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Sample records for intermittent androgen suppression

  1. Nonlinear system identification for prostate cancer and optimality of intermittent androgen suppression therapy.

    Science.gov (United States)

    Suzuki, Taiji; Aihara, Kazuyuki

    2013-09-01

    These days prostate cancer is one of the most common types of malignant neoplasm in men. Androgen ablation therapy (hormone therapy) has been shown to be effective for advanced prostate cancer. However, continuous hormone therapy often causes recurrence. This results from the progression of androgen-dependent cancer cells to androgen-independent cancer cells during the continuous hormone therapy. One possible method to prevent the progression to the androgen-independent state is intermittent androgen suppression (IAS) therapy, which ceases dosing intermittently. In this paper, we propose two methods to estimate the dynamics of prostate cancer, and investigate the IAS therapy from the viewpoint of optimality. The two methods that we propose for dynamics estimation are a variational Bayesian method for a piecewise affine (PWA) system and a Gaussian process regression method. We apply the proposed methods to real clinical data and compare their predictive performances. Then, using the estimated dynamics of prostate cancer, we observe how prostate cancer behaves for various dosing schedules. It can be seen that the conventional IAS therapy is a way of imposing high cost for dosing while keeping the prostate cancer in a safe state. We would like to dedicate this paper to the memory of Professor Luigi M. Ricciardi. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  2. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-07

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

    Energy Technology Data Exchange (ETDEWEB)

    Hamilton, Gerhard, E-mail: gerhard.hamilton@toc.lbg.ac.at; Olszewski-Hamilton, Ulrike [Ludwig Boltzmann Cluster of Translational of Oncology, Nussdorfer Strasse 64, Vienna A-1090 (Austria); Theyer, Gerhard [Hospital Kittsee, Kittsee A-2421, Burgenland (Austria)

    2011-09-15

    Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

  4. Measurements of free and total PSA, tissue polypeptide-specific antigen (TPS), and CYFRA 21-1 in prostate cancer patients under intermittent androgen suppression therapy.

    Science.gov (United States)

    Theyer, G; Dürer, A; Theyer, U; Haberl, I; Ulsperger, E; Baumgartner, G; Hamilton, G

    1999-10-01

    The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays. Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml. PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues. Copyright 1999 Wiley-Liss, Inc.

  5. Long-term side-effects of intermittent androgen suppression therapy in prostate cancer: results of a phase II study.

    Science.gov (United States)

    Malone, Shawn; Perry, Gad; Segal, Roanne; Dahrouge, Simone; Crook, Juanita

    2005-09-01

    To assess the feasibility and tolerability of intermittent androgen suppression therapy (IAS) in prostate cancer. Patients with recurrent or metastic prostate cancer received cyclical periods of treatment with leuprolide acetate and nilutamide for 8 months, and rest periods. Cycles were repeated at progression until the treatment failed to achieve normal prostate-specific antigen (PSA) levels. Patients were followed with PSA level, testosterone level, haemoglobin level, weight and bone mineral density evaluations. The median time to treatment failure, recovery from anaemia, or normalization of testosterone level was estimated by the Kaplan-Meier method. In all, 95 patients received 245 cycles; the median duration of rest periods was 8 months and median time to treatment failure 47 months. Testosterone recovery during rest periods was documented in 117 (61%) of cycles. Anaemia was mild and reported in 33%, 44% and 67% of cycles 1, 2 and 3, respectively. Sexual function recovered during the rest periods in 47% of cycles. There was no significant overall change in body mass index at the end of the treatment period. Osteoporosis was documented in at least one site evaluated in 41 patients (37%). IAS has the potential to reduce side-effects, including recovery of haemoglobin level, return of sexual function and absence of weight gain at the end of the study period.

  6. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2006-01-01

    .... Intermittent androgen ablation therapy (IAAT) may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  7. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2004-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  8. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2005-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  9. Enhancement of Intermittent Androgen Ablation Therapy by Finasteride Administration in Animal Models

    National Research Council Canada - National Science Library

    Wang, Zhou

    2003-01-01

    .... Intermittent androgen ablation therapy may slow down the development of androgen refractory tumors because intermittent recovery of androgens can induce differentiation of prostatic epithelial cells...

  10. Minoxidil may suppress androgen receptor-related functions.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, An-Chi; Yang, Chih-Hsun; Chung, Wen-Hung; Wu, Wen-Guey

    2014-04-30

    Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a K(d) value of 2.6 µM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

  11. Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy.

    Science.gov (United States)

    Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

    2016-01-01

    The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

  12. Intermittent Versus Continuous Androgen Deprivation Therapy for Prostate Cancer: A Systematic Review and Meta-analysis

    Directory of Open Access Journals (Sweden)

    Yu-xiao ZHENG

    2018-03-01

    Full Text Available Objective: The strategy of androgen deprivation therapy (ADT applied in patients with prostate cancer (PCa to achieve optimal clinical and oncologic outcomes has been a longstanding debate. The objective of our study was to perform a metaanalysis to compare the efficacy, quality of life and adverse events profile of intermittent versus continuous androgen deprivation for prostate cancer. Methods: We searched PubMed, EMBASE and Web of Science to extract the basic characteristics. Besides, data of endpoint such as overall survival (OS, progression free survival (PFS, cancer-specific survival (CSS and time to progression (TTP as well as quality of life (QoL were also collected. In addition, the results were expressed as hazard ratio (HR with 95% confidence interval (CI. Results: 17 articles including a total 6,733 patients with any stage of PCa were included in our review. No significant differences were found in PFS (HR = 0.93, 95% CI: 0.83-1.03, TTP (HR = 0.96, 95% CI: 0.84-1.07 between intermittent androgen deprivation (IAD and continuous androgen deprivation (CAD, whereas CAD showed benefits associated with OS (HR = 0.92, 95% CI: 0.85-0.98 and CSS (HR = 0.86, 95% CI: 0.74-0.98. In addition, IAD might have a superior outcome compared with CAD, especially in sexual functioning and headache favoring. Controversial outcomes were also seen in some aspects such as hot flushes, gynecomastia, breast pain or fatigue. Conclusion: PFS and TTP were similar between IAD and CAD, whereas CAD showed benefits associated with OS and CSS. IAD might have benefits in QoL and have less adverse effects, especially in sexual dysfunction and headache.

  13. Androgens as double-edged swords: Induction and suppression of follicular development.

    Science.gov (United States)

    Pan, Jie-Xue; Zhang, Jun-Yu; Ke, Zhang-Hong; Wang, Fang-Fang; Barry, John A; Hardiman, Paul J; Qu, Fan

    2015-01-01

    Androgens, which are mediated via the androgen receptor (AR), play important roles in normal follicular development and female fertility. However, just like a double-edged sword, besides the positive effects of androgen on follicular development, abnormal androgen levels, especially as in hyperandrogenism, seriously suppress normal follicular development. A crucial balance exists between the importance of androgens in follicular development and their negative effects when in excess. As the first meiotic division and epigenetic reprogramming are two critical events in oogenesis, abnormal androgen levels or deficiency in androgen/AR signaling in the ovary may affect these vital events. Oocytes have a tendency to develop genomic instability, thus resulting in an increasing incidence of unpredictable adult diseases. Although many studies have explored the effects of androgens and AR on follicular development, the conclusions are controversial and there has been no thorough review of this topic. This review focuses on the roles of androgens in the physiological process of follicular development, summarizes new insights into the roles of androgens in the arrested development of follicles, and discusses the potential risk of adult diseases originating from abnormal follicular androgen levels or androgen receptor signals, which may determine areas for future studies.

  14. Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma

    NARCIS (Netherlands)

    Kil, P. J. M.; Goldschmidt, H. M. J.; Wieggers, B. J. A.; Kariakine, O. B.; Studer, U. E.; Whelan, P.; Hetherington, J.; de Reijke, Th M.; Hoekstra, J. W.; Collette, L.

    2003-01-01

    To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to

  15. Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process.

    Science.gov (United States)

    Wang, Xueni; Tao, Rui; Yang, Jing; Miao, Lin; Wang, Yu; Munyangaju, Jose Edouard; Wichai, Nuttapong; Wang, Hong; Zhu, Yan; Liu, Erwei; Chang, Yanxu; Gao, Xiumei

    2017-01-01

    To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ER α or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. The nuclear translocation of ER α was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ER α and ER β were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ER α , ER β , and AR in the prostate. Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development.

  16. Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details.

    Science.gov (United States)

    Hussain, Maha; Tangen, Catherine; Higano, Celestia; Vogelzang, Nicholas; Thompson, Ian

    2016-01-20

    Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non-prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials. © 2015 by American Society of Clinical Oncology.

  17. Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer.

    LENUS (Irish Health Repository)

    D'Amico, Anthony V

    2011-12-10

    We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories.

  18. Radiotherapy and local hyperthermia plus androgen suppression in locally advanced prostate cancer

    International Nuclear Information System (INIS)

    Maluta, S.; Marciai, N.; Gabbani, M.; Palazzi, M.; Dall'Oglio, S.; Grandinetti, A.

    2005-01-01

    Full text: In advanced prostatic cancer, hyperthermia may be useful in order to enhance irradiation efficacy so to avoid delivering of too high dose of radiotherapy which increases acute and late sequelae. A multi-centric phase II study is warranted to give hyperthermia a level 3 evidence in prostate cancer treatment. A randomized phase III study to demonstrate efficacy of hyperthermia is not available because of the optimal results obtained by using radiotherapy combined with androgen suppression. To evaluate hyperthermia gain, LHT should be combined with radiotherapy alone in patients refusing androgen suppression or affected by hormone refractory prostate carcinoma (HRPC). Patients with HRPC have multiple possibilities of treatment improving performance status and median survival, as chemotherapy regimens, and new agents. All these treatments modalities need to be confirmed by phase III trials. Also hyperthermia may be considered among these promising approaches. (author)

  19. Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review

    International Nuclear Information System (INIS)

    Sasse, André D; Sasse, Elisa; Carvalho, Albertina M; Macedo, Ligia T

    2012-01-01

    Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the preferred treatment for this condition. More recent evidence from randomised trials has demonstrated clinical benefit with the combined use of androgen suppression in such cases. The aim of this meta-analysis is to compare the combination of distinct hormone therapy modalities versus radiotherapy alone for overall survival, disease-free survival and toxicity. Databases (MEDLINE, EMBASE, LILACS, Cochrane databases and ClinicalTrials.gov) were scanned for randomised clinical trials involving radiotherapy with or without androgen suppression in local prostate cancer. The search strategy included articles published until October 2011. The studies were examined and the data of interest were plotted for meta-analysis. Survival outcomes were reported as a hazard ratio with corresponding 95% confidence intervals. Data from ten trials published from 1988 to 2011 were included, comprising 6555 patients. There was a statistically significant advantage to the use of androgen suppression, in terms of both overall survival and disease free survival, when compared to radiotherapy alone. The use of long-term goserelin (up to three years) was the strategy providing the higher magnitude of clinical benefit. In contrast to goserelin, there were no trials evaluating the use of other luteinizing hormone-releasing hormone (LHRH) analogues as monotherapy. Complete hormonal blockade was not shown to be superior to goserelin monotherapy. Based on the findings of this systematic review, the evidence supports the use of androgen suppression with goserelin monotherapy as the standard treatment for patients with prostate cancer treated with radiotherapy, which are at high risk of recurrence or metastases

  20. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

    2010-01-01

    Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

  1. Intermittent Aeration Suppresses Nitrite-Oxidizing Bacteria in Membrane-Aerated Biofilms: A Model-Based Explanation

    DEFF Research Database (Denmark)

    Ma, Yunjie; Domingo Felez, Carlos; Plósz, Benedek G.

    2017-01-01

    . On the basis of dissolved oxygen (DO), ammonium, nitrite, and nitrate profiles within the biofilm and in the bulk, a 1-dimensional nitrifying biofilm model was developed and calibrated. The model was utilized to explore the potential mechanisms of NOB suppression associated with intermittent aeration...... nitritation, strategies to suppress nitrite-oxidizing bacteria (NOB) are needed, which are ideally grounded on an understanding of underlying mechanisms. In this study, a nitrifying MABR was operated under intermittent aeration. During eight months of operation, AOB dominated, while NOB were suppressed...... during intermittent aeration was mostly explained by periodic inhibition caused by free ammonia due to periodic transient pH upshifts. Dissolved oxygen limitation did not govern NOB suppression. Different intermittent aeration strategies were then evaluated for nitritation success in intermittently...

  2. First off-time treatment prostate-specific antigen kinetics predicts survival in intermittent androgen deprivation for prostate cancer.

    Science.gov (United States)

    Sanchez-Salas, Rafael; Olivier, Fabien; Prapotnich, Dominique; Dancausa, José; Fhima, Mehdi; David, Stéphane; Secin, Fernando P; Ingels, Alexandre; Barret, Eric; Galiano, Marc; Rozet, François; Cathelineau, Xavier

    2016-01-01

    Prostate-specific antigen (PSA) doubling time is relying on an exponential kinetic pattern. This pattern has never been validated in the setting of intermittent androgen deprivation (IAD). Objective is to analyze the prognostic significance for PCa of recurrent patterns in PSA kinetics in patients undergoing IAD. A retrospective study was conducted on 377 patients treated with IAD. On-treatment period (ONTP) consisted of gonadotropin-releasing hormone agonist injections combined with oral androgen receptor antagonist. Off-treatment period (OFTP) began when PSA was lower than 4 ng/ml. ONTP resumed when PSA was higher than 20 ng/ml. PSA values of each OFTP were fitted with three basic patterns: exponential (PSA(t) = λ.e(αt)), linear (PSA(t) = a.t), and power law (PSA(t) = a.t(c)). Univariate and multivariate Cox regression model analyzed predictive factors for oncologic outcomes. Only 45% of the analyzed OFTPs were exponential. Linear and power law PSA kinetics represented 7.5% and 7.7%, respectively. Remaining fraction of analyzed OFTPs (40%) exhibited complex kinetics. Exponential PSA kinetics during the first OFTP was significantly associated with worse oncologic outcome. The estimated 10-year cancer-specific survival (CSS) was 46% for exponential versus 80% for nonexponential PSA kinetics patterns. The corresponding 10-year probability of castration-resistant prostate cancer (CRPC) was 69% and 31% for the two patterns, respectively. Limitations include retrospective design and mixed indications for IAD. PSA kinetic fitted with exponential pattern in approximately half of the OFTPs. First OFTP exponential PSA kinetic was associated with a shorter time to CRPC and worse CSS. © 2015 Wiley Periodicals, Inc.

  3. Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

    Energy Technology Data Exchange (ETDEWEB)

    Morooka, Nobukatsu, E-mail: amorooka@gunma-u.ac.jp [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Ueguri, Kei [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Yee, Karen Kar Lye [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan); Human Resources Cultivation Center, Gunma University, 1-5-1 Tenjin-cho, Kiryushi, Gunma, 376-8515 (Japan); Yanase, Toshihiko [Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, 814-0180 (Japan); Sato, Takashi [Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512 (Japan)

    2016-09-02

    Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.

  4. Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation

    International Nuclear Information System (INIS)

    Morooka, Nobukatsu; Ueguri, Kei; Yee, Karen Kar Lye; Yanase, Toshihiko; Sato, Takashi

    2016-01-01

    Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue. - Highlights: • DHT, non-aromatizable androgen suppresses Mcp-1 expression in adipocytes. • Mcp-1 transcription was negatively regulated by DHT-AR action. • DHT-AR selectively regulates Mcp-1 transcription through distinct NF-κB sites.

  5. Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy

    Directory of Open Access Journals (Sweden)

    Andrew P. Lieberman

    2014-05-01

    Full Text Available Spinal and bulbar muscular atrophy (SBMA is caused by the polyglutamine androgen receptor (polyQ-AR, a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

  6. Measurement of serum testosterone during androgenic suppression in patients with prostate cancer: A systematic review.

    Science.gov (United States)

    Morote, J; Regis, L; Celma, A; Planas, J

    2016-10-01

    Clinical practice guidelines recommend measuring serum testosterone (ST) during androgenic suppression (AS) to assess its efficacy and define castration resistance (CR). The objectives of this systematic review were to assess the level of scientific evidence that justify checking ST levels during AS, when to perform it and for what purpose. We performed a search in PubMed with the following mesh terms: androgen suppression, testosterone, and prostate cancer. The search was narrowed to original articles published in English. We found 8 publications that analysed the clinical impact of ST concentrations during AS. In all of the series, ST was measured using chemiluminescent assays. However, only indirect methods based on liquid or gas chromatography for its extraction and subsequent quantification using mass spectrometry are recommended, especially for measuring low levels. The endpoints were specific survival and CR-free survival. Six studies were retrospective. The series were not uniform in terms of clinical stage, types of AS and ST assessment methods. In general, low ST levels (<20ng/dL or <32ng/dL) were related to longer CR-free survival. The measurements were performed every 3 or 6 months. Four studies confirmed the beneficial effect of adding bicalutamide when detecting microelevations above 50ng/dL. The level of scientific evidence justifying the measurement of ST during AS is low, and the methods employed for quantifying ST levels are inadequate. However, we consider it useful to check ST levels during AS, and there appears to be an association between low ST levels and better disease outcomes. In the event of microelevations above 50ng/dL, we recommend the administration of bicalutamide. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  7. Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test.

    Science.gov (United States)

    Rosenfield, Robert L; Mortensen, Monica; Wroblewski, Kristen; Littlejohn, Elizabeth; Ehrmann, David A

    2011-11-01

    Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A). Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4-7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all. Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671-0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, PPCOS-A, but present in 30% of PCOS-T (P PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese. Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.

  8. Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development.

    Science.gov (United States)

    Lu, Tianjing; Lin, Wen-Jye; Izumi, Kouji; Wang, Xiaohai; Xu, Defeng; Fang, Lei-Ya; Li, Lei; Jiang, Qi; Jin, Jie; Chang, Chawnshang

    2012-10-01

    Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-β2, were increased, and administration of anti-TGF-β2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic

  9. Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Young-Chae Kim

    Full Text Available The androgen receptor (AR mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT. However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR, and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.

  10. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    Liu, Shicheng; Yuan, Yiming; Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi

    2010-01-01

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser 81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [ 3 H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  11. Intermittent episodes of bright light suppress myopia in the chicken more than continuous bright light.

    Science.gov (United States)

    Lan, Weizhong; Feldkaemper, Marita; Schaeffel, Frank

    2014-01-01

    Bright light has been shown a powerful inhibitor of myopia development in animal models. We studied which temporal patterns of bright light are the most potent in suppressing deprivation myopia in chickens. Eight-day-old chickens wore diffusers over one eye to induce deprivation myopia. A reference group (n = 8) was kept under office-like illuminance (500 lux) at a 10:14 light:dark cycle. Episodes of bright light (15 000 lux) were super-imposed on this background as follows. Paradigm I: exposure to constant bright light for either 1 hour (n = 5), 2 hours (n = 5), 5 hours (n = 4) or 10 hours (n = 4). Paradigm II: exposure to repeated cycles of bright light with 50% duty cycle and either 60 minutes (n = 7), 30 minutes (n = 8), 15 minutes (n = 6), 7 minutes (n = 7) or 1 minute (n = 7) periods, provided for 10 hours. Refraction and axial length were measured prior to and immediately after the 5-day experiment. Relative changes were analyzed by paired t-tests, and differences among groups were tested by one-way ANOVA. Compared with the reference group, exposure to continuous bright light for 1 or 2 hours every day had no significant protective effect against deprivation myopia. Inhibition of myopia became significant after 5 hours of bright light exposure but extending the duration to 10 hours did not offer an additional benefit. In comparison, repeated cycles of 1:1 or 7:7 minutes of bright light enhanced the protective effect against myopia and could fully suppress its development. The protective effect of bright light depends on the exposure duration and, to the intermittent form, the frequency cycle. Compared to the saturation effect of continuous bright light, low frequency cycles of bright light (1:1 min) provided the strongest inhibition effect. However, our quantitative results probably might not be directly translated into humans, but rather need further amendments in clinical studies.

  12. Intermittent episodes of bright light suppress myopia in the chicken more than continuous bright light.

    Directory of Open Access Journals (Sweden)

    Weizhong Lan

    Full Text Available PURPOSE: Bright light has been shown a powerful inhibitor of myopia development in animal models. We studied which temporal patterns of bright light are the most potent in suppressing deprivation myopia in chickens. METHODS: Eight-day-old chickens wore diffusers over one eye to induce deprivation myopia. A reference group (n = 8 was kept under office-like illuminance (500 lux at a 10:14 light:dark cycle. Episodes of bright light (15 000 lux were super-imposed on this background as follows. Paradigm I: exposure to constant bright light for either 1 hour (n = 5, 2 hours (n = 5, 5 hours (n = 4 or 10 hours (n = 4. Paradigm II: exposure to repeated cycles of bright light with 50% duty cycle and either 60 minutes (n = 7, 30 minutes (n = 8, 15 minutes (n = 6, 7 minutes (n = 7 or 1 minute (n = 7 periods, provided for 10 hours. Refraction and axial length were measured prior to and immediately after the 5-day experiment. Relative changes were analyzed by paired t-tests, and differences among groups were tested by one-way ANOVA. RESULTS: Compared with the reference group, exposure to continuous bright light for 1 or 2 hours every day had no significant protective effect against deprivation myopia. Inhibition of myopia became significant after 5 hours of bright light exposure but extending the duration to 10 hours did not offer an additional benefit. In comparison, repeated cycles of 1:1 or 7:7 minutes of bright light enhanced the protective effect against myopia and could fully suppress its development. CONCLUSIONS: The protective effect of bright light depends on the exposure duration and, to the intermittent form, the frequency cycle. Compared to the saturation effect of continuous bright light, low frequency cycles of bright light (1:1 min provided the strongest inhibition effect. However, our quantitative results probably might not be directly translated into humans, but rather need further amendments in clinical studies.

  13. Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Lin Hui-Ping

    2011-08-01

    Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

  14. Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

    Science.gov (United States)

    Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

    2017-12-01

    Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

  15. In an Ovine Model of Polycystic Ovary Syndrome (PCOS) Prenatal Androgens Suppress Female Fetal Renal Gluconeogenesis

    Science.gov (United States)

    Connolly, Fiona; Rae, Michael T.; Späth, Katharina; Boswell, Lyndsey; McNeilly, Alan S.; Duncan, W. Colin

    2015-01-01

    Increased maternal androgen exposure during pregnancy programmes a polycystic ovary syndrome (PCOS)-like condition, with metabolic dysfunction, in adult female offspring. Other in utero exposures associated with the development of insulin resistance, such as intrauterine growth restriction and exposure to prenatal glucocorticoids, are associated with altered fetal gluconeogenesis. We therefore aimed to assess the effect of maternal androgenisation on the expression of PEPCK and G6PC in the ovine fetus. Pregnant Scottish Greyface sheep were treated with twice weekly testosterone propionate (TP; 100mg) or vehicle control from day 62 to day102 of gestation. At day 90 and day 112 fetal plasma and liver and kidney tissue was collected for analysis. PEPCK and G6PC expression were analysed by quantitative RT-PCR, immunohistochemistry and western blotting. PEPCK and G6PC were localised to fetal hepatocytes but maternal androgens had no effect on female or male fetuses. PEPCK and G6PC were also localised to the renal tubules and renal PEPCK (P<0.01) and G6PC (P = 0.057) were lower in females after prenatal androgenisation with no change in male fetuses. These tissue and sex specific observations could not be explained by alterations in fetal insulin or cortisol. The sexual dimorphism may be related to the increase in circulating estrogen (P<0.01) and testosterone (P<0.001) in females but not males. The tissue specific effects may be related to the increased expression of ESR1 (P<0.01) and AR (P<0.05) in the kidney when compared to the fetal liver. After discontinuation of maternal androgenisation female fetal kidney PEPCK expression normalised. These data further highlight the fetal and sexual dimorphic effects of maternal androgenisation, an antecedent to adult disease and the plasticity of fetal development. PMID:26148093

  16. Antioxidant tempol suppresses heart cytosolic phospholipase A(2)alpha stimulated by chronic intermittent hypoxia

    Czech Academy of Sciences Publication Activity Database

    Míčová, P.; Klevstig, Martina; Holzerová, Kristýna; Vecka, M.; Žurmanová, J.; Neckář, Jan; Kolář, František; Nováková, Olga; Novotný, J.; Hlaváčková, Markéta

    2017-01-01

    Roč. 95, č. 8 (2017), s. 920-927 ISSN 0008-4212 R&D Projects: GA ČR(CZ) GJ16-12420Y; GA ČR(CZ) GA13-10267S Institutional support: RVO:67985823 Keywords : heart * chronic intermittent hypoxia * oxidative stress * phospholipases A(2) * tempol Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery OBOR OECD: Biochemistry and molecular biology Impact factor: 1.822, year: 2016

  17. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigaby, James

    2003-01-01

    The purpose of this project is to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment...

  18. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigsby, James

    2004-01-01

    The purpose of this project is to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment...

  19. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigsby, James P; Brega, Angela G

    2006-01-01

    The purpose of this project was to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment (ADT...

  20. Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction.

    Science.gov (United States)

    Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J

    2014-01-01

    Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.

  1. Effects of exposure to intermittent versus continuous red light on human circadian rhythms, melatonin suppression, and pupillary constriction.

    Directory of Open Access Journals (Sweden)

    Ivan Ho Mien

    Full Text Available Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2 s(-1, intermittent red light (1 min on/off, or bright white light (2,500 lux near the onset of nocturnal melatonin secretion (n = 8 in each group. Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69, with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.

  2. Targeting Stromal Androgen Receptor Suppresses Prolactin-Driven Benign Prostatic Hyperplasia (BPH)

    Science.gov (United States)

    Lai, Kuo-Pao; Huang, Chiung-Kuei; Fang, Lei-Ya; Izumi, Kouji; Lo, Chi-Wen; Wood, Ronald; Kindblom, Jon; Yeh, Shuyuan

    2013-01-01

    Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development. We found Pb-PRL tg mice lacking stromal fibromuscular AR developed smaller prostates, with more marked changes in the dorsolateral prostate lobes with less proliferation index. Mechanistically, prolactin mediated hyperplastic prostate growth involved epithelial-stromal interaction through epithelial prolactin/prolactin receptor signals to regulate granulocyte macrophage-colony stimulating factor expression to facilitate stromal cell growth via sustaining signal transducer and activator of transcription-3 activity. Importantly, the stromal fibromuscular AR could modulate such epithelial-stromal interacting signals. Targeting stromal fibromuscular AR with the AR degradation enhancer, ASC-J9®, led to the reduction of prostate size, which could be used in future therapy. PMID:23893956

  3. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be

  4. A reason for intermittent fasting to suppress the awakening of dormant breast tumors.

    Science.gov (United States)

    Lankelma, Jan; Kooi, Bob; Krab, Klaas; Dorsman, Josephine C; Joenje, Hans; Westerhoff, Hans V

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors will contain anoxic living tumor cells. These cells are dangerous, because they are capable of inducing angiogenesis, which will "wake up" the tumor. Anoxic cells are dependent on anaerobic glucose breakdown for ATP generation. The local extracellular glucose concentration gradient is determined by the blood glucose concentration and by consumption by cells closer to the nearest blood vessel. The blood glucose concentration can be lowered by 20-40% during fasting. We calculated that glucose supply to the potentially hazardous anoxic cells can thereby be reduced significantly, resulting in cell death specifically of the anoxic tumor cells. We hypothesize that intermittent fasting will help to reduce the incidence of tumor relapse via reducing the number of anoxic tumor cells and tumor awakening. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. Intermittent Episodes of Bright Light Suppress Myopia in the Chicken More than Continuous Bright Light

    OpenAIRE

    Lan, Weizhong; Feldkaemper, Marita; Schaeffel, Frank

    2014-01-01

    PURPOSE: Bright light has been shown a powerful inhibitor of myopia development in animal models. We studied which temporal patterns of bright light are the most potent in suppressing deprivation myopia in chickens. METHODS: Eight-day-old chickens wore diffusers over one eye to induce deprivation myopia. A reference group (n = 8) was kept under office-like illuminance (500 lux) at a 10:14 light:dark cycle. Episodes of bright light (15 000 lux) were super-imposed on this background as follows....

  6. Survival Following Radiation and Androgen Suppression Therapy for Prostate Cancer in Healthy Older Men: Implications for Screening Recommendations

    International Nuclear Information System (INIS)

    Nguyen, Paul L.; Chen, Ming-Hui; Renshaw, Andrew A.; Loffredo, Marian; Kantoff, Philip W.; D'Amico, Anthony V.

    2010-01-01

    Purpose: The U.S. Preventive Services Task Force has recommended against screening men over 75 for prostate cancer. We examined whether older healthy men could benefit from aggressive prostate cancer treatment. Methods and Materials: 206 men with intermediate to high risk localized prostate cancer randomized to 70 Gy of radiation (RT) or RT plus 6 months of androgen suppression therapy (RT+AST) constituted the study cohort. Within subgroups stratified by Adult Comorbidity Evaluation-27 comorbidity score and age, Cox multivariable analysis was used to determine whether treatment with RT+AST as compared with RT was associated with a decreased risk of death. Results: Among healthy men (i.e., with mild or no comorbidity), 78 were older than the median age of 72.4 years, and in this subgroup, RT+AST was associated with a significantly lower risk of death on multivariable analysis (adjusted hazard ratio = 0.36 (95% CI=0.13-0.98), p = 0.046, with significantly lower 8-year mortality estimates of 16.5% vs. 41.4% (p = 0.011). Conversely, among men with moderate or severe comorbidity, 24 were older than the median age of 73, and in this subgroup, treatment with RT+AST was associated with a higher risk of death (adjusted hazard ratio = 5.2 (1.3-20.2), p = 0.018). Conclusion: In older men with mild or no comorbidity, treatment with RT+AST was associated with improved survival compared with treatment with RT alone, suggesting that healthy older men may derive the same benefits from prostate cancer treatment as younger men. We therefore suggest that prostate cancer screening recommendations should not be based on strict age cutoffs alone but should also take into account comorbidity.

