) and 30ngmL(-1) with a detection limit of 5.2pgmL(-1). A repeatability and intermediate precision of <14% was accomplished. The specificity and method accuracy in comparison with commercial PSA ELISA kit for analysis of human serum specimens were relatively satisfactory.

  9. Nanogold-functionalized g-C3N4 nanohybrids for sensitive impedimetric immunoassay of prostate-specific antigen using enzymatic biocatalytic precipitation.

    PubMed

    Ding, Li-Li; Ge, Jing-Ping; Zhou, Wen-Quan; Gao, Jian-Ping; Zhang, Zheng-Yu; Xiong, Ya

    2016-11-15

    This work reports on a new impedimetric immunosensing strategy for sensitive detection of prostate-specific antigen (PSA) in biological fluids. The assay was carried out on monoclonal anti-PSA capture antibody-modified glassy carbon electrode with a sandwich-type detection format. Gold nanoparticles-decorated g-C3N4 nanosheets (AuNP/g-C3N4), synthesized by the wet-chemistry method, were utilized for the labeling of polyclonal anti-PSA detection antibody and horseradish peroxidase (HRP). Upon target PSA introduction, the sandwiched immunocomplex could be formed between capture antibody and detection antibody. Followed by the AuNP/g-C3N4, the labeled HRP could catalyze 4-choloro-1-naphthol into benzo-4-chlorohexadienone. The as-generated insoluble product was coated on the electrode surface, thus increasing the Faradaic impedance of Fe(CN)6(4-/3)(-) indicator between the solution and the base electrode. Under the optimal conditions, the impedance increased with the increasing target PSA in the sample, and exhibited a wide linear range from 10pgmL(-1) and 30ngmL(-1) with a detection limit of 5.2pgmL(-1). A repeatability and intermediate precision of <14% was accomplished. The specificity and method accuracy in comparison with commercial PSA ELISA kit for analysis of human serum specimens were relatively satisfactory. PMID:27179136

  10. [Renal histology in 44 patients with specific antibodies of soluble nuclear antigens].

    PubMed

    Meyer, O; Gaudreau, A; Peltier, A P

    1980-10-01

    The authors studied the correlations between renal histology and specific antinuclear antibodies of soluble nuclear antigens (anti-Sm, anti-RNP, anti-protein) in 44 patients with such auto-antibodies. They were mostly patients with lupus erythematosus (35/44), more rarely mixed collagen disease or Sjögren's disease. The presence of any one of the specific antibodies of nuclear antigens is not associated with any special renal prognosis; thus the presence of anti-RNP does not mean that there are no histological renal lesions. The renal prognosis depends in fact on the presence of anti-ADN native antibodies. Among the other laboratory parameters (rheumatoid factors, complement levels, cryoglobulinemia) only hypocomplementemia seems to be associated with a poor renal prognosis, the presence of rheumatoid factor has perhaps a protective role.

  11. Human Prostate Cancer Hallmarks Map.

    PubMed

    Datta, Dipamoy; Aftabuddin, Md; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-08-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.

  12. Human Prostate Cancer Hallmarks Map

    PubMed Central

    Datta, Dipamoy; Aftabuddin, Md.; Gupta, Dinesh Kumar; Raha, Sanghamitra; Sen, Prosenjit

    2016-01-01

    Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process. PMID:27476486

  13. The Percent of Positive Biopsy Cores Improves Prediction of Prostate Cancer-Specific Death in Patients Treated With Dose-Escalated Radiotherapy

    SciTech Connect

    Qian Yushen; Feng, Felix Y.; Halverson, Schuyler; Blas, Kevin; Sandler, Howard M.; Hamstra, Daniel A.

    2011-11-01

    Purpose: To examine the prognostic utility of the percentage of positive cores (PPC) at the time of prostate biopsy for patients treated with dose-escalated external beam radiation therapy. Methods and Materials: We performed a retrospective analysis of patients treated at University of Michigan Medical Center to at least 75 Gy. Patients were stratified according to PPC by quartile, and freedom from biochemical failure (nadir + 2 ng/mL), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) were assessed by log-rank test. Receiver operator characteristic (ROC) curve analysis was used to determine the optimal cut point for PPC stratification. Finally, Cox proportional hazards multivariate regression was used to assess the impact of PPC on clinical outcome when adjusting for National Comprehensive Cancer Network (NCCN) risk group and androgen deprivation therapy. Results: PPC information was available for 651 patients. Increasing-risk features including T stage, prostate-specific antigen, Gleason score, and NCCN risk group were all directly correlated with increasing PPC. On log-rank evaluation, all clinical endpoints, except for OS, were associated with PPC by quartile, with worse clinical outcomes as PPC increased, with the greatest impact seen in the highest quartile (>66.7% of cores positive). ROC curve analysis confirmed that a cut point using two-thirds positive cores was most closely associated with CSS (p = 0.002; area under ROC curve, 0.71). On univariate analysis, stratifying patients according to PPC less than or equal to 66.7% vs. PPC greater than 66.7% was prognostic for freedom from biochemical failure (p = 0.0001), FFM (p = 0.0002), and CSS (p = 0.0003) and marginally prognostic for OS (p = 0.055). On multivariate analysis, after adjustment for NCCN risk group and androgen deprivation therapy use, PPC greater than 66.7% increased the risk for biochemical failure (p = 0.0001; hazard ratio [HR], 2.1 [95% confidence