  7. Overexpression of HepaCAM inhibits cell viability and motility through suppressing nucleus translocation of androgen receptor and ERK signaling in prostate cancer.

    Science.gov (United States)

    Song, Xuedong; Wang, Yin; Du, Hongfei; Fan, Yanru; Yang, Xue; Wang, Xiaorong; Wu, Xiaohou; Luo, Chunli

    2014-07-01

    HepaCAM is suppressed in a variety of human cancers, and involved in cell adhesion, growth, migration, invasion, and survival. However, the expression and function of HepaCAM in prostate cancer are still unknown. HepaCAM expression has been detected by RT-PCR, Western blotting and immunohistochemistry staining in prostate cell lines RWPE-1, LNCap, DU145, PC3, and in 75 human prostate tissue specimens, respectively. Meanwhile, the cell proliferation ability was detected by WST-8 assay. The role of HepaCAM in prostate cancer cell migration and invasion was examined by wound healing and transwell assay. And flow cytometry was used to observe the apoptosis of prostate cancer cells. Then we detected changes of Androgen Receptor translocation and ERK signaling using immunofluorescence staining and western blot after overexpression of HepaCAM. The HepaCAM expression was significantly down-regulated in prostate cancer tissues and undetected in prostate cancer cells. However, the low HepaCAM expression was not statistically associated with clinicopathological characteristics of prostate cancer. Overexpression of HepaCAM in prostate cancer cells decreased the cell proliferation, migration and invasion, and induced the cell apoptosis. Meanwhile, HepaCAM prevented the androgen receptor translocation from the cytoplasm to the nucleus and down-regulated the MAPK/ERK signaling. Our results suggested that HepaCAM acted as a tumor suppressor in prostate cancer. HepaCAM inhibited cell viability and motility which might be through suppressing the nuclear translocation of Androgen Receptor and down-regulating the ERK signaling. Therefore, it was indicated that HepaCAM may be a potential therapeutic target for prostate cancer. © 2014 Wiley Periodicals, Inc.

  8. A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy.

    Science.gov (United States)

    Tao, Youshan; Guo, Qian; Aihara, Kazuyuki

    2014-10-01

    Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

  9. Intermittent hypoxia suppression of growth hormone and insulin-like growth factor-I in the neonatal rat liver.

    Science.gov (United States)

    Cai, Charles; Ahmad, Taimur; Valencia, Gloria B; Aranda, Jacob V; Xu, Jiliu; Beharry, Kay D

    2018-03-08

    Extremely low gestational age neonates with chronic lung disease requiring oxygen therapy frequently experience fluctuations in arterial oxygen saturation or intermittent hypoxia (IH). These infants are at risk for multi-organ developmental delay, reduced growth, and short stature. The growth hormone (GH)/insulin-like growth factor-I (IGF-1) system, an important hormonal regulator of lipid and carbohydrate metabolism, promotes neonatal growth and development. We tested the hypothesis that increasing episodes of IH delay neonatal growth by influencing the GH/IGF-I axis. Newborn rats were exposed to 2, 4, 6, 8, 10, or 12 hypoxic episodes (12% O 2 ) during hyperoxia (50% O 2 ) from P0-P7, P0-P14 (IH), or allowed to recover from P7-P21 or P14-P21 (IHR) in room air (RA). RA littermates at P7, P14, and P21 served as RA controls; and groups exposed to hyperoxia only (50% O 2 ) served as zero IH controls. Histopathology of the liver; hepatic levels of GH, GHBP, IGF-I, IGFBP-3, and leptin; and immunoreactivities of GH, GHR, IGF-I and IGF-IR were determined. Pathological findings of the liver, including cellular swelling, steatosis, necrosis and focal sinusoid congestion were seen in IH, and were particularly severe in the P7 animals. Hepatic GH levels were significantly suppressed in the IH groups exposed to 6-12 hypoxic episodes per day and were not normalized during IHR. Deficits in the GH levels were associated with reduced body length and increase body weight during IHR suggesting increased adiposity and catchup fat. Catchup fat was also associated with elevations in GHBP, IGF-I, leptin. IH significantly impairs hepatic GH/IGF-1 signaling during the first few weeks of life, which is likely responsible for hepatic GH resistance, increased body fat, and hepatic steatosis. These hormonal perturbations may contribute to long-term organ and body growth impairment, and metabolic dysfunction in preterm infants experiencing frequent IH and/or apneic episodes. Copyright © 2018

  10. Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Lin, Ting-Wei; Chang, Ying-Hsu; Kuo, Yung-Chia; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Lee, Li-Yu; Ma, Wen-Lung; Lin, Chun-Cheng; Wu, Wen-Guey

    2017-09-19

    Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

  11. Suppressing methane emission and global warming potential from rice fields through intermittent drainage and green biomass amendment

    NARCIS (Netherlands)

    Haque, Md. M.; Biswas, J. C.; Kim, S. Y.; Kim, P. J.

    Winter cover crops are recommended to improve soil quality and carbon sequestration, although their use as green manure can significantly increase methane (CH4) emission from paddy soils. Soil management practices can be used to reduce CH4 emission from paddy soils, but intermittent drainage is

  12. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  13. Androgen receptor (AR) degradation enhancer ASC-J9® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth.

    Science.gov (United States)

    Cheng, Max A; Chou, Fu-Ju; Wang, Keliang; Yang, Rachel; Ding, Jie; Zhang, Qiaoxia; Li, Gonghui; Yeh, Shuyuan; Xu, Defeng; Chang, Chawnshang

    2018-03-28

    ASC-J9 ® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC 50 ) of ASC-J9 ® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC 50 values for ASC-J9 ® increased with increasing cell confluency. The IC 50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9 ® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9 ® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9 ® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9 ® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

    Science.gov (United States)

    Dejima, Takashi; Imada, Kenjiro; Takeuchi, Ario; Shiota, Masaki; Leong, Jeffrey; Tombe, Tabitha; Tam, Kevin; Fazli, Ladan; Naito, Seiji; Gleave, Martin E; Ong, Christopher J

    2017-02-01

    LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Androgen suppression plus radiation vs. radiation alone for patients with D1 (pN+) adenocarcinoma of the prostate (results based on a national prospective randomized trial RTOG 85-31)

    International Nuclear Information System (INIS)

    Lawton, Colleen A.; Pajak, Thomas F.; Byhardt, Roger; Sause, William T.; Hanks, Gerald E.; Russell, Anthony H.; Rotman, Marvin; Porter, Arthur; McGowan, David G.; DelRowe, John D.; Pilepich, Miljenko V.

    1996-01-01

    Purpose/Objective: To evaluate the effect of immediate androgen suppression in conjunction with standard external beam irradiation versus radiation alone on a group of pathologically staged lymph node positive patients with adenocarcinoma of the prostate. Methods and Materials: A national prospective randomized trial of standard external beam irradiation plus immediate androgen suppression vs. external beam irradiation alone was initiated in 1985 for patients with locally advanced adenocarcinoma of the prostate. One hundred seventy two of the patients in this trial had biopsy proven pathologically involved lymph nodes. Ninety Eight of these patients received radiation plus the immediate androgen suppression (LHRH agonist) while 74 received radiation alone with hormonal manipulation instituted at the time of relapse. Results: With a median followup of 3.9 years actuarial progression free survival at five years was 56% for the patients who received radiation plus immediate LHRH agonist versus 33% patients who received radiation alone with hormonal manipulation at relapse (p = .0009). Since all of these patients had locally advanced disease (i.e. pathologically positive lymph nodes) stage does not explain this difference in outcome and gleason grade was not statistically different between the two groups. Although not statistically different at this point both overall survival and cause specific survival favor radiation and immediate LHRH agonist. Actuarial overall survival at five years for the radiation and LHRH group was 69% versus 59% for the radiation alone group who received androgen suppression at relapse. Actuarial cause specific survival at five years was 84% for the radiation and immediate LHRH agonist group and 73% for the radiation alone group. Conclusion: Patients with adenocarcinoma of the prostate and pathologically involved pelvic lymph nodes (pN+ or clinical stage D 1 ) should be seriously considered for external beam irradiation plus immediate

  16. Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis.

    Science.gov (United States)

    Hsu, Cheng-Lung; Liu, Jai-Shin; Wu, Po-Long; Guan, Hong-Hsiang; Chen, Yuh-Ling; Lin, An-Chi; Ting, Huei-Ju; Pang, See-Tong; Yeh, Shauh-Der; Ma, Wen-Lung; Chen, Chung-Jung; Wu, Wen-Guey; Chang, Chawnshang

    2014-12-01

    Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5α-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  17. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial

    International Nuclear Information System (INIS)

    Denham, James W.; Steigler, Allison; Joseph, David; Lamb, David S.; Spry, Nigel A.; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett

    2015-01-01

    Background: The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. Methods: We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS ± 18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Results: Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p < 0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. Conclusion: RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration

  18. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

    Science.gov (United States)

    Denham, James W; Steigler, Allison; Joseph, David; Lamb, David S; Spry, Nigel A; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett; Oldmeadow, Christopher; Holliday, Elizabeth G; Attia, John

    2015-06-01

    The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (pRDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Effect of combined treatment with salvage radiotherapy plus androgen suppression on quality of life in patients with recurrent prostate cancer after radical prostatectomy

    International Nuclear Information System (INIS)

    Pearce, Andrew; Choo, Richard; Danjoux, Cyril; Morton, Gerard; Loblaw, D. Andrew; Szumacher, Ewa; Cheung, Patrick; Deboer, Gerrit; Chander, Sarat

    2006-01-01

    Purpose: To examine the effect of salvage radiotherapy (RT) plus 2-year androgen suppression (AS) on quality of life (QOL). Methods and Materials: A total of 74 patients with biopsy-proven local recurrence or PSA relapse after radical prostatectomy were treated with salvage RT plus 2-year AS, as per a phase II study. Quality of life was prospectively assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-Item Version 3.0 with the added prostate cancer-specific module at baseline and predefined follow-up visits. Results: Patients experienced a significant increase in bowel dysfunction (23%) by the end of RT (p < 0.0001). This bowel dysfunction improved after RT but remained slightly elevated (5-10%) throughout the 2-year AS period. This extent of residual bowel dysfunction would be considered of minimal clinical importance. A similar, but less pronounced, pattern of change did occur for urinary dysfunction. Erectile function showed no change during RT, but had an abrupt decline (10%) with initiation of AS that was of moderate clinical significance (p < 0.01). None of the other QOL domains demonstrated a persistent, significant change from baseline that would be considered of major clinical significance. Conclusion: The combined treatment with salvage RT plus 2-year AS had relatively minor long-term effects on QOL

  20. Hemoglobin levels do not predict biochemical outcome for localized prostate cancer treated with neoadjuvant androgen-suppression therapy and external-beam radiotherapy

    International Nuclear Information System (INIS)

    Pai, Howard Huaihan; Ludgate, Charles; Pickles, Tom; Paltiel, Chuck M.Sc.; Agranovich, Alex; Berthelet, Eric; Duncan, Graeme; Kim-Sing, Charmaine; Kwan, Winkle; Lim, Jan; Liu, Mitchell; Tyldesley, Scott

    2006-01-01

    Purpose: To investigate whether hemoglobin (Hb) levels affect outcome in men with localized prostate adenocarcinoma (LPA) treated with neoadjuvant androgen-suppression therapy (NAST) and external-beam radiotherapy (EBRT). Methods and Materials: A total of 563 men with LPA treated with NAST (median: 5.3 months) and EBRT who had Hb levels during treatment were retrospectively reviewed. Patient, tumor, and treatment variables, including the following Hb variables, were subjected to univariate and multivariable analyses to identify factors that predict biochemical control (bNED) and overall survival (OS): pre-EBRT Hb, Hb nadir during EBRT, and change in Hb from pre-EBRT to nadir during EBRT. Results: Median PSA follow-up was 4.25 years. Forty-nine percent of men were anemic during EBRT, with a median Hb of 13.4 g/dL, and 68% experienced a decline in Hb from pre-EBRT to during EBRT of median 0.6 g/dL. Five-year Nadir + 2 bNED and OS rates were similar for anemic and nonanemic patients during EBRT. High percent-positive biopsies, PSA and Gleason score, and use of AA monotherapy predicted worse bNED. High stage and age predicted worse OS. Hb variables were not predictive of bNED or OS. Conclusions: Anemia is a common side effect of NAST and is usually mild. Hb levels, however, do not predict biochemical control or survival

  1. The effect of intense intermittent training with and without taking vitamin E on mRNA expression of p53/PTEN tumor suppressing genes in prostate glands of male rats

    Directory of Open Access Journals (Sweden)

    Mohammad Esmaeil Afzalpour

    2016-11-01

    Full Text Available Physical activity and diet are the most important modifiable determinants of cancer risk. The objective of this study was to examine the effect of intense intermittent training with and without taking vitamin E on expression of p53 and PTEN tumor suppressing genes in the prostate gland of male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: [1] control (CON, n = 10, [2] sham (S, n = 10, [3] intense intermittent training (IIT, n = 10, [4] intense intermittent training + vitamin E (IIT + VE, n = 10, [5] vitamin E (VE, n = 10. Protocol of this study was implemented for 6 days per week for 6 weeks, with observing the overload principle on the motorized treadmill. After implementing training protocol, expression rate of p53 and PTEN genes reduced significantly (p<0.000, p<0.031, respectively. Taking vitamin E with intermittent training caused significant reduction in p53 expression (p<0.013, while it caused significant increase in expression of PTEN (p<0.035. These results showed that intense intermittent training reduces expression of p53 and PTEN tumor suppressing genes and taking supplementation vitamin E along with this type of training could cause different effects in expression of these tumor suppressor genes.

  2. Effect of androgen suppression on hemoglobin in prostate cancer patients undergoing salvage radiotherapy plus 2-year buserelin acetate for rising PSA after surgery

    International Nuclear Information System (INIS)

    Chander, Sarat; Choo, Richard; Danjoux, Cyril; Morton, Gerard; Pearse, Andrew; Deboer, Gerrit; Szumacher, Ewa; Loblaw, Andrew; Cheung, Patrick; Woo, Tony

    2005-01-01

    Purpose: To examine the effect of 2-year androgen suppression (AS) on the pattern and extent of hemoglobin (Hb) change. Methods and Materials: The basis of this report was a Phase II study evaluating a combined treatment of salvage radiotherapy plus 2-year AS for a rising prostate-specific antigen level after surgery. Patients had laboratory tests performed, including Hb and serum testosterone, and answered a quality-of-life questionnaire (European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire 30 item) at regular intervals during the AS and post-AS period. The pattern and extent of the change in Hb was analyzed in relation to the testosterone level. The clinical significance of the Hb change was evaluated with a correlation analysis between Hb and the three specific domains of the questionnaire (Global Health Status, Physical Functioning, and Fatigue). Results: Of a total of 74 accrued patients, 69 were identified as eligible for this report. The median patient age was 70 years. The median follow-up was 38.6 months. The mean Hb was 150.7 g/L at baseline and declined with radiotherapy by 5.9 g/L. The maximal Hb drop during AS was 16.0 g/L (p <0.0001), occurring at 16 months after the initiation of AS. Hb recovery in the post-AS period was slow. The decline and recovery of the mean Hb and hematocrit followed that of testosterone. The three quality-of-life domains did not show any significant correlation with the change in Hb. Conclusion: Two-year AS resulted in a statistically significant drop in the mean Hb, but had no clinically apparent adverse effect. The pattern of Hb change was similar to that of testosterone change

  3. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    likely to be mechanistic drivers behind the observed tumor growth suppression. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Energy intermittency

    CERN Document Server

    Sorensen, Bent

    2014-01-01

    The first book to consider intermittency as a key point of an energy system, Energy Intermittency describes different levels of variability for traditional and renewable energy sources, presenting detailed solutions for handling energy intermittency through trade, collaboration, demand management, and active energy storage. Addressing energy supply intermittency systematically, this practical text:Analyzes typical time-distributions and intervals between episodes of demand-supply mismatch and explores their dependence on system layouts and energy source characteristicsSimulates scenarios regar

  5. The early toxicity of escalated versus standard dose conformal radiotherapy with neo-adjuvant androgen suppression for patients with localised prostate cancer: Results from the MRC RT01 trial (ISRCTN47772397)

    International Nuclear Information System (INIS)

    Dearnaley, David P.; Sydes, Matthew R.; Langley, Ruth E.; Graham, John D.; Huddart, Robert A.; Syndikus, Isabel; Matthews, John H.L.; Scrase, Christopher D.; Jose, Chakiath C.; Logue, John; Stephens, Richard J.

    2007-01-01

    Background: Five-year disease-free survival rates for localised prostate cancer following standard doses of conventional radical external beam radiotherapy are around 80%. Conformal radiotherapy (CFRT) raises the possibility that radiotherapy doses can be increased and long-term efficacy outcomes improved, with safety an important consideration. Methods: MRC RT01 is a randomised controlled trial of 862 men with localised prostate cancer comparing Standard CFRT (64 Gy/32 f) versus Escalated CFRT (74 Gy/37 f), both administered with neo-adjuvant androgen suppression. Early toxicity was measured using physician-reported instruments (RTOG, LENT/SOM, Royal Marsden Scales) and patient-reported questionnaires (MOS SF-36, UCLA Prostate Cancer Index, FACT-P). Results: Overall early radiotherapy toxicity was similar, apart from increased bladder, bowel and sexual toxicity, in the Escalated Group during a short immediate post-radiotherapy period. Toxicity in both groups had abated by week 12. Using RTOG Acute Toxicity scores, cumulative Grade ≥2 bladder and bowel toxicity was 38% and 30% for Standard Group and 39% and 33% in Escalated Group, respectively. Urinary frequency (Royal Marsden Scale) improved in both groups from pre-androgen suppression to 6 months post-radiotherapy (p < 0.001), but bowel and sexual functioning deteriorated. This pattern was supported by patient-completed assessments. Six months after starting radiotherapy the incidence of RTOG Grade ≥2 side-effects was low (<1%); but there were six reports of rectal ulceration (6 Escalated Group), six haematuria (5 Escalated Group) and eight urethral stricture (6 Escalated Group). Conclusions: The two CFRT schedules with neo-adjuvant androgen suppression have broadly similar early toxicity profiles except for the immediate post-RT period. At 6 months and compared to before hormone therapy, bladder symptoms improved, whereas bowel and sexual symptoms worsened. These assessments of early treatment safety will be

  6. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Vuky, Jacqueline, E-mail: vukyja@ohsu.edu [Section of Community Hematology/Oncology, Knight Cancer Institute, Oregon Health Sciences University, Portland, OR (United States); Pham, Huong T. [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Warren, Sarah; Douglass, Erika [Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA (United States); Badiozamani, Kasra [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States); Madsen, Berit; Hsi, Alex [Peninsula Cancer Center, Poulsbo, WA (United States); Song Guobin [Section of Hematology/Oncology and Radiation Oncology, Virginia Mason Medical Center, Seattle, WA (United States)

    2012-03-15

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  7. Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

    International Nuclear Information System (INIS)

    Vuky, Jacqueline; Pham, Huong T.; Warren, Sarah; Douglass, Erika; Badiozamani, Kasra; Madsen, Berit; Hsi, Alex; Song Guobin

    2012-01-01

    Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes. Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28–40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be

  8. Characterizations of Factors Affecting Androgen Receptor Transcriptional Regulation in Prostate Cancer

    National Research Council Canada - National Science Library

    Garabedian, Michael

    2003-01-01

    .... Expression of ART-27 in LNCaP cells, an androgen-dependent prostate cancer cell line, reduces androgen-mediated cellular proliferation, suggesting that ART-27 plays a role in suppressing cell growth...

  9. Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice.

    Science.gov (United States)

    Kelly, Daniel M; Nettleship, Joanne E; Akhtar, Samia; Muraleedharan, Vakkat; Sellers, Donna J; Brooke, Jonathan C; McLaren, David S; Channer, Kevin S; Jones, T Hugh

    2014-07-30

    Non-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood. Testicular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis. Hepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered. An action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Intermittent hydronephrosis

    International Nuclear Information System (INIS)

    Knop, J.; Vogel, H.; Hupe, W.

    1981-01-01

    An intermittent hydronephrosis was observed in a 40-year old patient. This disease pattern is due to an incongruity between the formation of urine and the transport capacity in the ureteropelvic junction. The latent impediment of flow becomes manifest with increased urine secretion. Irreversible renal damage can be the result of the repeatedly occurring hydronephrotic crises. (orig.) [de

  11. Intermittency '93

    International Nuclear Information System (INIS)

    Bialas, A.

    1993-01-01

    The existing data definitely indicate the existence of intermittency, i.e. of self similar structures in the systems of particles created in high-energy collisions. The effect seems universal: it was found in most of the processes investigated and its measures parameters depend only weakly (if at all) on the process in question. Strong HBT effect was found, suggesting that intermittency is related to space-time structure of the pion source rather than to detailed momentum structure of the production amplitudes. There are indications that this space time structure may be fractal, but more data is needed to establish this. The theoretical explanation remains obscure: it seems that both parton cascade and hadronization play an important role. Their interrelation, however, remains a mystery. 5 figs., 19 refs

  12. Androgen insensitivity syndrome: gonadal androgen receptor activity

    International Nuclear Information System (INIS)

    Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

    1984-01-01

    To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

  13. Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

    Directory of Open Access Journals (Sweden)

    Day Wanda V

    2005-04-01

    Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

  14. Androgen excess: Investigations and management.

    Science.gov (United States)

    Lizneva, Daria; Gavrilova-Jordan, Larisa; Walker, Walidah; Azziz, Ricardo

    2016-11-01

    Androgen excess (AE) is a key feature of polycystic ovary syndrome (PCOS) and results in, or contributes to, the clinical phenotype of these patients. Although AE will contribute to the ovulatory and menstrual dysfunction of these patients, the most recognizable sign of AE includes hirsutism, acne, and androgenic alopecia or female pattern hair loss (FPHL). Evaluation includes not only scoring facial and body terminal hair growth using the modified Ferriman-Gallwey method but also recording and possibly scoring acne and alopecia. Moreover, assessment of biochemical hyperandrogenism is necessary, particularly in patients with unclear or absent hirsutism, and will include assessing total and free testosterone (T), and possibly dehydroepiandrosterone sulfate (DHEAS) and androstenedione, although these latter contribute limitedly to the diagnosis. Assessment of T requires use of the highest quality assays available, generally radioimmunoassays with extraction and chromatography or mass spectrometry preceded by liquid or gas chromatography. Management of clinical hyperandrogenism involves primarily either androgen suppression, with a hormonal combination contraceptive, or androgen blockade, as with an androgen receptor blocker or a 5α-reductase inhibitor, or a combination of the two. Medical treatment should be combined with cosmetic treatment including topical eflornithine hydrochloride and short-term (shaving, chemical depilation, plucking, threading, waxing, and bleaching) and long-term (electrolysis, laser therapy, and intense pulse light therapy) cosmetic treatments. Generally, acne responds to therapy relatively rapidly, whereas hirsutism is slower to respond, with improvements observed as early as 3 months, but routinely only after 6 or 8 months of therapy. Finally, FPHL is the slowest to respond to therapy, if it will at all, and it may take 12 to 18 months of therapy for an observable response. Copyright © 2016. Published by Elsevier Ltd.

  15. Intermittent hyperthyreosis

    International Nuclear Information System (INIS)

    Sulman, F.G.; Tal, E.; Pfeifer, Y.; Superstine, E.

    1975-01-01

    Intermittent hyperthyreosis occurs under various forms of stress, especially heat stress. The clinician may diagnose such cases as masked or apathetic hyperthyroidism or 'forme fruste' hyperthyreosis or thyroid autonomy. As most routine and standard tests may here yield inconsistent results, it is the patients' anamnesis which may provide the clue. Our Bioclimatology Unit has now seen over 100 cases in which thyroid hypersensitivity towards heat was the most prominent syndrome: 10-15% of weather-sensitive patients are affected. The patients complain before or during heat spells of such contradictory symptoms as insomnia, irritability, tension, tachycardia, palpitations, precordial pain, dyspnoe, flushes with sweating or chills, tremor, abdominal pain or diarrhea, polyuria or pollakisuria, weight loss in spite of ravenous appetite, fatigue, exhaustion, depression, adynamia, lack of concentration and confusion. Determination of urinary neurohormones allows a differential diagnosis, intermittent hyperthyreosis being characterized by three cardinal symptoms: tachycardia - every case with more than 80 pulse beats being suspect (not specific); urinary histamine - every case excreting more than 90 μg/day being suspect. Again the drawback of this test is its lack of specificity, as histamine may also be increased in cases of allergy and spondylitis; urinary thyroxine - every case excreting more than 20 μg/day T-4 being suspect. This is the only specific test. Therapy should make use of lithium carbonate and betablockers. Propyl thiouracil is rarely required. (orig.) [de

  16. Tumor Volume Changes on 1.5 Tesla Endorectal MRI During Neoadjuvant Androgen Suppression Therapy for Higher-Risk Prostate Cancer and Recurrence in Men Treated Using Radiation Therapy Results of the Phase II CALGB 9682 Study

    International Nuclear Information System (INIS)

    D'Amico, Anthony V.; Halabi, Susan; Tempany, Clare; Titelbaum, David; Philips, George K.; Loffredo, Marian; McMahon, Elizabeth; Sanford, Ben; Vogelzang, Nicholas J.; Small, Eric J.

    2008-01-01

    Purpose: We prospectively determined whether the change in tumor volume (TV) during 2 months of neoadjuvant androgen suppression therapy (nAST) measured using conventional 1.5 Tesla endorectal magnetic resonance imaging (eMRI) was associated with the risk of recurrence after radiation (RT) and 6 months of AST. Patients and Methods: Between 1997 and 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered. Fifteen were found to be ineligible and the institutional MR radiologist could not assess the TV in 32, leaving 133 for analysis. Multivariable Cox regression analysis was used to assess whether a significant association existed between eMRI-defined TV progression during nAST and time to recurrence adjusting for prostate-specific antigen (PSA) level, Gleason score (8 to 10 or 7 vs. 6 or less) and stage (T3 vs. T1-2). Results: After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a significant increase in the risk of PSA failure (HR, 2.3 [95% CI, 1.1-4.5; p = 0.025) in men with eMRI-defined TV progression during nAST. Specifically, adjusted estimates of PSA failure were significantly higher (p = 0.032) in men with, compared with men without, eMRI-defined TV progression reaching 38% vs. 19%, respectively, by 5 years. Conclusion: Eradicating intraprostatic hormone refractory prostate cancer (HRPC) by maximizing local control and randomized trials assessing whether survival is improved when agents active against HRPC are combined with maximal local therapy are needed in men who progress based on eMRI during nAST

  17. The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

    International Nuclear Information System (INIS)

    Chuu, Chih-pin; Chen, Rou-Yu; Hiipakka, Richard A.; Kokontis, John M.; Warner, Karen V.; Xiang, Jialing; Liao, Shutsung

    2007-01-01

    T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells

  18. Androgenic anabolic steroids also impair right ventricular function.

    Science.gov (United States)

    Kasikcioglu, Erdem; Oflaz, Huseyin; Umman, Berrin; Bugra, Zehra

    2009-05-01

    Chronic anabolic steroid use suppresses left ventricular functions. However, there is no information regarding the chronic effects of anabolic steroids on right ventricular function which also plays a key role in global cardiac function. The main objective of the present study was to investigate the effects of androgenic anabolic steroids usage among athletes on remodeling the right part of the heart. Androgenic-anabolic steroids-using bodybuilders had smaller diastolic velocities of both ventricles than drug-free bodybuilders and sedentary counterparts. This study shows that androgenic anabolic steroids-using bodybuilders exhibited depressed diastolic functions of both ventricles.

  19. A Counterregulatory Mechanism Impacting Androgen Suppression Therapy

    Science.gov (United States)

    2016-03-01

    improving public knowledge, attitudes , skills, and abilities; • changing behavior, practices, decision making, policies (including regulatory policies), or...colytic capacity of tumor cells in the presence of oxygen (69). Consequently, caution must be exercised in extrap- olating metabolic findings in...increased proliferation or enlargement in response to hypocalce- mia induced by a low calcium/vitamin D diet . These studies iden- tified Gcm2, a gene

  20. A Counterregulatory Mechanism Impacting Androgen Suppression Therapy

    Science.gov (United States)

    2016-08-01

    Present position: Student, Hochschule Mannheim, Mannheim, Germany 2015 - 2015 Verena Martinez Rodriguez, B.Sc., Rotation Student Study area: Hedgehog ...and Childhood, 8th edition Philadelphia: Elsevier Mosby; 2014:1076-1102. 14. Bornstein SR, Wilson DB. Anatomy of the adrenal cortex. In: Martini L...supporting a patho- genic association between aberrant hedgehog signaling and the- comaefibroma development. Abundant expression of GATA4 and its cofactor

  1. Molecular basis of androgen insensitivity

    NARCIS (Netherlands)

    Brinkmann, A.; Jenster, G.; Ris-Stalpers, C.; van der Korput, H.; Brüggenwirth, H.; Boehmer, A.; Trapman, J.

    1996-01-01

    Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the

  2. Pharmacodynamics of selective androgen receptor modulators.

    Science.gov (United States)

    Yin, Donghua; Gao, Wenqing; Kearbey, Jeffrey D; Xu, Huiping; Chung, Kiwon; He, Yali; Marhefka, Craig A; Veverka, Karen A; Miller, Duane D; Dalton, James T

    2003-03-01

    The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

  3. Ovarian overproduction of androgens

    Science.gov (United States)

    ... the body's testosterone. Tumors of the ovaries and polycystic ovary syndrome (PCOS) can both cause too much androgen production. ... come back after they have been removed. In polycystic ovary syndrome, the following measures can reduce symptoms caused by ...

  4. Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

    Science.gov (United States)

    Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

    2016-01-01

    Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

  5. Androgens and alopecia.

    Science.gov (United States)

    Kaufman, Keith D

    2002-12-30

    Androgens have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Androgenetic alopecia, referred to as male pattern hair loss (MPHL) in men and female pattern hair loss (FPHL) in women, is due to the progressive miniaturization of scalp hair. Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men. The development of finasteride, a type 2-selective 5alphaR inhibitor, further advanced our understanding of the role of DHT in the pathophysiology of scalp alopecia. Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies. In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL. Histopathological evaluation of scalp biopsies confirmed that finasteride treatment produced no benefit on scalp hair in these women. These findings suggest that MPHL and FPHL are distinct clinical entities, with disparate pathophysiologies. Studies that elucidate the molecular mechanisms by which androgens regulate hair growth would provide greater understanding of these differences. Copyright 2002 Elsevier Science Ireland Ltd.

  6. Androgenic alopecia; the risk–benefit ratio of Finasteride

    Directory of Open Access Journals (Sweden)

    David L. Rowland

    2018-04-01

    Full Text Available Finasteride is currently approved and largely used as a therapeutic option for androgenetic alopecia. Apparently a safe drug and effective at the onset, several concerns appeared over time regarding the frequency and magnitude of finasteride adverse effects, which in some cases seem to be even irreversible. This paper presents administration of finasteride in androgenic alopecia from two distinct perspectives. On one hand, androgenic alopecia is a condition that affects especially the self-image and esteem, aspects that are subjective, namely changeable and thus relative. On the other hand, this condition presents a multifactorial etiology, androgens being only in part involved. In addition, androgens have their own physiological roles within the body, so that any androgenic suppression should be carefully advised. Yet, adverse effects induced by Finasteride are only in part documented and treatable. Finally, alternative therapeutic approaches (like topical finasteride become available, so that the oral administration of Finasteride for androgenic alopecia should be in our opinion reevaluated. As a conclusion, a very detailed and informed discussion should take place with such patients accepting to start a therapy with finasteride for androgenic alopecia.

  7. Effect of propofol on androgen receptor activity in prostate cancer cells.

    Science.gov (United States)

    Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

    2017-08-15

    Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Androgen regulation of the androgen receptor coregulators

    International Nuclear Information System (INIS)

    Urbanucci, Alfonso; Waltering, Kati K; Suikki, Hanna E; Helenius, Merja A; Visakorpi, Tapio

    2008-01-01

    The critical role of the androgen receptor (AR) in the development of prostate cancer is well recognized. The transcriptional activity of AR is partly regulated by coregulatory proteins. It has been suggested that these coregulators could also be important in the progression of prostate cancer. The aim of this study was to identify coregulators whose expression is regulated by either the androgens and/or by the expression level of AR. We used empty vector and AR cDNA-transfected LNCaP cells (LNCaP-pcDNA3.1, and LNCaP-ARhi, respectively), and grew them for 4 and 24 hours in the presence of dihydrotestosterone (DHT) at various concentrations. The expression of 25 AR coregulators (SRC1, TIF2, PIAS1, PIASx, ARIP4, BRCA1, β-catenin, AIB3, AIB1, CBP, STAT1, NCoR1, AES, cyclin D1, p300, ARA24, LSD1, BAG1L, gelsolin, prohibitin, JMJD2C, JMJD1A, MAK, PAK6 and MAGE11) was then measured by using real-time quantitative RT-PCR (Q-RT-PCR). Five of the coregulators (AIB1, CBP, MAK, BRCA1 and β-catenin) showed more than 2-fold induction and 5 others (cyclin D1, gelsolin, prohibitin, JMJD1A, and JMJD2C) less than 2-fold induction. Overexpression of AR did not affect the expression of the coregulators alone. However, overexpression of AR enhanced the DHT-stimulated expression of MAK, BRCA1, AIB1 and CBP and reduced the level of expression of β-catenin, cyclinD1 and gelsolin. In conclusion, we identified 5 coactivators whose expression was induced by androgens suggesting that they could potentiate AR signaling. Overexpression of AR seems to sensitize cells for low levels of androgens

  9. Intermittent search strategies

    Science.gov (United States)

    Bénichou, O.; Loverdo, C.; Moreau, M.; Voituriez, R.

    2011-01-01

    This review examines intermittent target search strategies, which combine phases of slow motion, allowing the searcher to detect the target, and phases of fast motion during which targets cannot be detected. It is first shown that intermittent search strategies are actually widely observed at various scales. At the macroscopic scale, this is, for example, the case of animals looking for food; at the microscopic scale, intermittent transport patterns are involved in a reaction pathway of DNA-binding proteins as well as in intracellular transport. Second, generic stochastic models are introduced, which show that intermittent strategies are efficient strategies that enable the minimization of search time. This suggests that the intrinsic efficiency of intermittent search strategies could justify their frequent observation in nature. Last, beyond these modeling aspects, it is proposed that intermittent strategies could also be used in a broader context to design and accelerate search processes.

  10. Concept and viability of androgen annihilation for advanced prostate cancer.

    Science.gov (United States)

    Mohler, James L

    2014-09-01

    There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

  11. Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

    Science.gov (United States)

    Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

    2018-03-20

    The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

  12. Androgen receptor drives cellular senescence.

    Directory of Open Access Journals (Sweden)

    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  13. Intermittency in branching models

    International Nuclear Information System (INIS)

    Chiu, C.B.; Texas Univ., Austin; Hwa, R.C.; Oregon Univ., Eugene

    1990-01-01

    The intermittency properties of three branching models have been investigated. The factorial moments show power-law behavior as function of small rapidity width. The slopes and energy dependences reveal different characteristics of the models. The gluon model has the weakest intermittency. (orig.)

  14. Intermittent degradation and schizotypy

    Directory of Open Access Journals (Sweden)

    Matthew W. Roché

    2015-06-01

    Full Text Available Intermittent degradation refers to transient detrimental disruptions in task performance. This phenomenon has been repeatedly observed in the performance data of patients with schizophrenia. Whether intermittent degradation is a feature of the liability for schizophrenia (i.e., schizotypy is an open question. Further, the specificity of intermittent degradation to schizotypy has yet to be investigated. To address these questions, 92 undergraduate participants completed a battery of self-report questionnaires assessing schizotypy and psychological state variables (e.g., anxiety, depression, and their reaction times were recorded as they did so. Intermittent degradation was defined as the number of times a subject’s reaction time for questionnaire items met or exceeded three standard deviations from his or her mean reaction time after controlling for each item’s information processing load. Intermittent degradation scores were correlated with questionnaire scores. Our results indicate that intermittent degradation is associated with total scores on measures of positive and disorganized schizotypy, but unrelated to total scores on measures of negative schizotypy and psychological state variables. Intermittent degradation is interpreted as potentially derivative of schizotypy and a candidate endophenotypic marker worthy of continued research.

  15. A practical dexamethasone suppression test to evaluate hirsute women

    International Nuclear Information System (INIS)

    Wu, C.H.

    1982-01-01

    Fifty-five hirsute women were subjected to a 2-week dexamethasone (DXM) suppression test. The pre- and post-DXM plasma dehydroepiandrosteronesulfate (DS) and testosterone (T) were measured by radioimmunoassay to define the source of androgen excess in hirsute women. Four patients (7%) failed to have adequate adrenal suppression due to failure in medication. Among the 51 patients with adequate adrenal suppression, the source of androgen excess was clearly defined in 48 patients (94%). Seventeen patients (33%) showed ovarian source, 13 patients (26%) had adrenal source, while 18 patients (35%) revealed a mixed adrenal and ovarian source. Normal baseline DS and T levels were noted in 22% of hirsute women and more than half (55%) of them had ovarian androgen excess. Even in 17 patients with normal DS and elevated T, 6 patients (36%) suggested adrenal androgen excess. The source of androgen excess in hirsute women seems evenly distributed among the ovarian, the adrenal, and the mixed group. (author)

  16. Intermittent Explosive Disorder

    Directory of Open Access Journals (Sweden)

    Lut Tamam

    2011-09-01

    Full Text Available Intermittent explosive disorder is an impulse control disorder characterized by the occurrence of discrete episodes of failure to resist aggressive impulses that result in violent assault or destruction of property. Though the prevalence intermittent explosive disorder has been reported to be relatively rare in frontier studies on the field, it is now common opinion that intermittent explosive disorder is far more common than previously thought especially in clinical psychiatry settings. Etiological studies displayed the role of both psychosocial factors like childhood traumas and biological factors like dysfunctional neurotransmitter systems and genetics. In differential diagnosis of the disorder, disorders involving agression as a symptom such as alcohol and drug intoxication, antisocial and borderline personality disorders, personality changes due to general medical conditions and behavioral disorder should be considered. A combination of pharmacological and psychotherapeutic approaches are suggested in the treatment of the disorder. This article briefly reviews the historical background, diagnostic criteria, epidemiology, etiology and treatment of intermittent explosive disorder.

  17. Intermittent heating of buildings

    Energy Technology Data Exchange (ETDEWEB)

    Kohonen, K

    1983-02-01

    Conditions for intermittent heating of buildings are considered both theoretically and experimentally. Thermal behaviour of buildings adn rooms in intermittent heating is simulated by a program based on the convective heat balance equation and by simplified RC-models. The preheat times and the heating energy savings compared with continuous heating are presented for typical lightweight, mediumweight and heavyweight classroom and office modules. Formulaes for estimating the oversizing of the radiator network, the maximum heat output of heat exchangers in district heating and the efficiency of heating boilers in intermittent heating are presented. The preheat times and heating energy savings with different heating control systems are determined also experimentally in eight existing buildings. In addition some principles for the planning and application of intermittent heating systems are suggested.

  18. Optimal intermittent search strategies

    International Nuclear Information System (INIS)

    Rojo, F; Budde, C E; Wio, H S

    2009-01-01

    We study the search kinetics of a single fixed target by a set of searchers performing an intermittent random walk, jumping between different internal states. Exploiting concepts of multi-state and continuous-time random walks we have calculated the survival probability of a target up to time t, and have 'optimized' (minimized) it with regard to the transition probability among internal states. Our model shows that intermittent strategies always improve target detection, even for simple diffusion states of motion

  19. Ectopic adrenal rests in congenital adrenal hyperplasia as a cause of androgen excess after adrenalectomy detected by pelvic venous sampling.

    NARCIS (Netherlands)

    Claahsen-van der Grinten, H.L.; Stikkelbroeck, M.M.L.; Bulten, J.; Heyer, M. den

    2013-01-01

    BACKGROUND: Patients with classic congenital adrenal hyperplasia (CAH) due to CYP21 deficiency are treated with supraphysiological doses of glucocorticoids to suppress elevated androgen production. This implies also side effects of high-dose glucocorticoids, possibly leading to iatrogenic Cushing's

  20. Optimal intermittent search strategies

    Energy Technology Data Exchange (ETDEWEB)

    Rojo, F; Budde, C E [FaMAF, Universidad Nacional de Cordoba, Ciudad Universitaria, X5000HUA Cordoba (Argentina); Wio, H S [Instituto de Fisica de Cantabria, Universidad de Cantabria and CSIC E-39005 Santander (Spain)

    2009-03-27

    We study the search kinetics of a single fixed target by a set of searchers performing an intermittent random walk, jumping between different internal states. Exploiting concepts of multi-state and continuous-time random walks we have calculated the survival probability of a target up to time t, and have 'optimized' (minimized) it with regard to the transition probability among internal states. Our model shows that intermittent strategies always improve target detection, even for simple diffusion states of motion.

  1. Intermittency and random matrices

    Science.gov (United States)

    Sokoloff, Dmitry; Illarionov, E. A.

    2015-08-01

    A spectacular phenomenon of intermittency, i.e. a progressive growth of higher statistical moments of a physical field excited by an instability in a random medium, attracted the attention of Zeldovich in the last years of his life. At that time, the mathematical aspects underlying the physical description of this phenomenon were still under development and relations between various findings in the field remained obscure. Contemporary results from the theory of the product of independent random matrices (the Furstenberg theory) allowed the elaboration of the phenomenon of intermittency in a systematic way. We consider applications of the Furstenberg theory to some problems in cosmology and dynamo theory.

  2. Androgen excess in women: experience with over 1000 consecutive patients.

    Science.gov (United States)

    Azziz, R; Sanchez, L A; Knochenhauer, E S; Moran, C; Lazenby, J; Stephens, K C; Taylor, K; Boots, L R

    2004-02-01

    The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinically evident androgen excess and to document the degree of long-term success of suppressive and/or antiandrogen hormonal therapy in a large consecutive population of patients. All patients presenting for evaluation of symptoms potentially related to androgen excess between October 1987 and June 2002 were evaluated, and the data were maintained prospectively in a computerized database. For the assessment of therapeutic response, a retrospective review of the medical chart was performed, after the exclusion of those patients seeking fertility therapy only, or with inadequate follow-up or poor compliance. A total of 1281 consecutive patients were seen during the study period. Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status, determine ovulatory status, or find any evidence of androgen excess. In the remaining population of 873 patients, the unbiased prevalence of androgen-secreting neoplasms was 0.2%, 21-hydroxylase-deficient classic adrenal hyperplasia (CAH) was 0.6%, 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) was 1.6%, hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome was 3.1%, idiopathic hirsutism was 4.7%, and polycystic ovary syndrome (PCOS) was 82.0%. Fifty-nine (6.75%) patients had elevated androgen levels and hirsutism but normal ovulation. A total of 257 patients were included in the assessment of the response to hormonal therapy. The mean duration of follow-up was 33.5 months (range, 6-155). Hirsutism improved in 86%, menstrual dysfunction in 80%, acne in 81%, and hair loss in 33% of patients. The major side effects noted were irregular vaginal bleeding (16.1%), nausea (13.0%), and headaches (12.6%); only 36.6% of patients never complained of side effects. In this large study of consecutive patients presenting with clinically evident androgen excess

  3. Intermittent Testicular Torsion

    African Journals Online (AJOL)

    2017-06-02

    Jun 2, 2017 ... had prior episodes of testicular pain, suggesting that they may have had intermittent torsion before .... None of the patients had antecedent history of sexual exposure, fever, or urinary tract infection .... torsion of the spermatic cord portends an increased risk of acute testicular infarction. J Urol 2008;180 4 ...

  4. Androgens and polycystic ovary syndrome.

    Science.gov (United States)

    Nisenblat, Vicki; Norman, Robert J

    2009-06-01

    Polycystic ovary syndrome (PCOS) is a common complex endocrine genetic disorder, which involves overproduction of androgens, leading to heterogeneous range of symptoms and associated with increased metabolic and cardiovascular morbidity. This review focuses on androgen biosynthesis, use, metabolism in PCOS and clinical consequences of hyperandrogenism. Controversial definition of the disorder and different phenotypic subgroups present a challenge for clinical and basic research. Further investigation of different phenotypes highlights the fact that PCOS probably represents a group of disorders with different etiologies. Prenatal androgen exposure and adolescent studies suggest early in life androgen excess as initiating factor of PCOS, but insufficient evidence available to confirm this hypothesis. Various intracellular signaling pathways implicated in PCOS steroidogenesis and in androgen action have been studied, however, PCOS pathogenesis remains obscure. Growing evidence links androgens with pathophysiology of PCOS and metabolic derangements. Despite intensive investigation, etiology and underlying mechanisms of PCOS remain unclear, warranting further investigation. Better understanding of molecular and genetic basis might lead to invention of novel therapeutic approaches. Long-term interventional studies that lower androgen levels in women with hyperandrogenism might protect against metabolic and cardiovascular comorbidities are needed.

  5. ANDROGEN REPLACEMENT THERAPY IN POSTMENOPAUSE

    Directory of Open Access Journals (Sweden)

    Helena Meden Vrtovec

    2008-12-01

    Scientific studies and clinical experiences have not provided until now the answers to thequestion: »Whom to treat, when, why and for how long should androgens be used for HRTin postmenopausal women?«

  6. Epigenetic repression of regulator of G-protein signaling 2 promotes androgen-independent prostate cancer cell growth.

    Science.gov (United States)

    Wolff, Dennis W; Xie, Yan; Deng, Caishu; Gatalica, Zoran; Yang, Mingjie; Wang, Bo; Wang, Jincheng; Lin, Ming-Fong; Abel, Peter W; Tu, Yaping

    2012-04-01

    G-protein-coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation (Cao et al., Oncogene 2006;25:3719-34). Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 downregulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2'-deoxycytidine (5-Aza-dC) induced RGS2 reexpression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that reexpressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen sensitivity. Copyright © 2011 UICC.

  7. Quasistatic Dynamics with Intermittency

    International Nuclear Information System (INIS)

    Leppänen, Juho; Stenlund, Mikko

    2016-01-01

    We study an intermittent quasistatic dynamical system composed of nonuniformly hyperbolic Pomeau–Manneville maps with time-dependent parameters. We prove an ergodic theorem which shows almost sure convergence of time averages in a certain parameter range, and identify the unique physical family of measures. The theorem also shows convergence in probability in a larger parameter range. In the process, we establish other results that will be useful for further analysis of the statistical properties of the model.

  8. Quasistatic Dynamics with Intermittency

    Energy Technology Data Exchange (ETDEWEB)

    Leppänen, Juho; Stenlund, Mikko, E-mail: mikko.stenlund@helsinki.fi [University of Helsinki, Department of Mathematics and Statistics (Finland)

    2016-06-15

    We study an intermittent quasistatic dynamical system composed of nonuniformly hyperbolic Pomeau–Manneville maps with time-dependent parameters. We prove an ergodic theorem which shows almost sure convergence of time averages in a certain parameter range, and identify the unique physical family of measures. The theorem also shows convergence in probability in a larger parameter range. In the process, we establish other results that will be useful for further analysis of the statistical properties of the model.

  9. Expression of androgen receptor target genes in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Kesha Rana

    2014-10-01

    Full Text Available We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (ARΔZF2 versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR∆ZF2 muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7 , p57 Kip2, Igf2 and calcineurin Aa, was increased in AR∆ZF2 muscle, and the expression of all but p57 Kip2 was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.

  10. Intermittency in Complex Flows

    Science.gov (United States)

    Ben Mahjoub, Otman; Redondo, Jose M.

    2017-04-01

    Experimental results of the complex turbulent wake of a cilinder in 2D [1] and 3D flows [2] were used to investigate the scaling of structure functions, similar research was also performed on wave propagation and breaking in the Ocean [3], in the the stratified Atmosphere (ABL) [4] and in a 100large flume (UPC) for both regular and irregular waves, where long time series of waves propagating and generating breaking turbulence velocity rms and higher order measurements were taken in depth. [3,5] by means of a velocimeter SONTEK3-D. The probability distribution functions of the velocity differences and their non Gaussian distribution related to the energy spectrum indicate that irregularity is an important source of turbulence. From Kolmogorov's K41 and K61 intermittency correction: the p th-order longitudinal velocity structure function δul at scale l in the inertial range of three-dimensional fully developed turbulence is related by ⟨δup⟩ = ⟨(u(x+ l)- u(x))p⟩ ˜ ɛp0/3lp/3 l where ⟨...⟩ represents the spatial average over flow domain, with ɛ0 the mean energy dissipation per unit mass and l is the separation distance. The importance of the random nature of the energy dissipation led to the K62 theory of intermittency, but locality and non-homogeneity are key issues. p p/3 p/3 ξd ⟨δul⟩ ˜ ⟨ɛl ⟩l ˜ l and ξp = p 3 + τp/3 , where now ɛl is a fractal energy dissipation at scale l, τp/3 is the scaling of and ξp is the scaling exponent of the velocity structure function of order p. Both in K41 and K62, the structure functions of third order related to skewness is ξ3 = 1. But this is not true either. We show that scaling exponents ξp do deviate from early studies that only investigated homogeneous turbulence, where a large inertial range dominates. The use of multi-fractal analysis and improvements on Structure function calculations on standard Enhanced mixing is an essential property of turbulence and efforts to alter and to control

  11. Intermittency in nuclear multifragmentation

    International Nuclear Information System (INIS)

    Ploszajczak, M.; Tucholski, A.

    1990-07-01

    Fluctuations of the fragment size distribution in a percolation model and in nuclear multifragmentation following the breakup of high energy nuclei in the nuclear emulsion are studied using the method of scaled factorial moments. An intermittent patern of fluctuations is found in the data as well as in the percolation lattice calculation. This is a consequence of both a self-similarity in the fragment size distribution and a random character for the scaling law. These fluctuations are in general well-described by percolation model. The multifractal dimensions are calculated and their relevance to the study of possible critical behaviour is pointed out. (orig.)

  12. Multidimensional intermittency in hadronic collisions

    International Nuclear Information System (INIS)

    Pan, J.; Hwa, R.C.

    1992-06-01

    The study of intermittency in high-energy hadronic collisions by the Monte Carlo code ECCO is extended to 3-dimensional phase space. Strong intermittency is found in agreement with the data. Fluctuation in the impact parameter is responsible for the intermittency in lnp T , and the transverse-momentum conservation leads to negative intermittency slopes in the azimuthal angle φ. The Ochs-Wosiek plots are linear in all dimensions having universal slopes. An exponent ν = 1.448 emerges to characterize multiparticle production in pp collisions. The properties of G moments are also examined, and the fractal dimensions determined

  13. AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome.

    Science.gov (United States)

    O'Reilly, Michael W; Kempegowda, Punith; Walsh, Mark; Taylor, Angela E; Manolopoulos, Konstantinos N; Allwood, J William; Semple, Robert K; Hebenstreit, Daniel; Dunn, Warwick B; Tomlinson, Jeremy W; Arlt, Wiebke

    2017-09-01

    Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index-matched healthy controls, complemented by in vitro experiments. PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen-activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis. These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS. Copyright © 2017 Endocrine Society

  14. Genetics Home Reference: androgen insensitivity syndrome

    Science.gov (United States)

    ... Androgen insensitivity syndrome is a condition that affects sexual development before birth and during puberty. People with this ... characteristics or signs of both male and female sexual development. Complete androgen insensitivity syndrome occurs when the body ...

  15. Hypochlorite Oxidation of Select Androgenic Steroids

    Science.gov (United States)

    Steroid hormones are vital for regulation of various biological functions including sexual development. Elevated concentrations of natural and synthetic androgenic steroids have been shown to adversely affect normal development in indigenous aqueous species. Androgens and their s...

  16. Male patients with partial androgen insensitivity syndrome

    DEFF Research Database (Denmark)

    Hellmann, Philip; Christiansen, Peter; Johannsen, Trine Holm

    2012-01-01

    To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome.......To describe the natural history of phenotype, growth and gonadal function in patients with partial androgen insensitivity syndrome....

  17. Androgen Receptor Signaling in Bladder Cancer

    OpenAIRE

    Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

    2017-01-01

    Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in u...

  18. Intermittent intravenous followed by intermittent oral 1 alpha(OH)D3 treatment of secondary hyperparathyroidism in uraemia

    DEFF Research Database (Denmark)

    Brandi, L; Daugaard, H; Egsmose, C

    1996-01-01

    OBJECTIVES: To examine whether intermittent oral 1 alpha(OH)D3 treatment of patients on haemodialysis with secondary hyperparathyroidism (HPT) was able to maintain the marked suppression of PTH, which previously had been induced by an intermittent intravenous administration of 1 alpha(OH)D3....... Simultaneously, the effect of the different routes of administration of 1 alpha(OH)D3 on the circulating levels of N- and C-terminal PTH fragments was measured. DESIGN: An open study of patients on chronic haemodialysis. SETTING: Renal division, Rigshospitalet, Copenhagen, Denmark. SUBJECTS: A total of 26...

  19. Metabolic Effects of Intermittent Fasting.

    Science.gov (United States)

    Patterson, Ruth E; Sears, Dorothy D

    2017-08-21

    The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.

  20. Fate in intermittent claudication

    DEFF Research Database (Denmark)

    Jelnes, Rolf; Gaardsting, O; Hougaard Jensen, K

    1986-01-01

    , or an ankle/arm pressure index below 50% were individually significantly associated with progression of the arteriosclerotic disease. These findings show the importance of peripheral blood pressure measurements in the management of patients with intermittent claudication due to arteriosclerotic disease........ The rate of clinical progression of the arteriosclerotic disease (that is, rest pain or gangrene) of the worst affected leg was 7.5% in the first year after referral. Thereafter the rate was 2.2% a year. An ankle systolic blood pressure below 70 mm Hg, a toe systolic blood pressure below 40 mm Hg...... 113 of the patients (44%) had died. Causes of death were no different from those in the general population. Mortality was twice that of the general population matched for age and sex. Mortality among the men was twice that among the women. In men under 60 mortality was four times that expected...

  1. Abhydrolase domain containing 2, an androgen target gene, promotes prostate cancer cell proliferation and migration.

    Science.gov (United States)

    Obinata, Daisuke; Takada, Shogo; Takayama, Ken-ichi; Urano, Tomohiko; Ito, Akiko; Ashikari, Daisaku; Fujiwara, Kyoko; Yamada, Yuta; Murata, Taro; Kumagai, Jinpei; Fujimura, Tetsuya; Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Homma, Yukio; Takahashi, Satoru; Inoue, Satoshi

    2016-04-01

    The androgen receptor (AR) plays a key role in the development of prostate cancer. AR signalling mediates the expression of androgen-responsive genes, which are involved in prostate cancer development and progression. Our previous chromatin immunoprecipitation study showed that the region of abhydrolase domain containing 2 (ABHD2) includes a functional androgen receptor binding site. In this study, we demonstrated that ABHD2 is a novel androgen-responsive gene that is overexpressed in human prostate cancer tissues. The expression levels of ABHD2 in androgen-sensitive cells were evaluated by quantitative reverse transcription polymerase chain reaction and western-blot analyses. LNCaP and VCaP cells with ABHD2 overexpression or short interfering RNA (siRNA) knockdown were used for functional analyses. ABHD2 expression was examined in clinical samples of prostate cancer by immunohistochemistry. We showed that ABHD2 expression is increased by androgen in LNCaP and VCaP cells. This androgen-induced ABHD2 expression was diminished by bicalutamide. While stable expression of ABHD2 affected the enhancement of LNCaP cell proliferation and migration, siRNA-mediated ABHD2 knockdown suppressed cell proliferation and migration. In addition, the siRNA treatment significantly repressed the tumour growth derived from LNCaP cells in athymic mice. Immunohistochemical analysis of ABHD2 expression in tumour specimens showed a positive correlation of ABHD2 immunoreactivity with high Gleason score and pathological N stage. Moreover, patients with high immunoreactivity of ABHD2 showed low cancer-specific survival rates and a resistance to docetaxel-based chemotherapy. ABHD2 is a novel androgen-regulated gene that can promote prostate cancer growth and resistance to chemotherapy, and is a novel target for diagnosis and treatment of prostate cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, Seth A., E-mail: rosents@sutterhealth.org [Radiation Oncology, Sutter Cancer Centers, Roseville, California (United States); Hunt, Daniel [NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sartor, A. Oliver [Tulane University Medical Center, New Orleans, Louisiana (United States); Pienta, Kenneth J. [Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Gomella, Leonard [Thomas Jefferson University Hospital, Philadelphia, Pennsylvania (United States); Grignon, David [Indiana University, Bloomington, Indiana (United States); Rajan, Raghu [McGill University, Montreal, Quebec (Canada); Kerlin, Kevin J. [Community Clinical Oncology Program, Southeast Cancer Control Consortium, Inc, Winston-Salem, North Carolina (United States); Jones, Christopher U. [Radiation Oncology, Sutter Cancer Centers, Roseville, California (United States); Radiological Associates of Sacramento, Sacramento, California (United States); Dobelbower, Michael [University of Alabama at Birmingham Medical Center, Birmingham, Alabama (United States); Shipley, William U. [Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Zeitzer, Kenneth [Albert Einstein Medical Center, Bronx, New York (United States); Hamstra, Daniel A. [University of Michigan Medical Center, Ann Arbor, Michigan (United States); Donavanik, Viroon [Christiana Care Health Services, Inc, Wilmington, Delaware (United States); Rotman, Marvin [State University of New York Health Science Center–Brooklyn, Brooklyn, New York (United States); Hartford, Alan C. [Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire (United States); Michalski, Jeffrey [Washington University, St. Louis, Missouri (United States); Seider, Michael [Akron City Hospital, Akron, Ohio (United States); Kim, Harold [Wayne State University, Detroit, Michigan (United States); and others

    2015-10-01

    Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for

  3. Naftidrofuryl for intermittent claudication.

    Science.gov (United States)

    De Backer, T L M; Vander Stichele, R; Lehert, P; Van Bortel, L

    2008-04-16

    Lifestyle changes and cardiovascular prevention measures are a primary treatment for intermittent claudication (IC). Symptomatic treatment with vasoactive agents (Anatomic Therapeutic Chemical Classification (ATC) for medicines from the World Health Organisation class CO4A) is controversial. To evaluate evidence on the efficacy and safety of oral naftidrofuryl (ATC CO4 21) versus placebo on the pain-free walking distance (PFWD) of people with IC by using a meta-analysis based on individual patient data (IPD). The Cochrane Peripheral Vascular Diseases Group searched their Trials Register (last searched December 2007) and CENTRAL (last searched 2007, Issue 4). We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, the Science Citation Index and contacted the authors and checked the reference lists of retrieved articles. We asked the manufacturing company for IPD. We included only randomized controlled trials (RCTs) with low or moderate risk of bias for which the IPD were available. We collected data from the electronic data file or from the case report form and checked the data by a statistical quality control procedure. All randomized patients were analyzed following the intention-to-treat (ITT) principle. The geometric mean of the relative improvement in PFWD was calculated for both treatment groups in all identified studies. The effect of the drug was assessed compared with placebo on final walking distance (WDf) using multilevel and random-effect models and adjusting for baseline walking distance (WD0). For the responder analysis, therapeutic success was defined as an improvement of walking distance of at least 50%. We included seven studies in the IPD (n = 1266 patients). One of these studies (n = 183) was only used in the sensitivity analysis so that the main analysis included 1083 patients. The ratio of the relative improvement in PFWD (naftidrofuryl compared with placebo) was 1.37 (95% confidence interval (CI) 1.32 to 1.51, P < 0.001). The

  4. Intermedia and Intermittency

    Directory of Open Access Journals (Sweden)

    Veres Bálint

    2014-12-01

    Full Text Available It is commonly known that medial reflections have been initiated by attempts to secure the borders of discrete medial forms and to define the modus operandi of each essentialized medial area. Later on, the focus of study has shifted to plurimedial formations and the interactions between predefined medial genres. In the last few decades, taxonomic approaches to various multi-, inter-, and transmedial phenomena dominated the discussions, which offered invaluable support in mapping the terrain, but at the same time hindered the analysis of the ephemeral, time-dependent aspects of plurimedial operations. While we explore the properties of each medial configuration, we lose sight of the actual historical drivers that produce ever-new configurations. My thesis is that any discourse on intermediality should be paralleled by a discourse on cultural intermittency, and consequently, media studies should involve an approach that focuses on the “ecosystem” of the constantly renewing media configurations from the point of view of their vitalizing potential and capability to trigger heightened experiences. This approach draws much inspiration from K. Ludwig Pfeiffer’s media anthropology that gives orientation in my paper.