  14. Precursors of prostate cancer.

    PubMed

    Bostwick, David G; Cheng, Liang

    2012-01-01

    High-grade prostatic intraepithelial neoplasia (PIN) is the only accepted precursor of prostatic adenocarcinoma, according to numerous studies of animal models and man; other proposed precursors include atrophy and malignancy-associated changes (with no morphologic changes). PIN is characterized by progressive abnormalities of phenotype and genotype that are intermediate between benign prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. The only method of detection of PIN is biopsy because it does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultrasonography. The mean incidence of PIN in biopsies is 9% (range, 4%-16%), representing about 115,000 new cases of isolated PIN diagnosed each year in the United States. The clinical importance of PIN is its high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent carcinoma, especially when multifocal or observed in association with atypical small acinar proliferation (ASAP). Carcinoma develops in most patients with PIN within 10 years. Androgen deprivation therapy and radiation therapy decrease the prevalence and extent of PIN, suggesting that these forms of treatment may play a role in prevention of subsequent cancer. Multiple clinical trials to date of men with PIN have had modest success in delaying or preventing subsequent cancer. PMID:22212075

  15. High-Grade Prostatic Intraepithelial Neoplasia

    PubMed Central

    Bostwick, David G; Liu, Lina; Brawer, Michael K; Qian, Junqi

    2004-01-01

    High-grade prostatic intraepithelial neoplasia is considered the most likely precursor of prostatic carcinoma. The only method of detection is biopsy; prostatic intraepithelial neoplasia (PIN) does not significantly elevate serum prostate-specific antigen concentration and cannot be detected by ultra-sonography. The incidence of PIN in prostate biopsies averages 9% (range, 4%–16%), representing 115,000 new cases of PIN diagnosed each year in United States. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeated biopsy for concurrent or subsequent invasive carcinoma. Carcinoma will develop in most patients with PIN within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype that are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention. PMID:16985598

  16. Estrogen receptors in prostate development and cancer

    PubMed Central

    Yeh, Chiuan-Ren; Da, Jun; Song, Wenbin; Fazili, Anees; Yeh, Shuyuan

    2014-01-01

    Prostate cancer (PCa) is an androgen-sensitive disease, which can be pharmacologically controlled by androgen blockade. To date, a growing body of evidence showed that estrogen and estrogen receptors (ERs) could regulate prostate development, as well as cancer initiation and progression. This review will address the expression levels and function of ERs in different stages of PCa progression. The functions of ERs in different types of prostate cells, the ligand effect, and the potential applications of selective estrogen modulators (SERMs) will also be discussed. To further dissect ERs’ roles in prostate development, cell type specific ER knockout mouse models were generated. Results collected from the prostate cell type-specific ERαKO mouse models provided new insights about the cell type specific ERα roles in prostate development prenatally and postnatally. The results of ERs’ roles in mouse PCa mode and the correlation of ERs expression and biomedical outcome will also be discussed. PMID:25374919

  17. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

    PubMed

    McGrath, Meagan J; Binge, Lauren C; Sriratana, Absorn; Wang, Hong; Robinson, Paul A; Pook, David; Fedele, Clare G; Brown, Susan; Dyson, Jennifer M; Cottle, Denny L; Cowling, Belinda S; Niranjan, Birunthi; Risbridger, Gail P; Mitchell, Christina A

    2013-08-15

    It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

  18. Benign prostate hyperplasia (BPH) - resources

    MedlinePlus

    Resources - benign prostatic hyperplasia (BPH); Prostate enlargement resources; BPH resources ... organizations provide information on benign prostatic hyperplasia ( prostate enlargement ): National Kidney and Urologic Diseases Information Clearinghouse -- www. ...

  19. Prostate Cancer

    PubMed Central

    Vickers, Andrew J.; Lilja, Hans

    2010-01-01

    Two groundbreaking trials have this year reported conflicting results as to the benefit of screening for prostate cancer. Careful interpretation in the light of contemporary data might, however, reveal the true value of this intervention. PMID:19498406

  20. Enlarged prostate

    MedlinePlus

    ... Possible side effects include decreased sex drive and impotence . Antibiotics may be prescribed to treat chronic prostatitis ( ... less-invasive procedures carry a lower risk for impotence and incontinence than TURP, although the risk with ...

  1. Prostatitis - bacterial

    MedlinePlus

    ... emptying the bladder Foul-smelling urine Weak urine stream Other symptoms that may occur with this condition: ... the risk of spreading bacteria into the blood stream. The exam may reveal that the prostate is: ...

  2. PSA Velocity Does Not Improve Prostate Cancer Detection

    Cancer.gov

    A rapid increase in prostate-specific antigen (PSA) levels is not grounds for automatically recommending a prostate biopsy, according to a study published online February 24, 2011, in the Journal of the National Cancer Institute.

  3. Improved porous silicon (P-Si) microarray based PSA (prostate specific antigen) immunoassay by optimized surface density of the capture antibody

    PubMed Central

    Lee, SangWook; Kim, Soyoun; Malm, Johan; Jeong, Ok Chan; Lilja, Hans; Laurell, Thomas

    2014-01-01

    Enriching the surface density of immobilized capture antibodies enhances the detection signal of antibody sandwich mic