  5. Establishment of a novel immortalized human prostatic epithelial cell line stably expressing androgen receptor and its application for the functional screening of androgen receptor modulators

    International Nuclear Information System (INIS)

    Yu, Shan; Wang, Ming-Wei; Yao, Xiaoqiang; Chan, F.L.

    2009-01-01

    In this study, we developed a human prostatic epithelial cell line BPH-1-AR stably expressing AR by lentiviral transduction. Characterization by immunoblot and RT-PCR showed that AR was stably expressed in all representative BPH-1-AR clones. Androgen treatment induced a secretory differentiation phenotype in BPH-1-AR cells but suppressed their cell proliferation. Treatments with AR agonists induced transactivation of a transfected PSA-gene promoter reporter in BPH-1-AR cells, whereas this transactivation was suppressed by an AR antagonist flutamide, indicating that the transduced AR in BPH-1-AR cells was functional. Finally, we utilized BPH-1-AR cells to evaluate the androgenic activities and growth effects of five newly developed non-steroidal compounds. Results showed that these compounds showed androgenic activities and growth-inhibitory effects on BPH-1-AR cells. Our results showed that BPH-1-AR cell line would be a valuable in vitro model for the study of androgen-regulated processes in prostatic epithelial cells and identification of compounds with AR-modulating activities.

  6. Chronic Intermittent Hypoxia Induces Atherosclerosis

    OpenAIRE

    Savransky, Vladimir; Nanayakkara, Ashika; Li, Jianguo; Bevans, Shannon; Smith, Philip L.; Rodriguez, Annabelle; Polotsky, Vsevolod Y.

    2007-01-01

    Rationale: Obstructive sleep apnea, a condition leading to chronic intermittent hypoxia (CIH), is associated with hyperlipidemia, atherosclerosis, and a high cardiovascular risk. A causal link between obstructive sleep apnea and atherosclerosis has not been established.

  7. Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

    Science.gov (United States)

    Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

    2016-10-01

    Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of

  8. Chemical Suppression of the Reactivated Androgen Signaling Pathway in Androgen-Independent Prostate Cancer

    Science.gov (United States)

    2011-07-01

    when it is ingested during pregnancy [20,21]. Aside from its role in development, Hh signaling also supports stem cells in adult tissues [22-24]. However...For the mo.~t commonly uti - lized human prostate cancer cell lines (LNCaP and derivatives, DUI45, PC3 or CWR22rvl) grown in culture, Shh, Glil/2 and

  9. Dynamic characterizers of spatiotemporal intermittency

    OpenAIRE

    Gupte, Neelima; Jabeen, Zahera

    2006-01-01

    Systems of coupled sine circle maps show regimes of spatiotemporally intermittent behaviour with associated scaling exponents which belong to the DP class, as well as regimes of spatially intermittent behaviour (with associated regular dynamical behaviour) which do not belong to the DP class. Both types of behaviour are seen along the bifurcation boundaries of the synchronized solutions, and contribute distinct signatures to the dynamical characterizers of the system, viz. the distribution of...

  10. A selective androgen receptor modulator for hormonal male contraception.

    Science.gov (United States)

    Chen, Jiyun; Hwang, Dong Jin; Bohl, Casey E; Miller, Duane D; Dalton, James T

    2005-02-01

    The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies, including hormonal male contraception. The identification of an orally bioavailable SARM with the ability to mimic the central and peripheral androgenic and anabolic effects of testosterone would represent an important step toward the "male pill". We characterized the in vitro and in vivo pharmacologic activity of (S)-3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethylphenyl)propionamide (C-6), a novel SARM developed in our laboratories. C-6 was identified as an androgen receptor (AR) agonist with high AR binding affinity (K(i) = 4.9 nM). C-6 showed tissue-selective pharmacologic activity with higher anabolic activity than androgenic activity in male rats. The doses required to maintain the weight of the prostate, seminal vesicles, and levator ani muscle to half the size of the maximum effects (i.e., ED(50)) were 0.78 +/- 0.06, 0.88 +/- 0.1, and 0.17 +/- 0.04 mg/day, respectively. As opposed to other SARMs, gonadotropin levels in C-6-treated groups were significantly lower than control values. C-6 also significantly decreased serum testosterone concentration in intact rats after 2 weeks of treatment. Marked suppression of spermatogenesis was observed after 10 weeks of treatment with C-6 in intact male rats. Pharmacokinetic studies of C-6 in male rats revealed that C-6 was well absorbed after oral administration (bioavailability 76%), with a long (6.3 h) half-life at a dose of 10 mg/kg. These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

  11. Androgen Receptor Signaling in Bladder Cancer

    Science.gov (United States)

    Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

    2017-01-01

    Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

  12. Androgen Receptor Signaling in Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Peng Li

    2017-02-01

    Full Text Available Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

  13. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men...... 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...... not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial...

  14. Suppression effects on musical and verbal memory.

    Science.gov (United States)

    Schendel, Zachary A; Palmer, Caroline

    2007-06-01

    Three experiments contrasted the effects of articulatory suppression on recognition memory for musical and verbal sequences. In Experiment 1, a standard/comparison task was employed, with digit or note sequences presented visually or auditorily while participants remained silent or produced intermittent verbal suppression (saying "the") or musical suppression (singing "la"). Both suppression types decreased performance by equivalent amounts, as compared with no suppression. Recognition accuracy was lower during suppression for visually presented digits than during that for auditorily presented digits (consistent with phonological loop predictions), whereas accuracy was equivalent for visually presented notes and auditory tones. When visual interference filled the retention interval in Experiment 2, performance with visually presented notes but not digits was impaired. Experiment 3 forced participants to translate visually presented music sequences by presenting comparison sequences auditorily. Suppression effects for visually presented music resembled those for digits only when the recognition task required sensory translation of cues.

  15. 17β-Hydroxysteroid Dehydrogenase Type 2 Expression Is Induced by Androgen Signaling in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Chiaki Hashimoto

    2018-04-01

    Full Text Available Endometrial cancer is one of the most common female pelvic cancers and has been considered an androgen-related malignancy. Several studies have demonstrated the anti-cell proliferative effect of androgen on endometrial cancer cells; however, the mechanisms of the anti-cancer effect of androgen remain largely unclear. 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2, which catalyzes the conversion of E2 to E1, is known to be upregulated by androgen treatment in breast cancer cells. In this study, we therefore focused on the role of androgen on estrogen dependence in endometrial cancer. Dihydrotestosterone (DHT was found to induce 17β-HSD2 mRNA and protein expression in HEC-1B endometrial cancer cells. DHT could also inhibit cell proliferation of HEC-1B when induced by estradiol treatment. In 19 endometrioid endometrial adenocarcinoma (EEA tissues, intratumoral DHT concentration was measured by liquid chromatography/electrospray tandem mass spectrometry and was found to be significantly correlated with 17β-HSD2 immunohistochemical status. We further examined the correlations between 17β-HSD2 immunoreactivity and clinicopathological parameters in 53 EEA tissues. 17β-HSD2 status was inversely associated with the histological grade, clinical stage, and cell proliferation marker Ki-67, and positively correlated with progesterone receptor expression. 17β-HSD2 status tended to be positively associated with androgen receptor status. In 53 EEA cases, the 17β-HSD2-positive group tended to have better prognosis than that for the negative group with respect to progression-free survival and endometrial cancer-specific survival. These findings suggest that androgen suppresses the estrogen dependence of endometrial cancer through the induction of 17β-HSD2 in endometrial cancer.

  16. Intermittency in 197Au fragmentation

    International Nuclear Information System (INIS)

    Dabrowska, A.; Holynski, R.; Olszewski, A.; Szarska, M.; Wilczynska, B.; Wolter, W.; Wosiek, B.; Cherry, M.L.; Deines-Jones, P.; Jones, W.V.; Sengupta, K.; Wefel, B.

    1995-07-01

    The concept of factorial moments was applied to an analysis of the dynamical fluctuations in the charge distributions of the fragments emitted from gold nuclei with energies 10.6 and < 1.0 GeV/n interacting with emulsion nuclei. Clear evidence for intermittent fluctuations has been found in an analysis using all the particles released from the gold projectile, with a stronger effect observed below 1 GeV/n than at 10.6 GeV/n. For the full data sets, however, the intermittency effect was found to be very sensitive to the singly charged particles, and neglecting these particles strongly reduces the intermittency signal. When the analysis is restricted to the multiply charged fragments, an intermittency effect is revealed only for multifragmentation events, although one that is enhanced as compared to the analysis of all, singly and multiply charged, particles. The properties of the anomalous fractal dimensions suggest a sequential decay mechanism, rather than the existence of possible critical behaviour in the process of nuclear fragmentation. The likely influence of the charge conservation effects and the finite size of decaying systems on the observed intermittency signals was pointed out. (author). 37 refs, 9 figs, 5 tabs

  17. Modulation of Androgen Receptor Transcriptional Activity

    NARCIS (Netherlands)

    H.Y. Wong (Hao Yun)

    2009-01-01

    textabstractAndrogens, testosterone (T) and 5a-dihydrotestosterone (DHT), are important for male and female physiology, in particular for male sexual differentiation, development of secondary male characteristics and spermatogenesis. These hormones exert their actions by binding to the androgen

  18. Molecular mechanisms of androgen receptor functions

    NARCIS (Netherlands)

    K. Steketee (Karine)

    2007-01-01

    textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

  19. Androgens and the ageing male

    DEFF Research Database (Denmark)

    Juul, Anders; Skakkebaek, Niels E

    2002-01-01

    with severe primary or secondary hypogonadism. Thus, androgen substitution therapy is warranted in men with true hypogonadism at all ages. Symptoms experienced by otherwise healthy ageing males are non-specific and vague, although some may be similar to symptoms of hypogonadism. Therefore, the term...... 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...

  20. In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

    Directory of Open Access Journals (Sweden)

    Alison K. Heather

    2013-02-01

    Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

  1. Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

    NARCIS (Netherlands)

    D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

    1994-01-01

    textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated

  2. Inhibition of Androgen-Independent Prostate Cancer by Estrogenic Compounds Is Associated with Increased Expression of Immune-Related Genes

    Directory of Open Access Journals (Sweden)

    Ilsa M. Coleman

    2006-10-01

    Full Text Available The clinical utility of estrogens for treating prostate cancer (CaP was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical, preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17β estradiol (E2 against androgen-independent CaP, identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, LuCaP 58 in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses, regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgendepleted environments, suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

  3. Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure.

    Science.gov (United States)

    Fragkaki, A G; Angelis, Y S; Koupparis, M; Tsantili-Kakoulidou, A; Kokotos, G; Georgakopoulos, C

    2009-02-01

    Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone introduced for therapeutic purposes providing enhanced anabolic potency with reduced androgenic effects. Androgens mediate their action through their binding to the androgen receptor (AR) which is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system. This paper reviews some of the wide spectrum of testosterone and synthetic AAS structure modifications related to the intended enhancement in anabolic activity. The structural features of steroids necessary for effective binding to the AR and those which contribute to the stipulation of the androgenic and anabolic activities are also presented.

  4. Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

    Science.gov (United States)

    Omwancha, Josephat; Brown, Terry R

    2006-10-01

    The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

  5. Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

    Science.gov (United States)

    Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

    2008-07-01

    Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

  6. Suppressed Belief

    Directory of Open Access Journals (Sweden)

    Komarine Romdenh-Romluc

    2009-12-01

    Full Text Available Moran’s revised conception of conscious belief requires us to reconceptualise suppressed belief. The work of Merleau-Ponty offers a way to do this. His account of motor-skills allows us to understand suppressed beliefs as pre-reflective ways of dealing with the world.

  7. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    Directory of Open Access Journals (Sweden)

    Abbas Yavari

    2009-09-01

    Full Text Available According to the International Olympic Committee, the abuse of anabolic androgenic steroids (AASS is found in over 50% of positive doping tests. AASS abuse is not restricted to the organized sports andwidespread use. It remains as an unsolved public-health problem.Lower black market price, easier access to AASS, bodybuilding clubs and internet advertising are factors of this increasingly misuse. There is not real data about the prevalence of AASS abuse in various populations or countries, because most of athletes or students, due to their prohibition or ethical aspects do not admit to AASS abuse. Often they are aware of the risks of their choice and yet, are eager to put themselves at risk without deeper consideration. The abusers use them to improve their physical fitness and appearance.Present article has been collected to elucidate the risks and adverse effects of AASS and explanation of mechanisms of these events.

  8. A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer. | Office of Cancer Genomics

    Science.gov (United States)

    Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide.

  9. Three siblings with complete androgen insensitivity syndrome

    African Journals Online (AJOL)

    2013-01-13

    Jan 13, 2013 ... male reference range. A diagnosis of complete androgen insensitivity syndrome was made, based on this clinical ... Laboratory test. Value Normal ..... scenario, incomplete resistance may lead to virilisation during puberty.24, ...

  10. A Novel Mechanism of Androgen Receptor Action

    National Research Council Canada - National Science Library

    Roberts, Jr, Charles T

    2006-01-01

    .... Specifically, the authors had determined that the androgen receptor controls the expression of the cell-surface receptor for the hormone IGF-1 at the level of translation of the IGF-1 receptor mRNA...

  11. Scaling, Intermittency and Decay of MHD Turbulence

    International Nuclear Information System (INIS)

    Lazarian, A.; Cho, Jungyeon

    2005-01-01

    We discuss a few recent developments that are important for understanding of MHD turbulence. First, MHD turbulence is not so messy as it is usually believed. In fact, the notion of strong non-linear coupling of compressible and incompressible motions along MHD cascade is not tenable. Alfven, slow and fast modes of MHD turbulence follow their own cascades and exhibit degrees of anisotropy consistent with theoretical expectations. Second, the fast decay of turbulence is not related to the compressibility of fluid. Rates of decay of compressible and incompressible motions are very similar. Third, viscosity by neutrals does not suppress MHD turbulence in a partially ionized gas. Instead, MHD turbulence develops magnetic cascade at scales below the scale at which neutrals damp ordinary hydrodynamic motions. Forth, density statistics does not exhibit the universality that the velocity and magnetic field do. For instance, at small Mach numbers the density is anisotropic, but it gets isotropic at high Mach numbers. Fifth, the intermittency of magnetic field and velocity are different. Both depend on whether the measurements are done in a local system of reference oriented along the local magnetic field or in the global system of reference related to the mean magnetic field

  12. Androgen imprinting of the brain in animal models and humans with intersex disorders: review and recommendations.

    Science.gov (United States)

    Hrabovszky, Zoltan; Hutson, John M

    2002-11-01

    Psychosexual development, gender assignment and surgical treatment in patients with intersex are controversial issues in the medical literature. Some groups are of the opinion that gender identity and sexual orientation are determined prenatally secondary to the fetal hormonal environment causing irreversible development of the nervous system. We reviewed the evidence in animal and human studies to determine the possible role of early postnatal androgen production in gender development. An extensive literature review was performed of data from animal experiments and human studies. RESULTS Many animal studies show that adding or removing hormonal stimulus in early postnatal life can profoundly alter gender behavior of the adult animal. Human case studies show that late intervention is unable to reverse gender orientation from male to female. Most studies have not permitted testing of whether early gender assignment and treatment as female with suppression/ablation of postnatal androgen production leads to improved concordance of the gender identity and sex of rearing. Animal studies support a role for postnatal androgens in brain/behavior development with human studies neither completely supportive nor antagonistic. Therefore, gender assignment in infants with intersex should be made with the possibility in mind that postnatal testicular hormones at ages 1 to 6 months may affect gender identity. A case-control study is required to test the hypothesis that postnatal androgen exposure may convert ambisexual brain functions to committed male behavior patterns.

  13. Androgen Bioassay for the Detection of Nonlabeled Androgenic Compounds in Nutritional Supplements.

    Science.gov (United States)

    Cooper, Elliot R; McGrath, Kristine C Y; Li, XiaoHong; Heather, Alison K

    2018-01-01

    Both athletes and the general population use nutritional supplements. Athletes often turn to supplements hoping that consuming the supplement will help them be more competitive and healthy, while the general population hopes to improve body image or vitality. While many supplements contain ingredients that may have useful properties, there are supplements that are contaminated with compounds that are banned for use in sport or have been deliberately adulterated to fortify a supplement with an ingredient that will produce the advertised effect. In the present study, we have used yeast cell and mammalian cell androgen bioassays to characterize the androgenic bioactivity of 112 sports supplements available from the Australian market, either over the counter or via the Internet. All 112 products did not declare an androgen on the label as an included ingredient. Our findings show that six out of 112 supplements had strong androgenic bioactivity in the yeast cell bioassay, indicating products spiked or contaminated with androgens. The mammalian cell bioassay confirmed the strong androgenic bioactivity of five out of six positive supplements. Supplement 6 was metabolized to weaker androgenic bioactivity in the mammalian cells. Further to this, Supplement 6 was positive in a yeast cell progestin bioassay. Together, these findings highlight that nutritional supplements, taken without medical supervision, could expose or predispose users to the adverse consequences of androgen abuse. The findings reinforce the need to increase awareness of the dangers of nutritional supplements and highlight the challenges that clinicians face in the fast-growing market of nutritional supplements.

  14. Intermittency in multiparticle production produced by low momentum transfer at high energies

    International Nuclear Information System (INIS)

    Jang, Han Il; Jeong, Eun Mi; Kim, Jae Yool; Kim, Jae Young; Kim, Min Kyoung; Kim, Sin Joung; Kim, Tae Ick; Kim, Yeon Kyoung; Lee, Jin Ho; Lim, In Taek; Pac, Myoung Youl; Kim, Chong Oh; Bahk, Sang Yull

    1998-01-01

    We show the intermittent behavior of the distribution of the pseudo-rapidities of secondary charged particles produced by nucleus-nucleus interactions. In particular, using the modified G moments, which can be defined to suppress the statistical fluctuations, we study the intermittency in the low multiplicity processes produced by the 14.6-GeV/nucleon 28 Si - nucleus interactions. We have shown experimentally that the basic function B q,k (M), behaving as M λ(q,k) at large M, has the basic fractal behavior and that the exponent λ(q,k) depends linearly on the number of multiplicity in a bin

  15. Pituitary Androgen Receptor Signalling Regulates Prolactin but Not Gonadotrophins in the Male Mouse

    Science.gov (United States)

    O’Hara, Laura; Curley, Michael; Tedim Ferreira, Maria; Cruickshanks, Lyndsey; Milne, Laura; Smith, Lee B.

    2015-01-01

    Production of the androgen testosterone is controlled by a negative feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. Stimulation of testicular Leydig cells by pituitary luteinising hormone (LH) is under the control of hypothalamic gonadotrophin releasing hormone (GnRH), while suppression of LH secretion by the pituitary is controlled by circulating testosterone. Exactly how androgens exert their feedback control of gonadotrophin secretion (and whether this is at the level of the pituitary), as well as the role of AR in other pituitary cell types remains unclear. To investigate these questions, we exploited a transgenic mouse line (Foxg1Cre/+; ARfl/y) which lacks androgen receptor in the pituitary gland. Both circulating testosterone and gonadotrophins are unchanged in adulthood, demonstrating that AR signalling is dispensable in the male mouse pituitary for testosterone-dependent regulation of LH secretion. In contrast, Foxg1Cre/+; ARfl/y males have a significant increase in circulating prolactin, suggesting that, rather than controlling gonadotrophins, AR-signalling in the pituitary acts to suppress aberrant prolactin production in males. PMID:25799562

  16. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    International Nuclear Information System (INIS)

    Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

    2013-01-01

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  17. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  18. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  19. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

    2002-01-01

    The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

  20. Androgen circle of polycystic ovary syndrome.

    Science.gov (United States)

    Homburg, Roy

    2009-07-01

    Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

  1. Interocular suppression

    Science.gov (United States)

    Tuna, Ana Rita; Almeida Neves Carrega, Filipa; Nunes, Amélia Fernandes

    2017-08-01

    The objective of this work is to quantify the suppressive imbalance, based on the manipulation of ocular luminance, between a group of subjects with normal binocular vision and a group of subjects with amblyopia. The result reveals that there are statistically significant differences in interocular dominance between two groups, evidencing a greater suppressive imbalance in amblyopic subjects. The technique used, proved to be a simple, easy to apply and economic method, for quantified ocular dominance. It is presented as a technique with the potential to accompany subjects with a marked dominance in one of the eyes that makes fusion difficult.

  2. Discovery and therapeutic promise of selective androgen receptor modulators.

    Science.gov (United States)

    Chen, Jiyun; Kim, Juhyun; Dalton, James T

    2005-06-01

    Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.

  3. Enhanced Androgen Signaling With Androgen Receptor Overexpression in the Osteoblast Lineage Controls Skeletal Turnover, Matrix Quality and Bone Architecture

    National Research Council Canada - National Science Library

    Wiren, Kristine M; Jepsen, Karl

    2006-01-01

    .... We genetically engineered transgenic mice in which androgen receptor (AR) overexpression is skeletally targeted in two separate models to better understand the role of androgen signaling directly in bone...

  4. Three novel and two known androgen receptor gene mutations ...

    Indian Academy of Sciences (India)

    gene mutations associated with androgen insensitivity syndrome in sex-reversed XY female patients. J. Genet. ... signal and a C-terminal. Keywords. androgen insensitivity syndrome; androgen receptor; truncation mutation; N-terminal domain; XY sex reversal. .... and an increased risk of gonadal tumour. Mutations in SRY.

  5. Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia

    Directory of Open Access Journals (Sweden)

    Sung Won Lee

    2015-06-01

    Full Text Available Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

  6. Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

    OpenAIRE

    Chadha, D.; Pache, T.D.; Huikeshoven, Frans; Brinkmann, Albert; Kwast, Theo

    1994-01-01

    textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsexual female patients. This was compared with AR expression in the ovaries and uteri of premenopausal and postmenopausal women not receiving treatment and in 10 ovaries of female patients with polycy...

  7. The Yo-Yo intermittent recovery test

    DEFF Research Database (Denmark)

    Bangsbo, Jens; Iaia, F. Marcello; Krustrup, Peter

    2008-01-01

    The two Yo-Yo intermittent recovery (IR) tests evaluate an individual's ability to repeatedly perform intense exercise. The Yo-Yo IR level 1 (Yo-Yo IR1) test focuses on the capacity to carry out intermittent exercise leading to a maximal activation of the aerobic system, whereas Yo-Yo IR level 2...

  8. Intermittent behavior of the logistic system

    Science.gov (United States)

    Mayer-Kress, G.; Haken, H.

    1981-03-01

    In the discrete logistic model a transition to chaotic behavior via intermittency occurs in a neighborhood of periodic bands. Intermittent behavior is also induced if a stable periodic orbit is perturbed by low-level external noise, whereas alterations due to computer digitalisation produce remarkable periodicities. We compare our numerical results with the predictions of Pomeau and Manneville for the Lorenz system.

  9. Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

    Science.gov (United States)

    Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

    2016-12-01

    Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the

  10. Cosmic Rays in Intermittent Magnetic Fields

    International Nuclear Information System (INIS)

    Shukurov, Anvar; Seta, Amit; Bushby, Paul J.; Wood, Toby S.; Snodin, Andrew P.

    2017-01-01

    The propagation of cosmic rays in turbulent magnetic fields is a diffusive process driven by the scattering of the charged particles by random magnetic fluctuations. Such fields are usually highly intermittent, consisting of intense magnetic filaments and ribbons surrounded by weaker, unstructured fluctuations. Studies of cosmic-ray propagation have largely overlooked intermittency, instead adopting Gaussian random magnetic fields. Using test particle simulations, we calculate cosmic-ray diffusivity in intermittent, dynamo-generated magnetic fields. The results are compared with those obtained from non-intermittent magnetic fields having identical power spectra. The presence of magnetic intermittency significantly enhances cosmic-ray diffusion over a wide range of particle energies. We demonstrate that the results can be interpreted in terms of a correlated random walk.

  11. Cosmic Rays in Intermittent Magnetic Fields

    Energy Technology Data Exchange (ETDEWEB)

    Shukurov, Anvar; Seta, Amit; Bushby, Paul J.; Wood, Toby S. [School of Mathematics and Statistics, Newcastle University, Newcastle Upon Tyne NE1 7RU (United Kingdom); Snodin, Andrew P., E-mail: a.seta1@ncl.ac.uk, E-mail: amitseta90@gmail.com [Department of Mathematics, Faculty of Applied Science, King Mongkut’s University of Technology North Bangkok, Bangkok 10800 (Thailand)

    2017-04-10

    The propagation of cosmic rays in turbulent magnetic fields is a diffusive process driven by the scattering of the charged particles by random magnetic fluctuations. Such fields are usually highly intermittent, consisting of intense magnetic filaments and ribbons surrounded by weaker, unstructured fluctuations. Studies of cosmic-ray propagation have largely overlooked intermittency, instead adopting Gaussian random magnetic fields. Using test particle simulations, we calculate cosmic-ray diffusivity in intermittent, dynamo-generated magnetic fields. The results are compared with those obtained from non-intermittent magnetic fields having identical power spectra. The presence of magnetic intermittency significantly enhances cosmic-ray diffusion over a wide range of particle energies. We demonstrate that the results can be interpreted in terms of a correlated random walk.

  12. Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

    NARCIS (Netherlands)

    L.J. Blok (Leen); G.T.G. Chang; M. Steenbeek-Slotboom (M.); W.M. van Weerden (Wytske); H.G. Swarts; J.J.H.H.M. de Pont (J. J H H M); G.J. van Steenbrugge (Gert Jan); A.O. Brinkmann (Albert)

    1999-01-01

    textabstractThe β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of

  13. ANISOTROPIC INTERMITTENCY OF MAGNETOHYDRODYNAMIC TURBULENCE

    International Nuclear Information System (INIS)

    Osman, K. T.; Kiyani, K. H.; Chapman, S. C.; Hnat, B.

    2014-01-01

    A higher-order multiscale analysis of spatial anisotropy in inertial range magnetohydrodynamic turbulence is presented using measurements from the STEREO spacecraft in fast ambient solar wind. We show for the first time that, when measuring parallel to the local magnetic field direction, the full statistical signature of the magnetic and Elsässer field fluctuations is that of a non-Gaussian globally scale-invariant process. This is distinct from the classic multiexponent statistics observed when the local magnetic field is perpendicular to the flow direction. These observations are interpreted as evidence for the weakness, or absence, of a parallel magnetofluid turbulence energy cascade. As such, these results present strong observational constraints on the statistical nature of intermittency in turbulent plasmas

  14. Prolonged Intermittent Renal Replacement Therapy.

    Science.gov (United States)

    Edrees, Fahad; Li, Tingting; Vijayan, Anitha

    2016-05-01

    Prolonged intermittent renal replacement therapy (PIRRT) is becoming an increasingly popular alternative to continuous renal replacement therapy in critically ill patients with acute kidney injury. There are significant practice variations in the provision of PIRRT across institutions, with respect to prescription, technology, and delivery of therapy. Clinical trials have generally demonstrated that PIRRT is non-inferior to continuous renal replacement therapy regarding patient outcomes. PIRRT offers cost-effective renal replacement therapy along with other advantages such as early patient mobilization and decreased nursing time. However, due to lack of standardization of the procedure, PIRRT still poses significant challenges, especially pertaining to appropriate drug dosing. Future guidelines and clinical trials should work toward developing consensus definitions for PIRRT and ensure optimal delivery of therapy. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  15. Role of Androgen Receptor in Growth of Androgen Independent Prostate Cancer

    National Research Council Canada - National Science Library

    Chen, Charlie

    2003-01-01

    ...) overexpression is the only consistent change in the progression of prostate cancer. In the last grand period, I confirmed by western blot analysis that androgen receptor protein is higher in HR than HS tumors...

  16. PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

    International Nuclear Information System (INIS)

    Zhang, Zheng; Jin, Bo; Jin, Yaqiong; Huang, Shengquan; Niu, Xiaohua; Mao, Zebin; Xin, Dianqi

    2017-01-01

    Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

  17. The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction.

    Science.gov (United States)

    Escobar-Morreale, Héctor F

    2017-01-01

    Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

  18. Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

    Science.gov (United States)

    Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

    2015-10-01

    Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Sexual behavior reduces hypothalamic androgen receptor immunoreactivity

    NARCIS (Netherlands)

    Fernandez-Guasti, Alonso; Swaab, Dick; Rodríguez-Manzo, Gabriela

    2003-01-01

    Male sexual behavior is regulated by limbic areas like the medial preoptic nucleus (MPN), the bed nucleus of the stria terminalis (BST), the nucleus accumbens (nAcc) and the ventromedial hypothalamic nucleus (VMN). Neurons in these brain areas are rich in androgen receptors (AR) and express

  20. Therapeutic Use of Androgens in Women

    Science.gov (United States)

    ... in men, the same is not true for women. Media stories about how testosterone increases libido (sexual desire) ... medications, do have lower androgen levels than healthy women. In addition, despite claims in the popular media that getting testosterone levels checked is “a small ...

  1. The relationship between follicular fluid androgen concentrations ...

    African Journals Online (AJOL)

    Polycystic ovary syndrome (PCOS) is the most common cause of oligoanovulation, infertility, and hyperandrogenism in women and characterized by abnormal folliculogenesis. The androgen receptoe ( AR) is present in the ovary in almost all stages of folliculogenesis and has been suggested to play a proliferative role for ...

  2. Testosterone Suppression of CRH-stimulated Cortisol in Men

    OpenAIRE

    Rubinow, David R.; Roca, Catherine A.; Schmidt, Peter J.; Danaceau, Merry A.; Putnam, Karen; Cizza, Giovanni; Chrousos, George; Nieman, Lynnette

    2005-01-01

    Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in ten men (ages 18–45) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower ...

  3. Intermittent cranial lung herniation in two dogs.

    Science.gov (United States)

    Guglielmini, Carlo; De Simone, Antonio; Valbonetti, Luca; Diana, Alessia

    2007-01-01

    Two aged dogs with chronic obstructive airway disease were evaluated because of intermittent swelling of the ventral cervical region. Radiographs made at expiration and caudal positioning of the forelimbs allowed identification of intermittent cervical lung herniation of the left and right cranial lung lobe in both dogs. Pulmonary hyperinflation, increased expiratory effort, and chronic coughing were considered responsible for the lung herniation. Cervical lung hernia should be included in the differential diagnoses of intermittent cervical swelling in dogs with chronic respiratory disorders associated with increased expiratory effort and chronic coughing.

  4. HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling

    Directory of Open Access Journals (Sweden)

    Choi Chan

    2010-05-01

    Full Text Available Abstract Background Androgen signaling plays a critical role in the development of prostate cancer and its progression. However, androgen-independent prostate cancer cells emerge after hormone ablation therapy, resulting in significant clinical problems. We have previously demonstrated that the HOXB13 homeodomain protein functions as a prostate cancer cell growth suppressor by inhibiting androgen-mediated signals. However, the role of the HOXB13 in androgen-independent growth of prostate cancer cells remains unexplained. Results In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling. Conclusions Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.

  5. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    International Nuclear Information System (INIS)

    Cho, Eunpi; Mostaghel, Elahe A.; Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A.; Kurland, Brenda F.; Marck, Brett T.; Matsumoto, Alvin M.; Dalkin, Bruce L.; Montgomery, R. Bruce

    2015-01-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  6. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

    2015-06-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  7. Intermittent sea-level acceleration

    Science.gov (United States)

    Olivieri, M.; Spada, G.

    2013-10-01

    Using instrumental observations from the Permanent Service for Mean Sea Level (PSMSL), we provide a new assessment of the global sea-level acceleration for the last ~ 2 centuries (1820-2010). Our results, obtained by a stack of tide gauge time series, confirm the existence of a global sea-level acceleration (GSLA) and, coherently with independent assessments so far, they point to a value close to 0.01 mm/yr2. However, differently from previous studies, we discuss how change points or abrupt inflections in individual sea-level time series have contributed to the GSLA. Our analysis, based on methods borrowed from econometrics, suggests the existence of two distinct driving mechanisms for the GSLA, both involving a minority of tide gauges globally. The first effectively implies a gradual increase in the rate of sea-level rise at individual tide gauges, while the second is manifest through a sequence of catastrophic variations of the sea-level trend. These occurred intermittently since the end of the 19th century and became more frequent during the last four decades.

  8. Social Smoking among Intermittent Smokers

    Science.gov (United States)

    Shiffman, Saul; Li, Xiaoxue; Dunbar, Michael S.; Ferguson, Stuart G.; Tindle, Hilary A.; Scholl, Sarah M.

    2015-01-01

    Background “Social smoking” - smoking mostly or even only with others – may be an important pattern that implies smoking motivated extrinsically by social influences. Non-daily smokers (intermittent smokers; ITS) are often assumed to be social smokers, with some authors even assuming that all ITS are social smokers (SS+). We sought to identify and characterize social smokers in a sample of ITS. Methods 204 adult ITS (smoking 4–27 days/month) recorded the circumstances of smoking in their natural settings using Ecological Momentary Assessment, while also recording their circumstances in nonsmoking moments. SS+ were defined as ITS who were with others when they smoked most of their cigarettes, and who were ≥ 50% more likely to be with others when smoking than when not. Results Only 13% of ITS were SS+. Although defined solely on the basis of presence of others, SS+ showed a distinct pattern of smoking across multiple dimensions: Compared to other ITS (who were significantly less likely to smoke when with others), SS+ smoking was more associated with socializing, being with friends and acquaintances, drinking alcohol, weekends, evening or nighttime, being in other people’s homes, but not their own home. SS+ smoking was low in the morning and increased in the evening. SS+ smoked fewer days/week and were less dependent, but did not differ demographically. Conclusions Social smoking does constitute a highly distinct smoking pattern, but is not common among adult ITS. PMID:26205313

  9. Intermittent ileocoecal intususception in adult

    International Nuclear Information System (INIS)

    Cambal, M.; Zonca, P.; Maly, T.

    2013-01-01

    Aim: Aim of our paper is to present a case-report of chronic invagination in adult patient. Material: 28-years old woman with one year history of intermittent abdominal pain with symptoms of subileus state. She has underwent abdominal ultrasonography, abdominal X-ray, colonoscopy, irigography and abdominal CT. Appendectomy indicated for diagnosis of chronic appendicitis did not improve symptoms. Consecutively during acute problems were irigography and CT performed and diagnosis of an incomplete colon transversum obstruction of uncertain origin was established. There was stated suspicion of an intususception and patient was due to a repeated gastrointestinal passage indicated for an explorative laparotomy. During operation there was identified threefold invagination – colo-colonic, ileo-colonic and ileo-ileal. As a leading point of invagination was found in terminal ileum intraluminal polypous tumor 5 cm in diameter. Because of the secondary chronic changes of right colon wall and terminal ileum wall, after partial desinvagination right hemicolectomy was performed. Results: Patient was primary healed and now is without any subjective problems. Conclusion: Invagination is an acute abdominal event of obturative-strangulative type and it mainly occurs in infantile age. It is astonishing how long were patient´s difficulties lasting without obvious acute ileus. It is necessary in clinical practice to think on these rare reasons of gastrointestinal passage disorders. (author)

  10. Positive effects of intermittent fasting in ischemic stroke.

    Science.gov (United States)

    Fann, David Yang-Wei; Ng, Gavin Yong Quan; Poh, Luting; Arumugam, Thiruma V

    2017-03-01

    Intermittent fasting (IF) is a dietary protocol where energy restriction is induced by alternate periods of ad libitum feeding and fasting. Prophylactic intermittent fasting has been shown to extend lifespan and attenuate the progress and severity of age-related diseases such as cardiovascular (e.g. stroke and myocardial infarction), neurodegenerative (e.g. Alzheimer's disease and Parkinson's disease) and cancerous diseases in animal models. Stroke is the second leading cause of death, and lifestyle risk factors such as obesity and physical inactivity have been associated with elevated risks of stroke in humans. Recent studies have shown that prophylactic IF may mitigate tissue damage and neurological deficit following ischemic stroke by a mechanism(s) involving suppression of excitotoxicity, oxidative stress, inflammation and cell death pathways in animal stroke models. This review summarizes data supporting the potential hormesis mechanisms of prophylactic IF in animal models, and with a focus on findings from animal studies of prophylactic IF in stroke in our laboratory. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Emission Enhancement and Intermittency in Polycrystalline Organolead Halide Perovskite Films

    Directory of Open Access Journals (Sweden)

    Cheng Li

    2016-08-01

    Full Text Available Inorganic-organic halide organometal perovskites have demonstrated very promising performance for opto-electronic applications, such as solar cells, light-emitting diodes, lasers, single-photon sources, etc. However, the little knowledge on the underlying photophysics, especially on a microscopic scale, hampers the further improvement of devices based on this material. In this communication, correlated conventional photoluminescence (PL characterization and wide-field PL imaging as a function of time are employed to investigate the spatially- and temporally-resolved PL in CH3NH3PbI3−xClx perovskite films. Along with a continuous increase of the PL intensity during light soaking, we also observe PL blinking or PL intermittency behavior in individual grains of these films. Combined with significant suppression of PL blinking in perovskite films coated with a phenyl-C61-butyric acid methyl ester (PCBM layer, it suggests that this PL intermittency is attributed to Auger recombination induced by photoionized defects/traps or mobile ions within grains. These defects/traps are detrimental for light conversion and can be effectively passivated by the PCBM layer. This finding paves the way to provide a guideline on the further improvement of perovskite opto-electronic devices.

  12. PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade.

    Science.gov (United States)

    Özgür, Emre; Celik, Ayca Iribas; Darendeliler, Emin; Gezer, Ugur

    2017-07-01

    Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR + cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3-silenced and/or AR-blocked cells. PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR + cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women.

    Science.gov (United States)

    Secreto, Giorgio; Sieri, Sabina; Agnoli, Claudia; Grioni, Sara; Muti, Paola; Zumoff, Barnett; Sant, Milena; Meneghini, Elisabetta; Krogh, Vittorio

    2016-08-01

    Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.

  14. White adipose tissue coloring by intermittent fasting.

    Science.gov (United States)

    Kivelä, Riikka; Alitalo, Kari

    2017-11-01

    Intermittent fasting (IF) has been shown to promote metabolic health in several organisms. Two recent papers show that IF induces white adipose tissue beiging and increases thermogenesis, which improves metabolic health in mice.

  15. On-line intermittent connector anomaly detection

    Data.gov (United States)

    National Aeronautics and Space Administration — This paper investigates a non-traditional use of differential current sensor and current sensor to detect intermittent disconnection problems in connectors. An...

  16. Intermittent chaotic chimeras for coupled rotators

    DEFF Research Database (Denmark)

    Olmi, Simona; Martens, Erik Andreas; Thutupalli, Shashi

    2015-01-01

    Two symmetrically coupled populations of N oscillators with inertia m display chaotic solutions with broken symmetry similar to experimental observations with mechanical pendulums. In particular, we report evidence of intermittent chaotic chimeras, where one population is synchronized and the other...

  17. Feigenbaum attractor and intermittency in particle collisions

    International Nuclear Information System (INIS)

    Batunin, A.V.

    1992-01-01

    The hypothesis is proposed that the Feigenbaum attractor arising as a limit set in an infinite pichfork bifurcation sequence for unimodal one-dimensional maps underlies the intermittency phenomena in particle collisions. 23 refs.; 8 figs

  18. Intermittent fasting attenuates inflammasome activity in ischemic stroke.

    Science.gov (United States)

    Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

    2014-07-01

    Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Intermittent cold exposure enhances fat accumulation in mice.

    Directory of Open Access Journals (Sweden)

    Hyung Sun Yoo

    Full Text Available Due to its high energy consuming characteristics, brown adipose tissue (BAT has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE, unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis.

  20. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    International Nuclear Information System (INIS)

    Chen, Junyi; Jiao, Li; Xu, Chuanliang; Yu, Yongwei; Zhang, Zhensheng; Chang, Zheng; Deng, Zhen; Sun, Yinghao

    2012-01-01

    Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer

  1. The Androgen Receptor Gene Mutations Database.

    Science.gov (United States)

    Gottlieb, B; Lehvaslaiho, H; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

    1998-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 272 to 309 in the past year. We have expanded the database: (i) by giving each entry an accession number; (ii) by adding information on the length of polymorphic polyglutamine (polyGln) and polyglycine (polyGly) tracts in exon 1; (iii) by adding information on large gene deletions; (iv) by providing a direct link with a completely searchable database (courtesy EMBL-European Bioinformatics Institute). The addition of the exon 1 polymorphisms is discussed in light of their possible relevance as markers for predisposition to prostate or breast cancer. The database is also available on the internet (http://www.mcgill. ca/androgendb/ ), from EMBL-European Bioinformatics Institute (ftp. ebi.ac.uk/pub/databases/androgen ), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca).

  2. Androgen levels in women with various forms of ovarian dysfunction : Associations with cardiometabolic features

    NARCIS (Netherlands)

    Daan, N. M P; Jaspers, L.; Koster, M. P H; Broekmans, F. J M; De Rijke, Y. B.; Franco, O. H.; Laven, J. S E; Kavousi, M.; Fauser, B. C J M

    2015-01-01

    STUDY QUESTION Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were

  3. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Morris, W. James, E-mail: jmorris@bccancer.bc.ca [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Tyldesley, Scott [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Rodda, Sree [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); Halperin, Ross [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Centre for the Southern Interior, Vancouver, British Columbia (Canada); Pai, Howard [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Island Centre, Vancouver, British Columbia (Canada); McKenzie, Michael; Duncan, Graeme [Department of Surgery, University of British Columbia, Vancouver, British Columbia (Canada); BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Morton, Gerard [Department of Radiation Oncology, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario (Canada); Hamm, Jeremy [Department of Population Oncology, BC Cancer Agency, Vancouver, British Columbia (Canada); Murray, Nevin [BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia (Canada); Department of Medicine, University of British Columbia, Vancouver, British Columbia (Canada)

    2017-06-01

    Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.

  4. Dutasteride and enzalutamide synergistically suppress prostate tumor cell proliferation

    NARCIS (Netherlands)

    Hamid, A.R.; Verhaegh, G.W.C.T.; Smit, F.P.; RIjt-van de Westerlo, C.; Armandari, I.; Brandt, A.; Sweep, F.C.; Sedelaar, J.P.M.; Schalken, J.A.

    2015-01-01

    PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are

  5. Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor

    Science.gov (United States)

    Abi Ghanem, Charly; Degerny, Cindy; Hussain, Rashad; Liere, Philippe; Pianos, Antoine; Tourpin, Sophie; Habert, René; Schumacher, Michael

    2017-01-01

    The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis. PMID:29107990

  6. The Role of (BETA)-Catenin in Androgen Receptor Signaling

    National Research Council Canada - National Science Library

    Bhowmick, Neil A

    2006-01-01

    .... Our preliminary data seem indicate stromally derived paracrine Wnt family members activate theepithelial frizzled receptor to enable prostate epithelial survival in an androgen deficient environment...

  7. Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

    Science.gov (United States)

    2017-08-01

    disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

  8. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

    Science.gov (United States)

    Corbould, A

    2008-10-01

    Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd.

  9. Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

    International Nuclear Information System (INIS)

    Olsen, Jan Roger; Azeem, Waqas; Hellem, Margrete Reime; Marvyin, Kristo; Hua, Yaping; Qu, Yi; Li, Lisha; Lin, Biaoyang; Ke, XI- Song; Øyan, Anne Margrete; Kalland, Karl- Henning

    2016-01-01

    Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in

  10. Intermittent ephemeral river-breaching

    Science.gov (United States)

    Reniers, A. J.; MacMahan, J. H.; Gallagher, E. L.; Shanks, A.; Morgan, S.; Jarvis, M.; Thornton, E. B.; Brown, J.; Fujimura, A.

    2012-12-01

    In the summer of 2011 we performed a field experiment in Carmel River State Beach, CA, at a time when the intermittent natural breaching of the ephemeral Carmel River occurred due to an unusually rainy period prior to the experiment associated with El Nino. At this time the river would fill the lagoon over the period of a number of days after which a breach would occur. This allowed us to document a number of breaches with unique pre- and post-breach topographic surveys, accompanying ocean and lagoon water elevations as well as extremely high flow (4m/s) velocities in the river mouth during the breaching event. The topographic surveys were obtained with a GPS-equipped backpack mounted on a walking human and show the evolution of the river breaching with a gradually widening and deepening river channel that cuts through the pre-existing beach and berm. The beach face is qualified as a steep with an average beach slope of 1:10 with significant reflection of the incident waves (MacMahan et al., 2012). The wave directions are generally shore normal as the waves refract over the deep canyon that is located offshore of the beach. The tide is mixed semi-diurnal with a range on the order of one meter. Breaching typically occurred during the low-low tide. Grain size is highly variable along the beach with layers of alternating fine and coarse material that could clearly be observed as the river exit channel was cutting through the beach. Large rocky outcroppings buried under the beach sand are also present along certain stretches of the beach controlling the depth of the breaching channel. The changes in the water level measured within the lagoon and the ocean side allows for an estimate of the volume flux associated with the breach as function of morphology, tidal elevation and wave conditions as well as an assessment of the conditions and mechanisms of breach closure, which occurred on the time scale of O(0.5 days). Exploratory model simulations will be presented at the

  11. Coherent Structures and Intermittency in Plasma Turbulence

    International Nuclear Information System (INIS)

    Das, Amita; Kaw, Predhiman; Sen, Abhijit

    2008-01-01

    The paper discusses some fundamental issues related to the phenomenon of intermittency in plasma turbulence with particular reference to experimental observations in fusion devices. Intermittency is typically associated with the presence of coherent structures in turbulence. Since coherent structures can play an important role in governing the transport properties of a system they have received a great deal of attention in fusion research. We review some of the experimental measurements and numerical simulation studies on the presence and formation of coherent structures in plasmas and discuss their relevance to intermittency. Intermittency, as widely discussed in the context of neutral fluid turbulence, implies multiscaling behaviour in contrast to self-similar scaling patterns observed in self organized criticality (SOC) phenomenon. The experimental evidence from plasma turbulence measurements reveal a mixed picture--while some observations support the SOC model description others indicate the presence of multiscaling behaviour. We discuss these results in the light of our present understanding of plasma turbulence and in terms of certain unique aspects of intermittency as revealed by fluid models of plasmas.

  12. Intermittency in {sup 197}Au fragmentation

    Energy Technology Data Exchange (ETDEWEB)

    Dabrowska, A; Holynski, R; Olszewski, A; Szarska, M; Wilczynska, B; Wolter, W; Wosiek, B [Institute of Nuclear Physics, Cracow (Poland); Cherry, M L; Deines-Jones, P; Jones, W V; Sengupta, K; Wefel, B [Louisiana State Univ., Baton Rouge, LA (United States). Dept. of Physics and Astronomy; Waddington, C J [Minnesota Univ., Minneapolis, MN (United States). School of Physics and Astronomy; Pozharova, E A; Skorodko, T Yu [Inst. of Theoretical and Experimental Physics, Moscow (Russian Federation); KLMM Collaboration

    1995-07-01

    The concept of factorial moments was applied to an analysis of the dynamical fluctuations in the charge distributions of the fragments emitted from gold nuclei with energies 10.6 and < 1.0 GeV/n interacting with emulsion nuclei. Clear evidence for intermittent fluctuations has been found in an analysis using all the particles released from the gold projectile, with a stronger effect observed below 1 GeV/n than at 10.6 GeV/n. For the full data sets, however, the intermittency effect was found to be very sensitive to the singly charged particles, and neglecting these particles strongly reduces the intermittency signal. When the analysis is restricted to the multiply charged fragments, an intermittency effect is revealed only for multifragmentation events, although one that is enhanced as compared to the analysis of all, singly and multiply charged, particles. The properties of the anomalous fractal dimensions suggest a sequential decay mechanism, rather than the existence of possible critical behaviour in the process of nuclear fragmentation. The likely influence of the charge conservation effects and the finite size of decaying systems on the observed intermittency signals was pointed out. (author). 37 refs, 9 figs, 5 tabs.

  13. Effects of alcohol feeding on androgen receptors in the rat pituitary gland

    International Nuclear Information System (INIS)

    Chung, K.W.

    1987-01-01

    Specific binding of testosterone-1β,2β- 3 H by cytosol from anterior pituitary gland of ethanol-fed, isocaloric control, and castrated control and ethanol-fed rats with or without testosterone treatment has been investigated by charcoal assay. The number of androgen binding sites was significantly reduced in alcohol-fed rats when compared to the isocaloric control value, with no significant change in Kd. Castration significantly increased the number of receptor sites in control rats and when castrated control animals were treated with testosterone the binding sites were decreased to the intact control level. In contrast, castration or testosterone given to castrated alcohol-fed rats did not alter alcohol-induced reduction of the receptor sites. The binding affinity (Kd) is identical in all groups. The concentration of serum luteinizing hormone (LH) was significantly lower in alcohol-fed rats when compared to that of normal controls. An increased serum LH level with a decreased testosterone level was noted in castrated control rats. However, castration of alcohol-fed rats had little or no effects on the concentrations of LH and testosterone. Administration of testosterone suppressed castration-induced high LH in control rats but alcohol induced reduction of LH level was not altered by this treatment. These findings indicate that alcohol exerts a suppressive effect on the content of androgen receptors and secretory functions of gonadotropins in the pituitary gland. 23 references, 1 figure, 1 table

  14. The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling.

    Science.gov (United States)

    Correa, Ricardo G; Krajewska, Maryla; Ware, Carl F; Gerlic, Motti; Reed, John C

    2014-03-30

    Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) family proteins. Gene silencing procedures, in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Depleting NWD1 in PCa cell lines reduces AR levels and suppresses activity of androgen-driven reporter genes. NWD1 knockdown potently suppressed growth of androgen-dependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomic analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, these data suggest a role for tumor-associated over-expression of NWD1 in dysregulation of AR signaling in PCa.

  15. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    International Nuclear Information System (INIS)

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

    2010-01-01

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  16. Forces and energetics of intermittent swimming

    Science.gov (United States)

    Floryan, Daniel; Van Buren, Tyler; Smits, Alexander J.

    2017-08-01

    Experiments are reported on intermittent swimming motions. Water tunnel experiments on a nominally two-dimensional pitching foil show that the mean thrust and power scale linearly with the duty cycle, from a value of 0.2 all the way up to continuous motions, indicating that individual bursts of activity in intermittent motions are independent of each other. This conclusion is corroborated by particle image velocimetry (PIV) flow visualizations, which show that the main vortical structures in the wake do not change with duty cycle. The experimental data also demonstrate that intermittent motions are generally energetically advantageous over continuous motions. When metabolic energy losses are taken into account, this conclusion is maintained for metabolic power fractions less than 1.

  17. Chaos synchronization based on intermittent state observer

    Institute of Scientific and Technical Information of China (English)

    Li Guo-Hui; Zhou Shi-Ping; Xu De-Ming

    2004-01-01

    This paper describes the method of synchronizing slave to the master trajectory using an intermittent state observer by constructing a synchronizer which drives the response system globally tracing the driving system asymptotically. It has been shown from the theory of synchronization error-analysis that a satisfactory result of chaos synchronization is expected under an appropriate intermittent period and state observer. Compared with continuous control method,the proposed intermittent method can target the desired orbit more efficiently. The application of the method is demonstrated on the hyperchaotic Rossler systems. Numerical simulations show that the length of the synchronization interval rs is of crucial importance for our scheme, and the method is robust with respect to parameter mismatch.

  18. Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

    Science.gov (United States)

    Schweizer, Michael T; Wang, Hao; Luber, Brandon; Nadal, Rosa; Spitz, Avery; Rosen, D Marc; Cao, Haiyi; Antonarakis, Emmanuel S; Eisenberger, Mario A; Carducci, Michael A; Paller, Channing; Denmeade, Samuel R

    2016-09-01

    We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Unsteady propulsion by an intermittent swimming gait

    Science.gov (United States)

    Akoz, Emre; Moored, Keith W.

    2018-01-01

    Inviscid computational results are presented on a self-propelled swimmer modeled as a virtual body combined with a two-dimensional hydrofoil pitching intermittently about its leading edge. Lighthill (1971) originally proposed that this burst-and-coast behavior can save fish energy during swimming by taking advantage of the viscous Bone-Lighthill boundary layer thinning mechanism. Here, an additional inviscid Garrick mechanism is discovered that allows swimmers to control the ratio of their added mass thrust-producing forces to their circulatory drag-inducing forces by decreasing their duty cycle, DC, of locomotion. This mechanism can save intermittent swimmers as much as 60% of the energy it takes to swim continuously at the same speed. The inviscid energy savings are shown to increase with increasing amplitude of motion, increase with decreasing Lighthill number, Li, and switch to an energetic cost above continuous swimming for sufficiently low DC. Intermittent swimmers are observed to shed four vortices per cycle that form into groups that are self-similar with the DC. In addition, previous thrust and power scaling laws of continuous self-propelled swimming are further generalized to include intermittent swimming. The key is that by averaging the thrust and power coefficients over only the bursting period then the intermittent problem can be transformed into a continuous one. Furthermore, the intermittent thrust and power scaling relations are extended to predict the mean speed and cost of transport of swimmers. By tuning a few coefficients with a handful of simulations these self-propelled relations can become predictive. In the current study, the mean speed and cost of transport are predicted to within 3% and 18% of their full-scale values by using these relations.

  20. Shape of power spectrum of intermittent chaos

    International Nuclear Information System (INIS)

    So, B.C.; Mori, H.

    1984-01-01

    Power spectra of intermittent chaos are calculated analytically. It is found that the power spectrum near onset point consists of a large number of Lorentzian lines with two peaks around frequencies ω = 0 and ω = ω 0 , where ω 0 is a fundamental frequency of a periodic orbit before the onset point, and furthermore the envelope of lines around ω = 0 obeys the power law 1/ + ω +2 , whereas the envelope around ω 0 obeys 1/ + ω-ω 0 +4 . The universality of these power law dependence in a certain class of intermittent chaos are clarified from a phenomenological view point. (author)

  1. Identification of a novel androgen receptor agonist (or “androgen mimic”) of environmental concern: spironolactone

    Science.gov (United States)

    Spironolactone is a pharmaceutical that acts as an androgen receptor (AR) antagonist in humans to treat certain conditions such as hirsutism, various dermatologic afflictions, and female pattern hair loss. The drug is also used to treat hypertension as a diuretic. With this commo...

  2. ASSESSMENT OF IN VITRO ANDROGENIC ACTIVITY IN KRAFT MILL EFFLUENT

    Science.gov (United States)

    Detection of In Vitro Androgenic Activity in Feedlot Effluent. Lambright, CS 1 , Guillette, LJ, Jr.2, Gray, LE, Jr.1 , 1USEPA, NHEERL, RTP, NC, 2 University of Florida, Dept. of Zoology, Gainesville FLRecent studies have shown the presence of androgenic activity in water...

  3. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Gluud, C

    2006-01-01

    Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  4. Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

    Science.gov (United States)

    2017-10-01

    resistant prostate cancer ; docetaxel; cabazitaxel; chemotherapy; androgen receptor splice variants; microtubule; ligand-binding domain; microtubule... receptor splice variants (AR-Vs) are associated with resistance to taxane chemotherapy in castration- resistant prostate cancer (CRPC). However, this...androgen receptor inhibitors in prostate cancer . Nat Rev Cancer . 2015;15:701–11.

  5. Illicit use of androgens and other hormones: recent advances.

    Science.gov (United States)

    Kanayama, Gen; Pope, Harrison G

    2012-06-01

    To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

  6. ENVIRONMENTAL ANDROGENS AND ANTIANDROGENS: AN EXPANDING CHEMICAL UNIVERSE

    Science.gov (United States)

    Within the last ten years, awareness has grown about environmental chemicals that display antiandrogenic or androgenic activity. While studies in the early 1990s focused on pesticides that acted as androgen receptor (AR) antagonists, it soon became evident that this was not the ...

  7. ING3 promotes prostate cancer growth by activating the androgen receptor.

    Science.gov (United States)

    Nabbi, Arash; McClurg, Urszula L; Thalappilly, Subhash; Almami, Amal; Mobahat, Mahsa; Bismar, Tarek A; Binda, Olivier; Riabowol, Karl T

    2017-05-16

    The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development. Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3. We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more

  8. Androgen receptor-related diseases: what do we know?

    Science.gov (United States)

    Shukla, G C; Plaga, A R; Shankar, E; Gupta, S

    2016-05-01

    The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs. Because of AR's widely varied and important roles, its abnormalities have been identified in various diseases such as androgen insensitivity syndrome, spinal bulbar muscular atrophy, benign prostatic hyperplasia, and prostate cancer. This review provides an overview of the function of androgens and androgen-AR mediated diseases. In addition, the diseases delineated above are discussed with respect to their association with mutations and other post-transcriptional modifications in the AR. Finally, we present an introduction to the potential therapeutic application of most recent pharmaceuticals including miRNAs in prostate cancer that specifically target the transactivation function of the AR at post-transcriptional stages. © 2016 American Society of Andrology and European Academy of Andrology.

  9. Targets to treat androgen excess in polycystic ovary syndrome.

    Science.gov (United States)

    Luque-Ramírez, Manuel; Escobar-Morreale, Héctor Francisco

    2015-01-01

    The polycystic ovary syndrome (PCOS) is a common androgen disorder in reproductive-aged women. Excessive biosynthesis and secretion of androgens by steroidogenic tissues is its central pathogenetic mechanism. The authors review the potential targets and new drugs to treat androgen excess in PCOS. Besides our lab's experience, a systematic search (MEDLINE, Cochrane library, ClinicalTriasl.gov, EU Clinical Trials Register and hand-searching) regarding observational studies, randomized clinical trials, systematic reviews, meta-analyses and patents about this topic was performed. PCOS has a heterogeneous clinical presentation. It is unlikely that a single drug would cover all its possible manifestations. Available treatments for androgen excess are not free of side effects that are of particular concern in these women who suffer from cardiometabolic risk even without treatment. A precise characterization of the source of androgen excess must tailor antiandrogenic management in each woman, avoiding undesirable side effects.

  10. In vivo and in vitro anti-androgenic effects of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture

    International Nuclear Information System (INIS)

    Stoker, T.E.; Cooper, R.L.; Lambright, C.S.; Wilson, V.S.; Furr, J.; Gray, L.E.

    2005-01-01

    PBDEs have been synthesized in large quantities as flame retardants for commercial products, such as electronic equipment and textiles. The rising in levels of PBDEs in tissues in wildlife species and in human milk and plasma samples over the past several years have raised concerns about possible health effects. Recently, we showed that the PBDE mixture, DE-71, delayed puberty and suppressed the growth of androgen-dependent tissues in male Wistar rat following a peri-pubertal exposure. These effects suggested that DE-71 may be either inducing steroid hormone metabolism or acting as an androgen receptor (AR) antagonist. To elucidate the potential anti-androgenic effects of this mixture, we evaluated DE-71 in several in vivo assays, which are responsive to alterations in androgen activity. In a pubertal exposure study designed to further evaluate the delay in preputial separation (PPS), we observed a dose-dependent delay in PPS with 60 and 120 mg/kg/day of DE-71 (4 and 5 days) and a corresponding suppression of ventral prostate (VP) and seminal vesicle growth at both doses. Adult males exposed to 60 mg/kg DE-71 for 3 days resulted in a significant increase in luteinizing hormone and a non-significant increase in testosterone, androstenedione and estrone. DE-71 also tested positive for anti-androgenic activity in an immature rat Hershberger assay, with decreases in mean VP and seminal vesicle weight following doses of 30-240 mg/kg. DE-71 and the individual BDE congeners which comprise the mixture (BDE-47, -99, -100, -153, -154) were also evaluated in vitro. First, AR binding was evaluated in a competitive binding assay using rat VP cytosol. In addition, we evaluated gene activation in a transcriptional activation assay using the MDA-kb2 cell line which contains an endogenous human AR and a transfected luciferase reporter. DE-71 and BDE-100 (2, 4, 6-pentaBDE) both inhibited AR binding, with IC50s of approximately 5 μM. In addition, DE-71 and two of the congeners (BDE

  11. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men

    Science.gov (United States)

    Basaria, Shehzad; Collins, Lauren; Dillon, E. Lichar; Orwoll, Katie; Storer, Thomas W.; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Eder, Richard; Zientek, Heather; Gordon, Gilad; Kazmi, Syed; Sheffield-Moore, Melinda

    2013-01-01

    Background. Concerns about potential adverse effects of testosterone on prostate have motivated the development of selective androgen receptor modulators that display tissue-selective activation of androgenic signaling. LGD-4033, a novel nonsteroidal, oral selective androgen receptor modulator, binds androgen receptor with high affinity and selectivity. Objectives. To evaluate the safety, tolerability, pharmacokinetics, and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones. Methods. In this placebo-controlled study, 76 healthy men (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention. Results. LGD-4033 was well tolerated. There were no drug-related serious adverse events. Frequency of adverse events was similar between active and placebo groups. Hemoglobin, prostate-specific antigen, aspartate aminotransferase, alanine aminotransferase, or QT intervals did not change significantly at any dose. LGD-4033 had a long elimination half-life and dose-proportional accumulation upon multiple dosing. LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation. Conclusions. LGD-4033 was safe, had favorable pharmacokinetic profile, and increased lean body mass even during this short period without change in prostate-specific antigen. Longer randomized trials should

  12. Myocardial infarction, androgen and the skin.

    Science.gov (United States)

    Halim, M M; Meyrick, G; Jeans, W D; Murphy, D; Burton, J L

    1978-01-01

    Various indices of masculinity were compared in 48 men who had recovered from myocardial infarction and in their age-matched controls. We found little evidence to support the idea that myocardial infarction is related to increased androgenic stimulation. The patients with myocardial infarction had no increase in plasma testosterone, muscle thickness, sebum excretion rate, maximal sweat secretion rate, male pattern alopecia or density of terminal body hair, but as a group they had a slight increase in skin and bone thickness compared with the controls.

  13. Embodied masculinity and androgen deprivation therapy.

    Science.gov (United States)

    Oliffe, John

    2006-05-01

    This paper describes the findings from an ethnographic study of 16 Anglo-Australian men treated with androgen deprivation therapy (ADT) for advanced prostate cancer. Utilising a social constructionist gendered analysis, participants' experiences, particularly in relation to embodied masculinity, are described in the context of reduced testosterone that accompany ADT. The findings indicated that participants reformulated many ideals of hegemonic masculinity in response to functional body changes. However, hegemonic masculinity strongly influenced participants' philosophical resolve to "fight" prostate cancer. The findings are considered in broader ongoing debates about essentialist sex and the social construction of gender.

  14. Complete Androgen Insensitivity Syndrome in Three Sisters

    Directory of Open Access Journals (Sweden)

    Levent Verim

    2014-01-01

    Full Text Available Disorders of sexual development (DSD are congenital anomalies due to atypical development of chromosomes, gonads and anatomy. Complete androgen insensitivity syndrome (CAIS, also known as testicular feminization (TF is a rare DSD disease. The majority of CAIS patients apply to hospital with the complaint of primary amenorrhea or infertility. Given that CAIS patients are all phenotypically female while having 46, XY karyotypes, CAIS diagnosis should be disclosed in an age-appropriate manner preferably by a mental health professional. Cases are reported here for three 46XY siblings consistent with CAIS.

  15. Environmental concentrations of an androgenic progestin disrupts the seasonal breeding cycle in male three-spined stickleback (Gasterosteus aculeatus).

    Science.gov (United States)

    Svensson, Johan; Fick, Jerker; Brandt, Ingvar; Brunström, Björn

    2014-02-01

    Synthetic steroid hormones from contraceptive pharmaceuticals have become global aquatic contaminants. Progestins, the synthetic analogs to progesterone, are receiving increasing attention as contaminants and have been shown to impair reproduction in fish and amphibians at low ng L(-1) concentrations. Certain progestins, such as levonorgestrel have androgenic properties and seem to be several orders of magnitude more potent in terms of reproductive impairment in fish than non-androgenic progestins and progestagens. We recently reported that levonorgestrel has strong androgenic effects in female three-spined sticklebacks (Gasterosteus aculeatus), including induction of the normally male-specific glue protein spiggin and suppression of vitellogenesis. In light of this we investigated if exposure to levonorgestrel could disrupt the highly androgen-dependent seasonal reproductive cycle in male sticklebacks. Male sticklebacks that were in the final stage of a breeding period were exposed to various concentrations of levonorgestrel for six weeks in winter conditions in terms of light and temperature, after which reproductive status was evaluated from gross morphology, histology and key gene transcript levels. During the experimental period the controls had transitioned from full breeding condition into the non-breeding state, including regression of secondary sex characteristics, cessation of spiggin production in the kidney, and resumption of spermatogenesis in the testes. This is ascribed to the natural drop in plasma androgen levels after breeding. However, in the groups concurrently exposed to levonorgestrel, transition to the non-breeding condition was dose-dependently inhibited. Our results show that levonorgestrel can disrupt the seasonal breeding cycle in male sticklebacks. The fitness costs of such an effect could be detrimental to natural stickleback populations. Some effects occurred at a levonorgestrel concentration of 6.5 ng L(-1), well within the range of

  16. Prenatal and adult androgen activities in alcohol dependence.

    Science.gov (United States)

    Lenz, B; Mühle, C; Braun, B; Weinland, C; Bouna-Pyrrou, P; Behrens, J; Kubis, S; Mikolaiczik, K; Muschler, M-R; Saigali, S; Sibach, M; Tanovska, P; Huber, S E; Hoppe, U; Eichler, A; Heinrich, H; Moll, G H; Engel, A; Goecke, T W; Beckmann, M W; Fasching, P A; Müller, C P; Kornhuber, J

    2017-07-01

    Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Androgens and Hypertension in Men and Women: a Unifying View.

    Science.gov (United States)

    Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

    2017-05-01

    This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be

  18. Interocular suppression in children with deprivation amblyopia.

    Science.gov (United States)

    Hamm, Lisa; Chen, Zidong; Li, Jinrong; Black, Joanna; Dai, Shuan; Yuan, Junpeng; Yu, Minbin; Thompson, Benjamin

    2017-04-01

    In patients with anisometropic or strabismic amblyopia, interocular suppression can be minimized by presenting high contrast stimulus elements to the amblyopic eye and lower contrast elements to the fellow eye. This suggests a structurally intact binocular visual system that is functionally suppressed. We investigated whether suppression can also be overcome by contrast balancing in children with deprivation amblyopia due to childhood cataracts. To quantify interocular contrast balance, contrast interference thresholds were measured using an established dichoptic global motion technique for 21 children with deprivation amblyopia, 14 with anisometropic or mixed strabismic/anisometropic amblyopia and 10 visually normal children (mean age mean=9.9years, range 5-16years). We found that interocular suppression could be overcome by contrast balancing in most children with deprivation amblyopia, at least intermittently, and all children with anisometropic or mixed anisometropic/strabismic amblyopia. However, children with deprivation amblyopia due to early unilateral or bilateral cataracts could tolerate only very low contrast levels to the stronger eye indicating strong suppression. Our results suggest that treatment options reliant on contrast balanced dichoptic presentation could be attempted in a subset of children with deprivation amblyopia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Which factors make clean intermittent (self) catheterisation successful?

    NARCIS (Netherlands)

    Cobussen-Boekhorst, H.; Beekman, J.; Wijlick, E. van; Schaafstra, J.; Kuppevelt, D. van; Heesakkers, J.P.

    2016-01-01

    AIMS AND OBJECTIVES: To explore which factors determine successful intermittent catheterisation. BACKGROUND: Intermittent catheterisation is a safe, effective treatment and is associated with improved quality of life, although negative issues are reported. Factors which determine adherence are

  20. The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene

    NARCIS (Netherlands)

    Lucas-Herald, A.; S. Bertelloni (Silvano); A. Juul (Anders); J. Bryce (Jillian); Jiang, J.; M. Rodie (Martina); R. Sinnott (Richard); Boroujerdi, M.; Lindhardt Johansen, M.; O. Hiort (Olaf); P-M. Holterhus (Paul-Martin); M.L. Cools (Martine); Guaragna-Filho, G.; Guerra-Junior, G.; N. Weintrob (Naomi); S.E. Hannema (Sabine); S.L.S. Drop (Stenvert); T. Guran (Tulay); F. Darendeliler (Feyza); A. Nordenström (Anna); I.A. Hughes (Ieuan A.); Acerini, C.; Tadokoro-Cuccaro, R.; S.F. Ahmed (Faisal)

    2016-01-01

    textabstractBackground: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking. Objective: To assess the clinical characteristics and long-term

  1. Fractal structures and intermittency in QCD

    International Nuclear Information System (INIS)

    Gustafson, Goesta.

    1990-04-01

    New results are presented for fractal structures and intermittency in QCD parton showers. A geometrical interpretation of the anomalous dimension in QCD is given. It is shown that model predications for factorial moments in the PEP-PETRA energy range are increased. if the properties of directly produced pions are more carefully taken into account

  2. Intermittent demand : Linking forecasting to inventory obsolescence

    NARCIS (Netherlands)

    Teunter, Ruud H.; Syntetos, Aris A.; Babai, M. Zied

    2011-01-01

    The standard method to forecast intermittent demand is that by Croston. This method is available in ERP-type solutions such as SAP and specialised forecasting software packages (e.g. Forecast Pro), and often applied in practice. It uses exponential smoothing to separately update the estimated demand

  3. Acute intermittent porphyria presenting as progressive muscular ...

    African Journals Online (AJOL)

    Acute intermittent porphyria, the most common porphyria affecting the nervous system, typically presents with neurovisceral crises followed by a motor neuropathy. We describe a 23-year-old black South African man presenting with a progressive stuttering, lower motor neuron syndrome developing over months. He had not ...

  4. Cooling tower modification for intermittent operation

    International Nuclear Information System (INIS)

    Midkiff, W.S.

    1975-03-01

    One of the cooling towers at Los Alamos Scientific Laboratory is being operated intermittently. The cooling tower has been modified to restrict air flow and to keep the tower from drying out. The modifications are relatively inexpensive, simple to operate, and have proved effective. (U.S.)

  5. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Hansen, Kristian Schultz; Bygbjerg, Ib Christian

    2008-01-01

    The main objective of this study was to assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilisers could administer intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women. The study w...

  6. Management of patients with intermittent claudication

    NARCIS (Netherlands)

    S. Spronk (Sandra)

    2008-01-01

    textabstractIntermittent claudication is the first and mildest manifestation of peripheral arterial disease, caused by the atherosclerotic process of progressive narrowing of one or more of the arteries of the peripheral circulation.1 If the arterial system fails, it results in a progressive oxygen

  7. Intermittent resistive faults in digital cmos circuits

    NARCIS (Netherlands)

    Kerkhoff, Hans G.; Ebrahimi, Hassan

    2015-01-01

    A major threat in extremely dependable high-end process node integrated systems in e.g. Avionics are no failures found (NFF). One category of NFFs is the intermittent resistive fault, often originating from bad (e.g. Via or TSV-based) interconnections. This paper will show the impact of these faults

  8. Intermittent and global transitions in plasma turbulence

    International Nuclear Information System (INIS)

    Vlad, M.; Spineanu, F.; Itoh, K.; Itoh, S.-I.

    2003-07-01

    The dynamics of the transition processes in plasma turbulence described by the nonlinear Langevin equation (1) is studied. We show that intermittent or global transitions between metastable states can appear. The conditions for the generation of these transitions and their statistical characteristics are determined. (author)

  9. Control of spatio-temporal on-off intermittency in random driving diffusively coupled map lattices

    International Nuclear Information System (INIS)

    Ziabakhsh Deilami, M.; Rahmani Cherati, Z.; Jahed Motlagh, M.R.

    2009-01-01

    In this paper, we propose feedback methods for controlling spatio-temporal on-off intermittency which is an aperiodic switching between an 'off' state and an 'on' state. Diffusively coupled map lattice with spatially non-uniform random driving is used for showing spatio-temporal on-off intermittency. For this purpose, we apply three different feedbacks. First, we use a linear feedback which is a simple method but has a long transient time. To overcome this problem, two nonlinear feedbacks based on prediction strategy are proposed. An important advantage of the methods is that the feedback signal is vanished when control is realized. Simulation results show that all methods have suppressed the chaotic behavior.

  10. Intermittency in the particle production and in the nuclear multifragmentation

    International Nuclear Information System (INIS)

    Bozek, P.; Ploszajczak, M.

    1991-01-01

    Intermittency is a manifestation of scale invariance and randomness in physical systems. Intermittency in relativistic heavy-ion collisions and, in particular, the projectile dependence, multiplicity dependence and source-size dependence are discussed in the frame of the model of spatio-temporal intermittency. Moreover, recent theoretical results in intermittency studies of the nuclear multifragmentation are presented. (author) 35 refs., 4 figs., 1 tab

  11. Unraveling the Complexities of Androgen Receptor Signaling in Prostate Cancer Cells

    OpenAIRE

    Heemers, Hannelore V.; Tindall, Donald J.

    2009-01-01

    Androgen signaling is critical for proliferation of prostate cancer cells but cannot be fully inhibited by current androgen deprivation therapies. A study by Xu et al. in this issue of Cancer Cell provides insights into the complexities of androgen signaling in prostate cancer and suggests avenues to target a subset of androgen-sensitive genes.

  12. Intermittent Rivers and Biodiversity. Large scale analyses between hydrology and ecology in intermittent rivers

    OpenAIRE

    Blanchard, Q.

    2014-01-01

    Intermittent rivers are characterized by a temporary interruption of their flow which can manifest in a variety of ways, as much on a spatial scale as on a temporal one. This particular aspect of intermittent river hydrology gives rise to unique ecosystems, combining both aquatic and terrestrial habitats. Neglected for a long time by scientists and once considered biologically depauperate and ecologically unimportant, these fragile habitats are nowadays acknowledged for their rendered service...

  13. Androgens and estrogens in skeletal sexual dimorphism

    Directory of Open Access Journals (Sweden)

    Michaël Laurent

    2014-04-01

    Full Text Available Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T to estradiol (E2 by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refi ned our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen defi ciency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the fi eld of sex steroid actions in male bone homeostasis.

  14. Androgens and estrogens in skeletal sexual dimorphism

    Science.gov (United States)

    Laurent, Michaël; Antonio, Leen; Sinnesael, Mieke; Dubois, Vanessa; Gielen, Evelien; Classens, Frank; Vanderschueren, Dirk

    2014-01-01

    Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone (T) to estradiol (E2) by aromatase, or to dihydrotestosterone by 5α-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of (high resolution) peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis. PMID:24385015

  15. Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

    International Nuclear Information System (INIS)

    Liu, Qi; Wan, Qilong; Yang, Rongtao; Zhou, Haihua; Li, Zubing

    2012-01-01

    Highlights: ► Different PTH administration exerts different effects on condylar chondrocyte. ► Intermittent PTH administration suppresses condylar chondrocyte proliferation. ► Continuous PTH administration maintains condylar chondrocyte proliferating. ► Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presented enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.

  16. Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Qi; Wan, Qilong; Yang, Rongtao; Zhou, Haihua [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China); Li, Zubing, E-mail: lizubing0827@163.com [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China); Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presented enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular

  17. Increased MCP-1 gene expression in monocytes of severe OSA patients and under intermittent hypoxia.

    Science.gov (United States)

    Chuang, Li-Pang; Chen, Ning-Hung; Lin, Yuling; Ko, Wen-Shan; Pang, Jong-Hwei S

    2016-03-01

    Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. Monocyte chemoattractant protein-1 (MCP-1), as a critical factor for monocyte infiltration, is known to play a role in the development of atherosclerosis. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the MCP-1 expression of monocytes. Peripheral blood was sampled from 61 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of MCP-1. The effect of in vitro intermittent hypoxia on the regulation and function of MCP-1 was investigated on THP-1 monocytic cells and human monocytes. The mRNA and secreted protein levels were investigated by RT/real-time PCR and enzyme-linked immunosorbent assay, respectively. Monocytic MCP-1 gene expression was found to be increased significantly in severe OSA patients. In vitro intermittent hypoxia was demonstrated to increase the mRNA and protein expression levels of MCP-1 dose- and time-dependently in THP-1 monocytic cells. The MCP-1 mRNA expression in monocytes isolated from OSA patient was induced to a much higher level compared to that from normal control. Pre-treatment with inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of MCP-1 expression by intermittent hypoxia. This is the first study to demonstrate the increase of MCP-1 gene expression in monocytes of severe OSA patients. In addition, monocytic MCP-1 gene expression can be induced under intermittent hypoxia.

  18. Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome

    OpenAIRE

    Abbott, David H; Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Conley, Alan J

    2008-01-01

    Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of DHEAS, typical of PCOS women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in co...

  19. Androgens regulate gene expression in avian skeletal muscles.

    Directory of Open Access Journals (Sweden)

    Matthew J Fuxjager

    Full Text Available Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus, zebra finch (Taenopygia guttata, and ochre-bellied flycatcher (Mionectes oleagieus. Because skeletal muscles that control wing movement make up the bulk of a bird's body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T up-regulated expression of parvalbumin (PV and insulin-like growth factor I (IGF-I, two genes whose products enhance cellular Ca(2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction.

  20. ANABOLIC ANDROGENIC STEROIDS AND ADVERSE EVENTS OF THEIR APPLICATION

    Directory of Open Access Journals (Sweden)

    Nina Đukanović

    2011-08-01

    Full Text Available Anabolic androgenic steroids are synthetic compounds originating from testosterone. Their main effects are the control of development and expression of male secondary sexual characteristics, which are known as androgenic effects, and encourage muscle growth or anabolic effects. Anabolic androgenic steroids are most commonly used illegal substances. Besides these physiological effects, which are achieved using therapeutic doses of these preparations, higher doses than recommended, especially over the longer term, may be associated with the emergence of numerous adverse events. Adverse events may be registered in almost all organs and organ systems, but usually include changes in the reproductive system, skin, liver and cardiovascular system.

  1. Blood androgen levels in male baboons throughout the year

    International Nuclear Information System (INIS)

    Taranov, A.G.; Goncharov, N.P.

    1986-01-01

    This paper describes a study of possible dependence of the androgen level in male baboons on the time of year. Plasma was obtained by centrifugation of the blood at 3000 rpm and the following androgens were determined by radioimmunoassay, using chromatographic separation of the steroids on columns with celite: testosterone, 5s-dihydrotestosterone, and dehydroepiandrosterone. Plasma steriod concentrations were calculated and the results were subjected to statistical analysis by Students test. Seasonal change in the concentration of steroids in the animals' blood plasma were discovered. The results of androgen assay throughout the year and determination of their mean annual concentrations are shown

  2. Early androgen exposure and human gender development.

    Science.gov (United States)

    Hines, Melissa; Constantinescu, Mihaela; Spencer, Debra

    2015-01-01

    During early development, testosterone plays an important role in sexual differentiation of the mammalian brain and has enduring influences on behavior. Testosterone exerts these influences at times when the testes are active, as evidenced by higher concentrations of testosterone in developing male than in developing female animals. This article critically reviews the available evidence regarding influences of testosterone on human gender-related development. In humans, testosterone is elevated in males from about weeks 8 to 24 of gestation and then again during early postnatal development. Individuals exposed to atypical concentrations of testosterone or other androgenic hormones prenatally, for example, because of genetic conditions or because their mothers were prescribed hormones during pregnancy, have been consistently found to show increased male-typical juvenile play behavior, alterations in sexual orientation and gender identity (the sense of self as male or female), and increased tendencies to engage in physically aggressive behavior. Studies of other behavioral outcomes following dramatic androgen abnormality prenatally are either too small in their numbers or too inconsistent in their results, to provide similarly conclusive evidence. Studies relating normal variability in testosterone prenatally to subsequent gender-related behavior have produced largely inconsistent results or have yet to be independently replicated. For studies of prenatal exposures in typically developing individuals, testosterone has been measured in single samples of maternal blood or amniotic fluid. These techniques may not be sufficiently powerful to consistently detect influences of testosterone on behavior, particularly in the relatively small samples that have generally been studied. The postnatal surge in testosterone in male infants, sometimes called mini-puberty, may provide a more accessible opportunity for measuring early androgen exposure during typical development. This

  3. Intermittent control: a computational theory of human control.

    Science.gov (United States)

    Gawthrop, Peter; Loram, Ian; Lakie, Martin; Gollee, Henrik

    2011-02-01

    The paradigm of continuous control using internal models has advanced understanding of human motor control. However, this paradigm ignores some aspects of human control, including intermittent feedback, serial ballistic control, triggered responses and refractory periods. It is shown that event-driven intermittent control provides a framework to explain the behaviour of the human operator under a wider range of conditions than continuous control. Continuous control is included as a special case, but sampling, system matched hold, an intermittent predictor and an event trigger allow serial open-loop trajectories using intermittent feedback. The implementation here may be described as "continuous observation, intermittent action". Beyond explaining unimodal regulation distributions in common with continuous control, these features naturally explain refractoriness and bimodal stabilisation distributions observed in double stimulus tracking experiments and quiet standing, respectively. Moreover, given that human control systems contain significant time delays, a biological-cybernetic rationale favours intermittent over continuous control: intermittent predictive control is computationally less demanding than continuous predictive control. A standard continuous-time predictive control model of the human operator is used as the underlying design method for an event-driven intermittent controller. It is shown that when event thresholds are small and sampling is regular, the intermittent controller can masquerade as the underlying continuous-time controller and thus, under these conditions, the continuous-time and intermittent controller cannot be distinguished. This explains why the intermittent control hypothesis is consistent with the continuous control hypothesis for certain experimental conditions.

  4. Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor.

    Science.gov (United States)

    Batista, Rafael Loch; Rodrigues, Andresa De Santi; Machado, Aline Zamboni; Nishi, Mirian Yumie; Cunha, Flávia Siqueira; Silva, Rosana Barbosa; Costa, Elaine M F; Mendonca, Berenice B; Domenice, Sorahia

    2018-01-26

    Androgen insensitivity syndrome (AIS) is the most frequent etiology of 46,XY disorders of sex development (DSDs), and it is an X-linked disorder caused by mutations in the androgen receptor (AR) gene. AIS patients present a broad phenotypic spectrum and individuals with a partial phenotype present with different degrees of undervirilized external genitalia. There are more than 500 different AR gene allelic variants reported to be linked to AIS, but the presence of somatic mosaicisms has been rarely identified. In the presence of a wild-type AR gene, a significant degree of spontaneous virilization at puberty can be observed, and it could influence the gender assignment, genetic counseling and the clinical and psychological management of these patients and the psychosexual outcomes of these patients are not known. In this study, we report two patients with AR allelic variants in heterozygous (c.382G>T and c.1769-1G>C) causing a partial AIS (PAIS) phenotype. The first patient was raised as female and she had undergone a gonadectomy at puberty. In both patients there was congruency between gender of rearing and gender identity and gender role. Somatic mosaicism is rare in AIS and nonsense AR variant allelic can cause partial AIS phenotype in this situation. Despite the risk of virilization and prenatal androgen exposure, the gender identity and gender role was concordant with sex of rearing in both cases. A better testosterone response can be expected in male individuals and this should be considered in the clinical management.

  5. CONDITIONED ANALYSIS OF HIGH-LATITUDE SOLAR WIND INTERMITTENCY

    International Nuclear Information System (INIS)

    D'Amicis, R.; Consolini, G.; Bavassano, B.; Bruno, R.

    2012-01-01

    The solar wind is a turbulent medium displaying intermittency. Its intermittent features have been widely documented and studied, showing how the intermittent character is different in fast and slow wind. In this paper, a statistical conditioned analysis of the solar wind intermittency for a period of high-latitude fast solar wind is presented. In particular, the intermittent features are investigated as a function of the Alfvénic degree of fluctuations at a given scale. The results show that the main contribution to solar wind intermittency is due to non-Alfvénic structures, while Alfvénic increments are found to be characterized by a smaller level of intermittency than the previous ones. Furthermore, the lifetime statistics of Alfvénic periods are discussed in terms of a multiscale texture of randomly oriented flux tubes.

  6. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  7. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

    Science.gov (United States)

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

  8. Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

    Science.gov (United States)

    Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

    2016-01-01

    Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

  9. Intermittent character of interplanetary magnetic field fluctuations

    International Nuclear Information System (INIS)

    Bruno, Roberto; Carbone, Vincenzo; Chapman, Sandra; Hnat, Bogdan; Noullez, Alain; Sorriso-Valvo, Luca

    2007-01-01

    Interplanetary magnetic field magnitude fluctuations are notoriously more intermittent than velocity fluctuations in both fast and slow wind. This behavior has been interpreted in terms of the anomalous scaling observed in passive scalars in fully developed hydrodynamic turbulence. In this paper, the strong intermittent nature of the interplanetary magnetic field is briefly discussed comparing results performed during different phases of the solar cycle. The scaling properties of the interplanetary magnetic field magnitude show solar cycle variation that can be distinguished in the scaling exponents revealed by structure functions. The scaling exponents observed around the solar maximum coincide, within the errors, to those measured for passive scalars in hydrodynamic turbulence. However, it is also found that the values are not universal in the sense that the solar cycle variation may be reflected in dependence on the structure of the velocity field

  10. Intermittency exponent of the turbulent energy cascade

    International Nuclear Information System (INIS)

    Cleve, J.; Greiner, M.; Pearson, B.R.; Sreenivasan, K.R.

    2006-12-01

    We consider the turbulent energy dissipation from one-dimensional records in experiments using air and gaseous helium at cryogenic temperatures, and obtain the intermittency exponent via the two-point correlation function of the energy dissipation. The air data are obtained in a number of flows in a wind tunnel and the atmospheric boundary layer at a height of about 35 m above the ground. The helium data correspond to the centerline of a jet exhausting into a container. The air data on the intermittency exponent are consistent with each other and with a trend that increases with the Taylor microscale Reynolds number, R λ , of up to about 1000 and saturates thereafter. On the other hand, the helium data cluster around a constant value at nearly all R λ , this being about half of the asymptotic value for the air data. Some possible explanation is offered for this anomaly. (author)

  11. Effects of intermittent hypoxia on running economy.

    Science.gov (United States)

    Burtscher, M; Gatterer, H; Faulhaber, M; Gerstgrasser, W; Schenk, K

    2010-09-01

    We investigated the effects of two 5-wk periods of intermittent hypoxia on running economy (RE). 11 male and female middle-distance runners were randomly assigned to the intermittent hypoxia group (IHG) or to the control group (CG). All athletes trained for a 13-wk period starting at pre-season until the competition season. The IHG spent additionally 2 h at rest on 3 days/wk for the first and the last 5 weeks in normobaric hypoxia (15-11% FiO2). RE, haematological parameters and body composition were determined at low altitude (600 m) at baseline, after the 5 (th), the 8 (th) and the 13 (th) week of training. RE, determined by the relative oxygen consumption during submaximal running, (-2.3+/-1.2 vs. -0.3+/-0.7 ml/min/kg, Ptraining phase. Georg Thieme Verlag KG Stuttgart . New York.

  12. Optimal intermittent search strategies: smelling the prey

    International Nuclear Information System (INIS)

    Revelli, J A; Wio, H S; Rojo, F; Budde, C E

    2010-01-01

    We study the kinetics of the search of a single fixed target by a searcher/walker that performs an intermittent random walk, characterized by different states of motion. In addition, we assume that the walker has the ability to detect the scent left by the prey/target in its surroundings. Our results, in agreement with intuition, indicate that the prey's survival probability could be strongly reduced (increased) if the predator is attracted (or repelled) by the trace left by the prey. We have also found that, for a positive trace (the predator is guided towards the prey), increasing the inhomogeneity's size reduces the prey's survival probability, while the optimal value of α (the parameter that regulates intermittency) ceases to exist. The agreement between theory and numerical simulations is excellent.

  13. Optimal intermittent search strategies: smelling the prey

    Energy Technology Data Exchange (ETDEWEB)

    Revelli, J A; Wio, H S [Instituto de Fisica de Cantabria, Universidad de Cantabria and CSIC, E-39005 Santander (Spain); Rojo, F; Budde, C E [Fa.M.A.F., Universidad Nacional de Cordoba, Ciudad Universitaria, X5000HUA Cordoba (Argentina)

    2010-05-14

    We study the kinetics of the search of a single fixed target by a searcher/walker that performs an intermittent random walk, characterized by different states of motion. In addition, we assume that the walker has the ability to detect the scent left by the prey/target in its surroundings. Our results, in agreement with intuition, indicate that the prey's survival probability could be strongly reduced (increased) if the predator is attracted (or repelled) by the trace left by the prey. We have also found that, for a positive trace (the predator is guided towards the prey), increasing the inhomogeneity's size reduces the prey's survival probability, while the optimal value of {alpha} (the parameter that regulates intermittency) ceases to exist. The agreement between theory and numerical simulations is excellent.

  14. Optimal Dynamics of Intermittent Water Supply

    Science.gov (United States)

    Lieb, Anna; Wilkening, Jon; Rycroft, Chris

    2014-11-01

    In many urban areas of the developing world, piped water is supplied only intermittently, as valves direct water to different parts of the water distribution system at different times. The flow is transient, and may transition between free-surface and pressurized, resulting in complex dynamical features with important consequences for water suppliers and users. These consequences include degradation of distribution system components, compromised water quality, and inequitable water availability. The goal of this work is to model the important dynamics and identify operating conditions that mitigate certain negative effects of intermittent water supply. Specifically, we will look at valve parameters occurring as boundary conditions in a network model of transient, transition flow through closed pipes. Optimization will be used to find boundary values to minimize pressure gradients and ensure equitable water availability.

  15. AN ELDERLY WOMAN WITH INTERMITTENT CLAUDICATION

    Directory of Open Access Journals (Sweden)

    Nayyer Naveed Wazir

    2006-01-01

    Full Text Available This case report illustrates the misdiagnosis of intermittent claudication in an elderly with multiple cardiac risk factors. Careful clinical evaluation and imaging shifts the diagnosis from peripheral vascular disease to spinal stenosis. The decision whether to offer conservative therapy or proceed to spinal surgery requires an accurate assessment of the severity of the symptoms without ignoring the important role of patient preferences.

  16. Long-range forecasting of intermittent streamflow

    OpenAIRE

    F. F. van Ogtrop; R. W. Vervoort; G. Z. Heller; D. M. Stasinopoulos; R. A. Rigby

    2011-01-01

    Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a statistical model to forecast streamflow up to 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS) to determine th...

  17. Long-range forecasting of intermittent streamflow

    OpenAIRE

    F. F. van Ogtrop; R. W. Vervoort; G. Z. Heller; D. M. Stasinopoulos; R. A. Rigby

    2011-01-01

    Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a probabilistic statistical model to forecast streamflow 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS) to determine the probabil...

  18. Androgenic alopecia in women: an Indian perspective.

    Science.gov (United States)

    Sehgal, Virendra N; Srivastava, Govind; Aggarwal, Ashok K; Midha, Reshmi

    2013-01-01

    The authors sought to investigate androgenic alopecia (AA) utilizing clinical and investigative procedures to establish the pattern of AA in the Indian subcontinent. A total of 35 consecutive women presenting with AA were included. After obtaining informed consent, a detailed history/examination, hair pull test, trichogram, and a scalp biopsy were performed in patients. AA classification was attempted across Ludwig and Norwood guidelines. Of 35 women, 16 had grade I, 10 had grade II, and 1 had grade III Ludwig classification. In addition, 6 other women had Christmas tree baldness: 1 each of fronto-parietal and male pattern baldness. Several investigations including hormonal profile were inconclusive; however, hair pull test and trichogram may be helpful in understanding the sequence in AA in women. AA has infrequently been reported, particularly India and in Asia in general.

  19. The transcriptional programme of the androgen receptor (AR) in prostate cancer.

    Science.gov (United States)

    Lamb, Alastair D; Massie, Charlie E; Neal, David E

    2014-03-01

    The androgen receptor (AR) is essential for normal prostate and prostate cancer cell growth. AR transcriptional activity is almost always maintained even in hormone relapsed prostate cancer (HRPC) in the absence of normal levels of circulating testosterone. Current molecular techniques, such as chromatin-immunoprecipitation sequencing (ChIP-seq), have permitted identification of direct AR-binding sites in cell lines and human tissue with a distinct coordinate network evident in HRPC. The effectiveness of novel agents, such as abiraterone acetate (suppresses adrenal androgens) or enzalutamide (MDV3100, potent AR antagonist), in treating advanced prostate cancer underlines the on-going critical role of the AR throughout all stages of the disease. Persistent AR activity in advanced disease regulates cell cycle activity, steroid biosynthesis and anabolic metabolism in conjunction with regulatory co-factors, such as the E2F family, c-Myc and signal transducer and activator of transcription (STAT) transcription factors. Further treatment approaches must target these other factors. © 2013 The Authors. BJU International © 2013 BJU International.

  20. IκBα mediates prostate cancer cell death induced by combinatorial targeting of the androgen receptor

    International Nuclear Information System (INIS)

    Carter, Sarah Louise; Centenera, Margaret Mary; Tilley, Wayne Desmond; Selth, Luke Ashton; Butler, Lisa Maree

    2016-01-01

    Combining different clinical agents to target multiple pathways in prostate cancer cells, including androgen receptor (AR) signaling, is potentially an effective strategy to improve outcomes for men with metastatic disease. We have previously demonstrated that sub-effective concentrations of an AR antagonist, bicalutamide, and the histone deacetylase inhibitor, vorinostat, act synergistically when combined to cause death of AR-dependent prostate cancer cells. In this study, expression profiling of human prostate cancer cells treated with bicalutamide or vorinostat, alone or in combination, was employed to determine the molecular mechanisms underlying this synergistic action. Cell viability assays and quantitative real time PCR were used to validate identified candidate genes. A substantial proportion of the genes modulated by the combination of bicalutamide and vorinostat were androgen regulated. Independent pathway analysis identified further pathways and genes, most notably NFKBIA (encoding IκBα, an inhibitor of NF-κB and p53 signaling), as targets of this combinatorial treatment. Depletion of IκBα by siRNA knockdown enhanced apoptosis of prostate cancer cells, while ectopic overexpression of IκBα markedly suppressed cell death induced by the combination of bicalutamide and vorinostat. These findings implicate IκBα as a key mediator of the apoptotic action of this combinatorial AR targeting strategy and a promising new therapeutic target for prostate cancer. The online version of this article (doi:10.1186/s12885-016-2188-2) contains supplementary material, which is available to authorized users

  1. Efficient search by optimized intermittent random walks

    International Nuclear Information System (INIS)

    Oshanin, Gleb; Lindenberg, Katja; Wio, Horacio S; Burlatsky, Sergei

    2009-01-01

    We study the kinetics for the search of an immobile target by randomly moving searchers that detect it only upon encounter. The searchers perform intermittent random walks on a one-dimensional lattice. Each searcher can step on a nearest neighbor site with probability α or go off lattice with probability 1 - α to move in a random direction until it lands back on the lattice at a fixed distance L away from the departure point. Considering α and L as optimization parameters, we seek to enhance the chances of successful detection by minimizing the probability P N that the target remains undetected up to the maximal search time N. We show that even in this simple model, a number of very efficient search strategies can lead to a decrease of P N by orders of magnitude upon appropriate choices of α and L. We demonstrate that, in general, such optimal intermittent strategies are much more efficient than Brownian searches and are as efficient as search algorithms based on random walks with heavy-tailed Cauchy jump-length distributions. In addition, such intermittent strategies appear to be more advantageous than Levy-based ones in that they lead to more thorough exploration of visited regions in space and thus lend themselves to parallelization of the search processes.

  2. Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment.

    Science.gov (United States)

    Vasconcelos, Andrea R; Yshii, Lidia M; Viel, Tania A; Buck, Hudson S; Mattson, Mark P; Scavone, Cristoforo; Kawamoto, Elisa M

    2014-05-06

    Systemic bacterial infections often result in enduring cognitive impairment and are a risk factor for dementia. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that intermittent fasting (IF) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of IF on the cognitive sequelae of systemic and brain inflammation is unknown. Rats on IF for 30 days received 1 mg/kg of lipopolysaccharide (LPS) or saline intravenously. Half of the rats were subjected to behavioral tests and the other half were euthanized two hours after LPS administration and the hippocampus was dissected and frozen for analyses. Here, we report that IF ameliorates cognitive deficits in a rat model of sepsis by a mechanism involving NF-κB activation, suppression of the expression of pro-inflammatory cytokines, and enhancement of neurotrophic support. Treatment of rats with LPS resulted in deficits in cognitive performance in the Barnes maze and inhibitory avoidance tests, without changing locomotor activity, that were ameliorated in rats that had been maintained on the IF diet. IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 levels. Taken together, our results suggest that IF induces adaptive responses in the brain and periphery that can suppress inflammation and preserve cognitive function in an animal model of systemic bacterial infection.

  3. Multiple arterial thromboses associated with anabolic androgenic steroids.

    Science.gov (United States)

    McCulloch, Neil Arthur; Abbas, Jonathan Raihan; Simms, Malcolm Harold

    2014-03-01

    The use of supraphysiological doses of anabolic androgenic steroids can have serious side effects. This article reports the case of a young man who suffered potentially life-threatening arterial thromboses following the use of these drugs.

  4. Performance of the Androgen Deficiency in Aging Male ...

    African Journals Online (AJOL)

    failure, chronic liver disease, chronic renal failure, tuberculosis, chronic obstructive pulmonary diseases, acquired immunodeficiency syndrome and malignancy. Relevant socio- demographic and diabetes-related information were documented. Clinical evaluation of androgen deficiency. Participants completed the original ...

  5. Plasma androgen concentrations in initial samples from spotted ...

    African Journals Online (AJOL)

    1990-01-31

    Jan 31, 1990 ... initial samples, the immobilization stress response and the response to exogenous GnRH administration, for ... the sex-specific differences in plasma androgens is confounded by other variables such as the reproductive.

  6. Three novel and two known androgen receptor gene mutations ...

    Indian Academy of Sciences (India)

    with androgen insensitivity syndrome in sex-reversed XY female patients. BALACHANDRAN .... Three novel AR gene mutations associated with AIS in XY sex-reversed females. Ta b le. 1 . ( contd. ) ..... disease, 1st edition. Springer Science + ...

  7. Three novel and two known androgen receptor gene mutations ...

    Indian Academy of Sciences (India)

    BALACHANDRAN SARANYA

    with androgen insensitivity syndrome in sex-reversed XY female patients. BALACHANDRAN ..... from the subjects, their family members and controls who participated in the ..... disease, 1st edition. Springer Science + Business Media, New.

  8. A PRACTICAL APPROACH TO THE DETECTION OF ANDROGEN RECEPTOR GENE-MUTATIONS AND PEDIGREE ANALYSIS IN FAMILIES WITH X-LINKED ANDROGEN INSENSITIVITY

    NARCIS (Netherlands)

    RISSTALPERS, C; HOOGENBOEZEM, T; SLEDDENS, HFBM; VERLEUNMOOIJMAN, MCT; DEGENHART, HJ; DROP, SLS; HALLEY, DJJ; Oosterwijk, Jan; HODGINS, MB; TRAPMAN, J; BRINKMANN, AO

    Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

  9. A practical approach to the detection of androgen receptor gene mutations and pedigree analysis in families with x-linked androgen insensitivity

    NARCIS (Netherlands)

    Ris-Stalpers, C.; Hoogenboezem, T.; Sleddens, H. F.; Verleun-Mooijman, M. C.; Degenhart, H. J.; Drop, S. L.; Halley, D. J.; Oosterwijk, J. C.; Hodgins, M. B.; Trapman, J.

    1994-01-01

    Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of

  10. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation

    NARCIS (Netherlands)

    H.T. Brüggenwirth (Hennie); A.L.M. Boehmer (Annemie); S. Ramnarain; M.C. Verleun-Mooijman; D.P.E. Satijn (David); J. Trapman (Jan); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

    1997-01-01

    textabstractIn the coding part and the intron-exon boundaries of the androgen-receptor gene of a patient with partial androgen insensitivity, no mutation was found. The androgen receptor of this patient displayed normal ligand-binding parameters and migrated as a

  11. Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor.

    Directory of Open Access Journals (Sweden)

    Biaoyang Lin

    2009-08-01

    Full Text Available The androgen receptor (AR plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied.Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR under different growth conditions (i.e. with or without androgens and at different concentration of androgens and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff even without the addition of androgens (i.e. in ethanol control, suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate cut off of 0.05. About 22.4% (638 of 2,849 can be mapped to within 2 kb of the transcription start site (TSS. Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/6,629. In contrast, only about 2.9% (190/6,629 of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database, which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor

  12. Luteinizing hormone-induced Akt phosphorylation and androgen production are modulated by MAP Kinase in bovine theca cells

    Directory of Open Access Journals (Sweden)

    Fukuda Shin

    2009-11-01

    Full Text Available Abstract Background Theca cells play an important role in controlling ovarian steroidogenesis by providing aromatizable androgens for granulosa cell estrogen biosynthesis. Although it is well established that the steroidogenic activity of theca cells is mainly regulated by LH, the intracellular signal transduction mechanisms that regulate thecal proliferation and/or steroidogenesis remain obscure. In this study, we examined whether and how LH controls the PI3K/Akt signaling pathway and androgen production in bovine theca cells. We also explored whether this LH-induced PI3K/Akt activation is modulated with other signaling pathways (i.e. PKA and MAPK. Methods Ovarian theca cells were isolated from bovine small antral follicles and were incubated with LH for various durations. Phospho-Akt and total-Akt content in the cultured theca cells were examined using Western blotting. Androstenedione levels in the spent media were determined using EIA. Semi-quantitative RT-PCR analyses were conducted to analyze the mRNA levels of CYP17A1 and StAR in the theca cells. To examine whether Akt activity is involved in theca cell androgen production, the PI3K inhibitors wortmannin and LY294002 were also added to the cells. Results Akt is constitutively expressed, but is gradually phosphorylated in cultured bovine theca cells through exposure to LH. LH significantly increased androstenedione production in bovine theca cells, whereas addition of the wortmannin and LY294002 significantly decreased LH-induced androstenedione production. LH significantly increased CYP17A1 mRNA level in theca cells, whereas addition of LY294002 significantly decreased LH-induced CYP17A1 expression. Neither LH nor PI3K inhibitors alter the mRNA levels of StAR in theca cells. Although H89 (a selective inhibitor of PKA does not affect LH-mediated changes in Akt, U0126 (a potent MEK inhibitor suppressed LH-induced Akt phosphorylation, CYP17A1 expression, and androgen production in theca

  13. Smoking Patterns and Stimulus Control in Intermittent and Daily Smokers

    Science.gov (United States)

    Shiffman, Saul; Dunbar, Michael S.; Li, Xiaoxue; Scholl, Sarah M.; Tindle, Hilary A.; Anderson, Stewart J.; Ferguson, Stuart G.

    2014-01-01

    Intermittent smokers (ITS) – who smoke less than daily – comprise an increasing proportion of adult smokers. Their smoking patterns challenge theoretical models of smoking motivation, which emphasize regular and frequent smoking to maintain nicotine levels and avoid withdrawal, but yet have gone largely unexamined. We characterized smoking patterns among 212 ITS (smoking 4–27 days per month) compared to 194 daily smokers (DS; smoking 5–30 cigarettes daily) who monitored situational antecedents of smoking using ecological momentary assessment. Subjects recorded each cigarette on an electronic diary, and situational variables were assessed in a random subset (n = 21,539 smoking episodes); parallel assessments were obtained by beeping subjects at random when they were not smoking (n = 26,930 non-smoking occasions). Compared to DS, ITS' smoking was more strongly associated with being away from home, being in a bar, drinking alcohol, socializing, being with friends and acquaintances, and when others were smoking. Mood had only modest effects in either group. DS' and ITS' smoking were substantially and equally suppressed by smoking restrictions, although ITS more often cited self-imposed restrictions. ITS' smoking was consistently more associated with environmental cues and contexts, especially those associated with positive or “indulgent” smoking situations. Stimulus control may be an important influence in maintaining smoking and making quitting difficult among ITS. PMID:24599056

  14. Smoking patterns and stimulus control in intermittent and daily smokers.

    Directory of Open Access Journals (Sweden)

    Saul Shiffman

    Full Text Available Intermittent smokers (ITS - who smoke less than daily - comprise an increasing proportion of adult smokers. Their smoking patterns challenge theoretical models of smoking motivation, which emphasize regular and frequent smoking to maintain nicotine levels and avoid withdrawal, but yet have gone largely unexamined. We characterized smoking patterns among 212 ITS (smoking 4-27 days per month compared to 194 daily smokers (DS; smoking 5-30 cigarettes daily who monitored situational antecedents of smoking using ecological momentary assessment. Subjects recorded each cigarette on an electronic diary, and situational variables were assessed in a random subset (n=21,539 smoking episodes; parallel assessments were obtained by beeping subjects at random when they were not smoking (n=26,930 non-smoking occasions. Compared to DS, ITS' smoking was more strongly associated with being away from home, being in a bar, drinking alcohol, socializing, being with friends and acquaintances, and when others were smoking. Mood had only modest effects in either group. DS' and ITS' smoking were substantially and equally suppressed by smoking restrictions, although ITS more often cited self-imposed restrictions. ITS' smoking was consistently more associated with environmental cues and contexts, especially those associated with positive or "indulgent" smoking situations. Stimulus control may be an important influence in maintaining smoking and making quitting difficult among ITS.

  15. Intermittent Oral Versus Intravenous Alfacalcidol in Dialysis Patients

    Directory of Open Access Journals (Sweden)

    Mitwalli Ahmed

    2000-01-01

    Full Text Available Patients with end-stage renal failure (ESRF on maintenance dialysis, commonly develop secondary hyperparathyroidism and renal osteodystrophy (ROD. Alfacalcidol, taken orally or administered intravenously, is known to reverse these complications. In this study, 19 ESRF patients, who were on dialysis (13 on hemodialysis and six on peritoneal dialysis for longer than six months and having serum parathormone levels at least four times normal and serum calcium less than 2.1 mmol/L, were randomly allocated to treatment with oral or intravenous (i.v. alfacalcidol for a period of 12 months. There were six patients on hemodialysis (HD and three on peritoneal dialysis (PD in the oral treatment group while in the i.v. group there were seven patients on HD and three on PD. Clinical and serial biochemical assessments showed no statistically significant difference between the orally- and i.v.-treated patients in terms of suppressing secondary hyperparathyroidism and osteodystrophy. However, patients with features of mild ROD on bone histology, had more satisfactory changes in biochemistry when compared to others. Our results further support the use of intermittent oral alfacalcidol in ESRF patients because of its cost effectiveness, ease of administration and convenience, especially for peritoneal dialysis patients.

  16. Androgen receptor and histone lysine demethylases in ovine placenta.

    Directory of Open Access Journals (Sweden)

    Ellane R Cleys

    Full Text Available Sex steroid hormones regulate developmental programming in many tissues, including programming gene expression during prenatal development. While estradiol is known to regulate placentation, little is known about the role of testosterone and androgen signaling in placental development despite the fact that testosterone rises in maternal circulation during pregnancy and in placenta-induced pregnancy disorders. We investigated the role of testosterone in placental gene expression, and focused on androgen receptor (AR. Prenatal androgenization decreased global DNA methylation in gestational day 90 placentomes, and increased placental expression of AR as well as genes involved in epigenetic regulation, angiogenesis, and growth. As AR complexes with histone lysine demethylases (KDMs to regulate AR target genes in human cancers, we also investigated if the same mechanism is present in the ovine placenta. AR co-immunoprecipitated with KDM1A and KDM4D in sheep placentomes, and AR-KDM1A complexes were recruited to a half-site for androgen response element (ARE in the promoter region of VEGFA. Androgenized ewes also had increased cotyledonary VEGFA. Finally, in human first trimester placental samples KDM1A and KDM4D immunolocalized to the syncytiotrophoblast, with nuclear KDM1A and KDM4D immunostaining also present in the villous stroma. In conclusion, placental androgen signaling, possibly through AR-KDM complex recruitment to AREs, regulates placental VEGFA expression. AR and KDMs are also present in first trimester human placenta. Androgens appear to be an important regulator of trophoblast differentiation and placental development, and aberrant androgen signaling may contribute to the development of placental disorders.

  17. Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

    Science.gov (United States)

    2015-06-01

    Wittmann, B.; Dwyer, M.; Cui, H.; Dye, D.; McDonnell, D.; Norris , J. Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists...Wittmann, B.; Dwyer, M.; Cui, H.; Dye, D.; McDonnell, D.; Norris , J. Inhibition of prostate cancer cell growth by second-site androgen receptor...important clin- ical problem in diseases such as asthma (51, 52), ne- phrotic syndrome (53), and malignancies such as acute lymphoblastic leukemia (54

  18. Anabolic-androgenic steroids for alcoholic liver disease

    DEFF Research Database (Denmark)

    Rambaldi, A; Iaquinto, G; Gluud, C

    2003-01-01

    Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

  19. Muscle Dysfunction in Androgen Deprivation: Role of Ryanodine Receptor

    Science.gov (United States)

    2016-11-01

    reversible pharmacological treatment is a key therapeutic goal in prostate cancer patients. This life prolonging treatment is accompanied by the adverse... reversible pharmacological treatment, is a key therapeutic goal of androgen deprivation therapies (ADT) used in patients with androgen-dependent...gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab. Aug 2000;85(8):2839

  20. Estrogens and Androgens in Skeletal Physiology and Pathophysiology

    OpenAIRE

    Almeida, Maria; Laurent, Michaël R.; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A.; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C.

    2016-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably t...

  1. Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

    Science.gov (United States)

    Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

    2014-08-01

    Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

  2. Dexamethasone-suppression adrenal scintigraphy in hyperandrogenism: concise communication

    Energy Technology Data Exchange (ETDEWEB)

    Gross, M.D.; Freitas, J.E.; Swanson, D.P.; Woodbury, M.C.; Schteingart, D.E.; Beierwaltes, W.H.

    1981-01-01

    To assess the contribution of adrenal-derived androgens in women with hirsutism, adrenal scintigrams under dexamethasone suppression (DS) were performed on 35 women with increasing facial or body hair and irregular or absent menses. Based upon the DS regimen chosen (8 mg/d for 2 days or 4 md/d for 7 days before the injection of 6..beta..-(/sup 131/I)iodomethylnorcholesterol), three imaging patterns were identified. The first was the absence of uptake before 3 days (8-mg DS) or before 5 days (4-mg DS) after injection. This imaging pattern was seen in 17 of the 35 patients studied and was considered normal. The second pattern was bilateral uptake earlier than 3 days (8-mg DS regimen) or 5 days (4-mg DS) after injection. This was seen in 13 of the 35 patients and was interpreted as bilateral early visualization. Adrenal-vein catheterization performed on six patients with this pattern showed increased adrenal-vein testosterone. The third pattern, observed in five patients, was unilateral early visualization, which in four cases investigated to date was the result of an adrenocortical adenoma. This study confirms the adrenal cortex as a source of androgens in women with hirsutism and hyperandrogenism and demonstrates that DS adrenal scintigraphy can be utilized to identify those women in whom adrenal-derived androgens contribute to their hyperandrogenism.

  3. Dissecting the roles of the androgen receptor in prostate cancer from molecular perspectives.

    Science.gov (United States)

    Hu, Jieping; Wang, Gongxian; Sun, Ting

    2017-05-01

    Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants' formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.

  4. Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters.

    Science.gov (United States)

    Otsuki, Hideo; Kimura, Toru; Yamaga, Takashi; Kosaka, Takeo; Suehiro, Jun-Ichi; Sakurai, Hiroyuki

    2017-02-01

    Leucine stimulates cancer cell proliferation through the mTOR pathway, therefore, inhibiting leucine transporters may be a novel therapeutic target for cancer. L-type amino acid transporter (LAT) 1, a Na + -independent amino acid transporter, is highly expressed in many tumor cells. However, leucine transporter(s) in different stages of prostate cancer, particularly in the stages of castration resistance with androgen receptor (AR) expression, is unclear. LNCaP and DU145 and PC-3 cell lines were used as a model of androgen dependent, and metastatic prostate cancer. A new "LN-cr" cell line was established after culturing LNCaP cells for 6 months under androgen-free conditions, which is considered a model of castration resistant prostate cancer (CRPC) with androgen AR expression. The expression of leucine transporters was investigated with quantitative PCR and immunofluorescence. Uptake of 14 C Leucine was examined in the presence or absence of BCH (a pan-LAT inhibitor), JPH203 (an LAT1-specific inhibitor), or Na + . Cell growth was assessed with MTT assay. siRNA studies were performed to evaluate the indispensability of y + LAT2 on leucine uptake and cell viability in LN-cr. Cell viability showed a 90% decrease in the absence of leucine in all four cell lines. LNCaP cells principally expressed LAT3, and their leucine uptake was more than 90% Na + -independent. BCH, but not JPH203, inhibited leucine uptake, and cell proliferation (IC 50BCH :15 mM). DU145 and PC-3 cells predominantly expressed LAT1. Leucine uptake and cell growth were suppressed by BCH or JPH203 in a dose-dependent manner (IC 50BCH : ∼20 mM, IC 50JPH203 : ∼5 µM). In LN-cr cells, Na + -dependent uptake of leucine was 3.8 pmol/mgprotein/min, while, Na + -independent uptake was only 0.52 (P prostate cancer. Prostate 77:222-233, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  5. Female adipocyte androgen synthesis and the effects of insulin

    Directory of Open Access Journals (Sweden)

    David Cadagan

    2014-01-01

    Full Text Available The metabolic syndrome is a cluster of metabolic disorders characterized by insulin resistance and hyperinsulinaemia, and its presence can increase the risk of cardiovascular disease significantly. The metabolic syndrome is associated with increased circulating androgen levels in women, which may originate from the ovaries and adrenal glands. Adipocytes are also able to synthesise steroid hormones, and this output has been hypothesised to increase with elevated insulin plasma concentrations. However, the contribution of the adipocytes to the circulating androgen levels in women with metabolic syndrome is limited and the effects of insulin are not fully understood. The aim of this study was to investigate the presence of steroid precursors and synthetic enzymes in human adipocyte biopsies as markers of possible adipocyte androgen synthesis. We examined pre and mature adipocytes taken from tissue biopsies of abdominal subcutaneous adipose tissue of participating women from the Department of Obstetrics and Gynaecology, of the Royal Derby Hospital. The results showed the potential for localised adipocyte androgen synthesis through the presence of the androgen precursor progesterone, as well as the steroid-converting enzyme 17α-hydroxylase. Furthermore, we found the controlled secretion of androstenedione in vitro and that insulin treatment caused levels to increase. Continued examination of a localised source of androgen production is therefore of clinical relevance due to its influence on adipocyte metabolism, its negative impact on female steroidogenic homeostasis, and the possible aggravation this may have when associated to obesity and obesity related metabolic abnormalities such as hyperinsulinaemia.

  6. Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

    Science.gov (United States)

    Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

    2017-01-01

    Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

  7. Testosterone regulates the autophagic clearance of androgen binding protein in rat Sertoli cells

    Science.gov (United States)

    Ma, Yi; Yang, Hao-Zheng; Xu, Long-Mei; Huang, Yi-Ran; Dai, Hui-Li; Kang, Xiao-Nan

    2015-01-01

    Dysregulation of androgen-binding protein (ABP) is associated with a number of endocrine and andrology diseases. However, the ABP metabolism in Sertoli cells is largely unknown. We report that autophagy degrades ABP in rat Sertoli cells, and the autophagic clearance of ABP is regulated by testosterone, which prolongs the ABP biological half-life by inhibiting autophagy. Further studies identified that the autophagic clearance of ABP might be selectively regulated by testosterone, independent of stress (hypoxia)-induced autophagic degradation. These data demonstrate that testosterone up-regulates ABP expression at least partially by suppressing the autophagic degradation. We report a novel finding with respect to the mechanisms by which ABP is cleared, and by which the process is regulated in Sertoli cells. PMID:25745956

  8. Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

    Energy Technology Data Exchange (ETDEWEB)

    Whang, Kee Suk [Kyungpook National University School of Medicine, Deagu (Korea, Republic of)

    1967-03-15

    Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma-{sup 59}Fe-disappearance rate, RBC {sup 59}Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

  9. Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

    International Nuclear Information System (INIS)

    Whang, Kee Suk

    1967-01-01

    Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma- 59 Fe-disappearance rate, RBC 59 Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

  10. Dexamethasone suppression test

    Science.gov (United States)

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medicine. Afterward, your blood is drawn ...

  11. The ErbB family and androgen receptor signaling are targets of Celecoxib in prostate cancer.

    Science.gov (United States)

    Brizzolara, Antonella; Benelli, Roberto; Venè, Roberta; Barboro, Paola; Poggi, Alessandro; Tosetti, Francesca; Ferrari, Nicoletta

    2017-08-01

    Inflammation plays a central role in prostate cancer (PCa) development through significant crosstalk between the COX-2-ErbB family receptor network and androgen receptor (AR)-EGFR signaling pathways. The purpose of this work was to determine the ability of the COX-2 inhibitor Celecoxib to modulate the EGFR-AR signaling pathway in androgen-dependent PCa cells and to provide a rationale for its beneficial use in chemopreventive strategies. Functional studies of Celecoxib activity were performed on LNCaP prostate cancer cells. Western blotting, gene expression analysis, dual-luciferase reporter assay and ELISA were applied to assess the Celecoxib mechanisms of action. We found that Celecoxib, through EGF and amphiregulin (AREG) induction, caused EGFR and ErbB2 activation and consequent degradation associated with the inhibition of androgenic signaling. By upregulating the E3 ubiquitin ligase Nrdp1, Celecoxib also efficiently downregulated ErbB3, which is strongly implicated in castration-resistant prostate cancer. Lastly, Celecoxib directly regulated AR transcription and translation independent of ErbB activation by downregulating the RNA binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K). The simultaneous suppression of ErbB kinases and androgen signaling by Celecoxib represents a novel strategy to interrupt the vicious cycle of AR/ErbB cross-talk with the primary purpose of undermining their resilient signaling in prostate cancer progression. Our data provide important premises for the chemopreventive use of Celecoxib in the clinical management of prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Deconstructing continuous flash suppression

    OpenAIRE

    Yang, Eunice; Blake, Randolph

    2012-01-01

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in co...

  13. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment

    DEFF Research Database (Denmark)

    Juul, A; Müller, J; Skakkebaek, N E

    1997-01-01

    antigen (PSA) is a marker of the androgen-dependent prostatic epithelial cell activity and it is used in the diagnosis and surveillance of adult patients with prostatic cancer. We have measured PSA concentrations in serum from boys with precocious puberty before and during gonadal suppression with Gn......In healthy boys, the pituitary-gonadal axis exhibits diurnal variation in early puberty. Serum testosterone levels are higher during the night and low or immeasurable during the day. These fluctuating levels of circulating androgens in early pubertal boys are difficult to monitor. Prostate specific...

  14. The promotion on cell growth of androgen-dependent prostate cancer by antimony via mimicking androgen activity.

    Science.gov (United States)

    Zhang, Changwen; Li, Penghao; Wen, Yingwu; Feng, Guowei; Liu, Yu; Zhang, Yangyi; Xu, Yong; Zhang, Zhihong

    2018-05-15

    Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Hovering and intermittent flight in birds

    International Nuclear Information System (INIS)

    Tobalske, Bret W

    2010-01-01

    Two styles of bird locomotion, hovering and intermittent flight, have great potential to inform future development of autonomous flying vehicles. Hummingbirds are the smallest flying vertebrates, and they are the only birds that can sustain hovering. Their ability to hover is due to their small size, high wingbeat frequency, relatively large margin of mass-specific power available for flight and a suite of anatomical features that include proportionally massive major flight muscles (pectoralis and supracoracoideus) and wing anatomy that enables them to leave their wings extended yet turned over (supinated) during upstroke so that they can generate lift to support their weight. Hummingbirds generate three times more lift during downstroke compared with upstroke, with the disparity due to wing twist during upstroke. Much like insects, hummingbirds exploit unsteady mechanisms during hovering including delayed stall during wing translation that is manifest as a leading-edge vortex (LEV) on the wing and rotational circulation at the end of each half stroke. Intermittent flight is common in small- and medium-sized birds and consists of pauses during which the wings are flexed (bound) or extended (glide). Flap-bounding appears to be an energy-saving style when flying relatively fast, with the production of lift by the body and tail critical to this saving. Flap-gliding is thought to be less costly than continuous flapping during flight at most speeds. Some species are known to shift from flap-gliding at slow speeds to flap-bounding at fast speeds, but there is an upper size limit for the ability to bound (∼0.3 kg) and small birds with rounded wings do not use intermittent glides.

  16. Hovering and intermittent flight in birds

    Energy Technology Data Exchange (ETDEWEB)

    Tobalske, Bret W, E-mail: bret.tobalske@mso.umt.ed [Field Research Station at Fort Missoula, Division of Biological Sciences, University of Montana, Missoula, MT 59812 (United States)

    2010-12-15

    Two styles of bird locomotion, hovering and intermittent flight, have great potential to inform future development of autonomous flying vehicles. Hummingbirds are the smallest flying vertebrates, and they are the only birds that can sustain hovering. Their ability to hover is due to their small size, high wingbeat frequency, relatively large margin of mass-specific power available for flight and a suite of anatomical features that include proportionally massive major flight muscles (pectoralis and supracoracoideus) and wing anatomy that enables them to leave their wings extended yet turned over (supinated) during upstroke so that they can generate lift to support their weight. Hummingbirds generate three times more lift during downstroke compared with upstroke, with the disparity due to wing twist during upstroke. Much like insects, hummingbirds exploit unsteady mechanisms during hovering including delayed stall during wing translation that is manifest as a leading-edge vortex (LEV) on the wing and rotational circulation at the end of each half stroke. Intermittent flight is common in small- and medium-sized birds and consists of pauses during which the wings are flexed (bound) or extended (glide). Flap-bounding appears to be an energy-saving style when flying relatively fast, with the production of lift by the body and tail critical to this saving. Flap-gliding is thought to be less costly than continuous flapping during flight at most speeds. Some species are known to shift from flap-gliding at slow speeds to flap-bounding at fast speeds, but there is an upper size limit for the ability to bound ({approx}0.3 kg) and small birds with rounded wings do not use intermittent glides.

  17. Renewable energies: the cost of intermittency

    International Nuclear Information System (INIS)

    Crassous, Renaud; Roques, Fabien

    2013-01-01

    The authors indicate the different adaptations which will be required for the electric system to cope with the intermittency of solar and wind energy production, and propose an approximate assessment of the associated costs. Different types of adaptation are addressed: secure production in case of absence of wind or sun (electricity imports, construction of additional power stations), use of more flexible production means (gas turbines), grid extensions (connection to offshore production sites, routing of production one part of the country to the other). They think that beyond a 20 per cent share for renewable energies, these costs could rapidly increase

  18. Spatio-temporal intermittency on the sandpile

    International Nuclear Information System (INIS)

    Erzan, A.; Sinha, S.

    1990-08-01

    The self-organized critical state exhibited by a sandpile model is shown to correspond to motion on an attractor characterized by an invariant distribution of the height variable. The largest Lyapunov exponent is equal to zero. The model nonetheless displays intermittent chaos, with a multifractal distribution of local expansion coefficients in history space. Laminar spatio-temporal regions are interrupted by chaotic bursts caused by avalanches. We introduce the concept of local histories in configuration space and show that their expansion parameters also exhibit a multifractal distribution in time and space. (author). 22 refs, 5 figs

  19. Intermittent claudication in a professional rugby player.

    Science.gov (United States)

    Bray, A E; Lewis, W A

    1992-04-01

    Intermittent claudication in a professional rugby player is described. The typical features of a delayed and difficult diagnosis of an external iliac artery stenosis were found. The noninvasive diagnostic protocol used to investigate this young patient with a minimal arterial lesion enabled accurate localization and angioplasty to be performed at the same time as diagnostic angiography. The patient was symptom free with normal arterial pressures on follow-up. It is suggested that appropriate noninvasive investigations should be performed before angiography in young people with minimal lesions.

  20. A stochastic model for intermittent search strategies

    International Nuclear Information System (INIS)

    Benichou, O; Coppey, M; Moreau, M; Suet, P H; Voituriez, R

    2005-01-01

    It is often necessary, in scientific or everyday life problems, to find a randomly hidden target. What is then the optimal strategy to reach it as rapidly as possible? In this article, we develop a stochastic theory for intermittent search behaviours, which are often observed: the searcher alternates phases of intensive search and slow motion with fast displacements. The first results of this theory have already been announced recently. Here we provide a detailed presentation of the theory, as well as the full derivation of the results. Furthermore, we explicitly discuss the minimization of the time needed to find the target

  1. Intermittent oral iron supplementation during pregnancy (Review)

    Science.gov (United States)

    Peña-Rosas, Juan Pablo; De-Regil, Luz Maria; Dowswell, Therese; Viteri, Fernando E

    2014-01-01

    Background Anaemia is a frequent condition during pregnancy, particularly among women from developing countries who have insufficient iron intake to meet increased iron needs of both the mother and the fetus. Traditionally, gestational anaemia has been prevented with the provision of daily iron supplements throughout pregnancy, but adherence to this regimen due to side effects, interrupted supply of the supplements, and concerns about safety among women with an adequate iron intake, have limited the use of this intervention. Intermittent (i.e. one, two or three times a week on non-consecutive days) supplementation with iron alone or in combination with folic acid or other vitamins and minerals has recently been proposed as an alternative to daily supplementation. Objectives To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (23 March 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing studies and contacted relevant organisations for the identification of ongoing and unpublished studies (23 March 2012). Selection criteria Randomised or quasi-randomised trials. Data collection and analysis We assessed the methodological quality of trials using standard Cochrane criteria. Two review authors independently assessed trial eligibility, extracted data and conducted checks for accuracy. Main results This review includes 21 trials from 13 different countries, but only 18 trials (with 4072 women) reported on our outcomes of interest and contributed data to the review. All of these studies compared daily versus intermittent iron supplementation. Three studies provided iron alone, 12 iron+folic acid and three more iron plus multiple vitamins and minerals. Their methodological quality was mixed

  2. Intermittent fasting and cardiovascular disease: current evidence and unresolved questions.

    Science.gov (United States)

    Tinsley, Grant M; Horne, Benjamin D

    2018-01-01

    Intermittent fasting has produced a variety of beneficial health effects in animal models, although high-quality research in humans has been limited. This special report examines current evidences for intermittent fasting in humans, discusses issues that require further examination, and recommends new research that can improve the knowledge base in this emerging research area. While potentially useful for health improvement, intermittent fasting requires further study prior to widespread implementation for health purposes. Randomized, longer-term studies are needed to determine whether using intermittent fasting as a lifestyle rather than a diet is feasible and beneficial for the health of some members of the human population.

  3. Atomistic Model of Fluorescence Intermittency of Colloidal Quantum Dots

    KAUST Repository

    Voznyy, O.; Sargent, E. H.

    2014-01-01

    with foreign cations can stabilize the vacancies, inhibiting intermittency and improving quantum yield, providing an explanation of recent experimental observations. © 2014 American Physical Society.

  4. Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

    Science.gov (United States)

    Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

    2017-03-02

    Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

  5. THE EFFECT OF ADRENAL MEDULLECTOMY ON METABOLIC RESPONSES TO CHRONIC INTERMITTENT HYPOXIA

    Science.gov (United States)

    Shin, Mi-Kyung; Han, Woobum; Bevans-Fonti, Shannon; Jun, Jonathan C.; Punjabi, Naresh M.; Polotsky, Vsevolod Y.

    2014-01-01

    Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with insulin resistance and type 2 diabetes. IH increases plasma catecholamine levels, which may increase insulin resistance and suppress insulin secretion. The objective of this study was to determine if adrenal medullectomy (MED) prevents metabolic dysfunction in IH. MED or sham surgery was performed in 60 male C57BL/6J mice, which were then exposed to IH or control conditions (intermittent air) for 6 weeks. IH increased plasma epinephrine and norepinephrine levels, increased fasting blood glucose and lowered basal and glucose-stimulated insulin secretion. MED decreased baseline epinephrine and prevented the IH induced increase in epinephrine, whereas the norepinephrine response remained intact. MED improved glucose tolerance in mice exposed to IH, attenuated the impairment in basal and glucose-stimulated insulin secretion, but did not prevent IH-induced fasting hyperglycemia or insulin resistance. We conclude that the epinephrine release from the adrenal medulla during IH suppresses insulin secretion causing hyperglycemia. PMID:25179887

  6. Androgen receptor function links human sexual dimorphism to DNA methylation.

    Directory of Open Access Journals (Sweden)

    Ole Ammerpohl

    Full Text Available Sex differences are well known to be determinants of development, health and disease. Epigenetic mechanisms are also known to differ between men and women through X-inactivation in females. We hypothesized that epigenetic sex differences may also result from sex hormone functions, in particular from long-lasting androgen programming. We aimed at investigating whether inactivation of the androgen receptor, the key regulator of normal male sex development, is associated with differences of the patterns of DNA methylation marks in genital tissues. To this end, we performed large scale array-based analysis of gene methylation profiles on genomic DNA from labioscrotal skin fibroblasts of 8 males and 26 individuals with androgen insensitivity syndrome (AIS due to inactivating androgen receptor gene mutations. By this approach we identified differential methylation of 167 CpG loci representing 162 unique human genes. These were significantly enriched for androgen target genes and low CpG content promoter genes. Additional 75 genes showed a significant increase of heterogeneity of methylation in AIS compared to a high homogeneity in normal male controls. Our data show that normal and aberrant androgen receptor function is associated with distinct patterns of DNA-methylation marks in genital tissues. These findings support the concept that transcription factor binding to the DNA has an impact on the shape of the DNA methylome. These data which derived from a rare human model suggest that androgen programming of methylation marks contributes to sexual dimorphism in the human which might have considerable impact on the manifestation of sex-associated phenotypes and diseases.

  7. Total glucosides of paeony inhibits lipopolysaccharide-induced proliferation, migration and invasion in androgen insensitive prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Zhi-Hui Zhang

    Full Text Available Previous studies demonstrated that inflammatory microenvironment promoted prostate cancer progression. This study investigated whether total glucosides of paeony (TGP, the active constituents extracted from the root of Paeonia Lactiflora Pall, suppressed lipopolysaccharide (LPS-stimulated proliferation, migration and invasion in androgen insensitive prostate cancer cells. PC-3 cells were incubated with LPS (2.0 μg/mL in the absence or presence of TGP (312.5 μg /mL. As expected, cells at S phase and nuclear CyclinD1, the markers of cell proliferation, were increased in LPS-stimulated PC-3 cells. Migration activity, as determined by wound-healing assay and transwell migration assay, and invasion activity, as determined by transwell invasion assay, were elevated in LPS-stimulated PC-3 cells. Interestingly, TGP suppressed LPS-stimulated PC-3 cells proliferation. Moreover, TGP inhibited LPS-stimulated migration and invasion of PC-3 cells. Additional experiment showed that TGP inhibited activation of nuclear factor kappa B (NF-κB and mitogen-activated protein kinase (MAPK/p38 in LPS-stimulated PC-3 cells. Correspondingly, TGP attenuated upregulation of interleukin (IL-6 and IL-8 in LPS-stimulated PC-3 cells. In addition, TGP inhibited nuclear translocation of signal transducer and activator of transcription 3 (STAT3 in LPS-stimulated PC-3 cells. These results suggest that TGP inhibits inflammation-associated STAT3 activation and proliferation, migration and invasion in androgen insensitive prostate cancer cells.

  8. Illicit Anabolic-Androgenic Steroid Use

    Science.gov (United States)

    Kanayama, Gen; Hudson, James I.; Pope, Harrison G.

    2009-01-01

    The anabolic-androgenic steroids (AAS) are a family of hormones that includes testosterone and its derivatives. These substances have been used by elite athletes since the 1950s, but they did not become widespread drugs of abuse in the general population until the 1980s. Thus, knowledge of the medical and behavioral effects of illicit AAS use is still evolving. Surveys suggest that many millions of boys and men, primarily in Western countries, have abused AAS to enhance athletic performance or personal appearance. AAS use among girls and women is much less common. Taken in supraphysiologic doses, AAS show various long-term adverse medical effects, especially cardiovascular toxicity. Behavioral effects of AAS include hypomanic or manic symptoms, sometimes accompanied by aggression or violence, which usually occur while taking AAS, and depressive symptoms occurring during AAS withdrawal. However, these symptoms are idiosyncratic and afflict only a minority of illicit users; the mechanism of these idiosyncratic responses remains unclear. AAS users may also ingest a range of other illicit drugs, including both “body-image” drugs to enhance physical appearance or performance, and classical drugs of abuse. In particular, AAS users appear particularly prone to opioid use. There may well be a biological basis for this association, since both human and animal data suggest that AAS and opioids may share similar brain mechanisms. Finally, AAS may cause a dependence syndrome in a substantial minority of users. AAS dependence may pose a growing public health problem in future years, but remains little studied. PMID:19769977

  9. Hematopoiesis-activating effects of androgen (fluoxymesterone)

    International Nuclear Information System (INIS)

    Shirakura, Takuo; Inoue, Tatsu; Maekawa, Tadashi.

    1978-01-01

    Hematopoiesis-activating effect of fluoxymesterone (FMT) (androgen preparation) on hematopoietic hematoblast was evaluated. The results were as follows. (1) To C 3 H/He strain male mice, 2 mg/day of FMT was injected into each femoral muscle alternatively. On the 5th day of the first injection, radioactive iron was injected intraperitoneally; after 48 hrs, blood was collected for examining the incorporation rate of 59 Fe. The results showed significant increase. (2) After 4 mg of FMT was injected once into the femoral muscle, spleen colony-forming cells (CFU-S) of the mouse femur were examined. Calculation of either of surface colonies and microscopic colonies showed absolute increase of the number of CFU-S in the femoral marrow. The microscopic colonies were classified into three colony types of erythrocytes, granulocytes, and megakaryocytes on the basis of histology of the cellular component; and changes were evaluated in each type of the colonies. This evaluation clarified that an increase in colonies which appeared 24 hrs after the injection of the hormon was due to an increase in the erythrocyte and megakaryocyte colonies and that which appeared 48 hrs after the injection was due to an increase in granulocyte colonies. (Ueda, J.)

  10. Mass spectrometry of selective androgen receptor modulators.

    Science.gov (United States)

    Thevis, Mario; Schänzer, Wilhelm

    2008-07-01

    Nonsteroidal selective androgen receptor modulators (SARMs) are an emerging class of drugs for treatment of various diseases including osteoporosis and muscle wasting as well as the correction of age-related functional decline such as muscle strength and power. Several SARMs, which have advanced to preclinical and clinical trials, are composed of diverse chemical structures including arylpropionamide-, bicyclic hydantoin-, quinoline-, and tetrahydroquinoline-derived nuclei. Since January 2008, SARMs have been categorized as anabolic agents and prohibited by the World Anti-Doping Agency (WADA). Suitable detection methods for these low-molecular weight drugs were based on mass spectrometric approaches, which necessitated the elucidation of dissociation pathways in order to characterize and identify the target analytes in doping control samples as well as potential metabolic products and synthetic analogs. Fragmentation patterns of representatives of each category of SARMs after electrospray ionization (ESI) and collision-induced dissociation (CID) as well as electron ionization (EI) are summarized. The complexity and structural heterogeneity of these drugs is a daunting challenge for detection methods. Copyright 2008 John Wiley & Sons, Ltd.

  11. Predictors of future anabolic androgenic steroid use.

    Science.gov (United States)

    Wichstrøm, Lars

    2006-09-01

    To prospectively study the stability of anabolic androgenic steroid (AAS) use and predictors of AAS use, and to investigate whether AAS use alters the risk of later emotional and behavioral problems. Survey of a national sample of Norwegian high school students (age 15-19) in 1994 followed up in 1999 (N = 2924). Measures of frequent alcohol intoxication (50+ times per 12 months), cannabis use (12 months), hard drug use (12 months), being offered cannabis, eating problems, conduct problems, sexual debut before age 15, BMI, involvement in power sports, perceived physical appearance, and satisfaction with body parts were obtained. Life-time prevalence of AAS use were 1.9 and 0.8% in the follow-up period. Multivariate logistic regression revealed that future AAS use was predicted by young age, male gender, previous AAS use, involvement in power sports, and frequent alcohol intoxication. AAS use did not predict future emotional or behavioral problems other than reducing the risk of future frequent alcohol intoxication. Frequent alcohol intoxication and involvement in power sports appear to predict future AAS use. At the population level there was little stability in individual AAS use from adolescence to early adulthood. No detrimental effects of AAS use could be detected in this study, but low statistical power limits this conclusion.

  12. Review of Androgenic Anabolic Steroid Use

    Energy Technology Data Exchange (ETDEWEB)

    T. Borges; G. Eisele; C. Byrd

    2001-07-31

    An area that has been overlooked within personnel security evaluations is employee use of androgenic-anabolic steroids (AAS). Current drug testing within the federal government does not include testing for anabolic steroids, and the difficulties to implement such testing protocols-not to mention the cost involved-make AAS testing highly improbable. The basis of this report is to bring to the forefront the damage that anabolic steroids can cause from both a physical and a psychological standpoint. Most individuals who use AASs do so to increase their muscle mass because they wish to gain some type of competitive edge during athletic competition or they wish to enhance their physical features for self-satisfaction and self-esteem (i.e., body building). Security officers are one group of men who often take high doses of anabolic steroids, according to the Second Report of the Senate Standing Committee (1990). The negative psychological characteristics for AAS use is extensive and includes prominent hostility, aggressiveness, irritability, euphoria, grandiose beliefs, hyperactivity, reckless behavior, increased sexual appetite, unpredictability, poor impulse control, mood fluctuations, and insomnia. The drug may invoke a sense of power and invincibility (Leckman and Scahill, 1990). Depressive symptoms, such as anhedonia, fatigue, impaired concentration, decreased libido, and even suicidality (Pope and Katz, 1992) have been noted with steroid withdrawal. It appears that long-term users of AAS experience similar characteristics as other substance abusers (i.e., craving, dependence, and withdrawal symptoms).

  13. Randomized, controlled trial comparing synchronized intermittent mandatory ventilation and synchronized intermittent mandatory ventilation plus pressure support in preterm infants.

    Science.gov (United States)

    Reyes, Zenaida C; Claure, Nelson; Tauscher, Markus K; D'Ugard, Carmen; Vanbuskirk, Silvia; Bancalari, Eduardo

    2006-10-01

    Prolonged mechanical ventilation is associated with lung injury in preterm infants. In these infants, weaning from synchronized intermittent mandatory ventilation may be delayed by their inability to cope with increased respiratory loads. The addition of pressure support to synchronized intermittent mandatory ventilation can offset these loads and may facilitate weaning. The purpose of this work was to compare synchronized intermittent mandatory ventilation and synchronized intermittent mandatory ventilation plus pressure support in weaning from mechanical ventilation and the duration of supplemental oxygen dependency in preterm infants with respiratory failure. Preterm infants weighing 500 to 1000 g at birth who required mechanical ventilation during the first postnatal week were randomly assigned to synchronized intermittent mandatory ventilation or synchronized intermittent mandatory ventilation plus pressure support. In both groups, weaning followed a set protocol during the first 28 days. Outcomes were assessed during the first 28 days and until discharge or death. There were 107 infants enrolled (53 synchronized intermittent mandatory ventilation plus pressure support and 54 synchronized intermittent mandatory ventilation). Demographic and perinatal data, mortality, and morbidity did not differ between groups. During the first 28 days, infants in the synchronized intermittent mandatory ventilation plus pressure support group reached minimal ventilator settings and were extubated earlier than infants in the synchronized intermittent mandatory ventilation group. Total duration of mechanical ventilation, duration of oxygen dependency, and oxygen need at 36 weeks' postmenstrual age alone or combined with death did not differ between groups. However, infants in synchronized intermittent mandatory ventilation plus pressure support within the 700- to 1000-g birth weight strata had a shorter oxygen dependency. The results of this study suggest that the addition of

  14. Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemo-resistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

    Science.gov (United States)

    Cui, Yun; Sun, Yin; Hu, Shuai; Luo, Jie; Li, Lei; Li, Xin; Yeh, Shuyuan; Jin, Jie; Chang, Chawnshang

    2016-01-01

    Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa. PMID:27375022

  15. New Strategy for Prostate Cancer Prevention Based on Selenium Suppression of Androgen Receptor Signaling

    Science.gov (United States)

    2010-04-01

    combination in prostate cancer chemoprevention. Emodin is a phytochemical that has been shown to induce AR degradation (18). We hypothesize that the...Since the induction of PSA screening , the majority of the prostate cancers diagnosed are asymptomatic, early-stage, small volume diseases. Current

  16. Androgen action during male sex differentiation includes suppression of cranial suspensory ligament development

    NARCIS (Netherlands)

    J.M.A. Emmen (Judith); A. McLuskey; J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

    1998-01-01

    textabstractThe cranial suspensory ligament is located on the border of the cranial (mesonephric) mesentery in adult female mammals, which runs between the cranial pole of the internal genitalia and the dorsal abdominal wall. Absence of the cranial suspensory ligament

  17. Ferruginol suppresses survival signaling pathways in androgen-independent human prostate cancer cells

    NARCIS (Netherlands)

    de Jesus, Marcelo Bispo; Zambuzzi, Willian Fernando; Ruela de Sousa, Roberta Regina; Areche, Carlos; Santos de Souza, Ana Carolina; Aoyama, Hiroshi; Schmeda-Hirschmann, Guillermo; Rodriguez, Jaime A.; Monteiro de Souza Brito, Alba Regina; Peppelenbosch, Maikel P.; den Hertog, Jeroen; de Paula, Eneida; Ferreira, Carmen Verissima

    Ferruginol, a bioactive compound isolated from a Chilean tree (Podocarpaceae), attracts attention as a consequence of its pharmacological properties, which include anti-fungal, anti-bacterial, cardioprotective, anti-oxidative, anti-plasmodial and anti-ulcerogenic actions. Nevertheless, the molecular

  18. Abscopal suppression of bone marrow erythropoiesis

    International Nuclear Information System (INIS)

    Werts, E.D.; Johnson, M.J.; DeGowin, R.L.

    1978-01-01

    Abscopal responses of hemopoietic tissue, which we noted in preliminary studies of mice receiving partial-body irradiation, led us to clarify these effects. In studies reported here, one hind leg of CF-1 female mice received 1000, 5000, or 10,000 rad of x radiation. We found a persistent shift from medullary to splenic erythropoiesis preventing anemia in mice receiving 5000 or 10,000 rad. Splenectomy prior to 5000-rad irradiation resulted in anemia, which was not ameliorated by exposure to intermittent hypoxia. Despite evidence for increased levels of erythropoietin in the animals, namely, a reticulocytosis and increased erythrocyte radioiron incorporation, both 59 Fe uptake and erythroblast counts in shielded marrow remained below normal. We found 50 to 90% suppression of the growth of marrow stromal colonies (MSC) from bone marrow aspirates of the shielded and irradiated femoral marrow at 1 month and at least 20% depression of MSC at 1 year, with each dose. We conclude that: (i) high doses of x radiation to one leg of mice caused prolonged suppression of medullary erythropoiesis with splenic compensation to prevent anemia; (ii) splenectomy, anemia, and hypoxia prevented the severe abscopal depression of medullary erythropoiesis; and (iii) suppressed medullary erythropoiesis with decreased growth of MSC suggested a change in the hemopoietic microenvironment of the bone marrow

  19. Chaos as an intermittently forced linear system.

    Science.gov (United States)

    Brunton, Steven L; Brunton, Bingni W; Proctor, Joshua L; Kaiser, Eurika; Kutz, J Nathan

    2017-05-30

    Understanding the interplay of order and disorder in chaos is a central challenge in modern quantitative science. Approximate linear representations of nonlinear dynamics have long been sought, driving considerable interest in Koopman theory. We present a universal, data-driven decomposition of chaos as an intermittently forced linear system. This work combines delay embedding and Koopman theory to decompose chaotic dynamics into a linear model in the leading delay coordinates with forcing by low-energy delay coordinates; this is called the Hankel alternative view of Koopman (HAVOK) analysis. This analysis is applied to the Lorenz system and real-world examples including Earth's magnetic field reversal and measles outbreaks. In each case, forcing statistics are non-Gaussian, with long tails corresponding to rare intermittent forcing that precedes switching and bursting phenomena. The forcing activity demarcates coherent phase space regions where the dynamics are approximately linear from those that are strongly nonlinear.The huge amount of data generated in fields like neuroscience or finance calls for effective strategies that mine data to reveal underlying dynamics. Here Brunton et al.develop a data-driven technique to analyze chaotic systems and predict their dynamics in terms of a forced linear model.

  20. Transient analysis of intermittent multijet sprays

    Energy Technology Data Exchange (ETDEWEB)

    Panao, Miguel R.O.; Moreira, Antonio Luis N. [Universidade Tecnica de Lisboa, IN, Center for Innovation, Technology and Policy Research, Instituto Superior Tecnico, Lisboa (Portugal); Durao, Diamantino G. [Universidade Lusiada, Lisboa (Portugal)

    2012-07-15

    This paper analyzes the transient characteristics of intermittent sprays produced by the single-point impact of multiple cylindrical jets. The aim is to perform a transient analysis of the intermittent atomization process to study the effect of varying the number of impinging jets in the hydrodynamic mechanisms of droplet formation. The results evidence that hydrodynamic mechanisms underlying the physics of ligament fragmentation in 2-impinging jets sprays also apply to sprays produced with more than 2 jets during the main period of injection. Ligaments detaching from the liquid sheet, as well as from its bounding rim, have been identified and associated with distinct droplet clusters, which become more evident as the number of impinging jets increases. Droplets produced by detached ligaments constitute the main spray, and their axial velocity becomes more uniformly distributed with 4-impinging jets because of a delayed ligament fragmentation. Multijet spray dispersion patterns are geometric depending on the number of impinging jets. Finally, an analysis on the Weber number of droplets suggests that multijet sprays are more likely to deposit on interposed surfaces, thus becoming a promising and competitive atomization solution for improving spray cooling. (orig.)

  1. Impact of intermittent fasting on glucose homeostasis.

    Science.gov (United States)

    Varady, Krista A

    2016-07-01

    This article provides an overview of the most recent human trials that have examined the impact of intermittent fasting on glucose homeostasis. Our literature search retrieved one human trial of alternate day fasting, and three trials of Ramadan fasting published in the past 12 months. Current evidence suggests that 8 weeks of alternate day fasting that produces mild weight loss (4% from baseline) has no effect on glucose homeostasis. As for Ramadan fasting, decreases in fasting glucose, insulin, and insulin resistance have been noted after 4 weeks in healthy normal weight individuals with mild weight loss (1-2% from baseline). However, Ramadan fasting may have little impact on glucoregulatory parameters in women with polycystic ovarian syndrome who failed to observe weight loss. Whether intermittent fasting is an effective means of regulating glucose homeostasis remains unclear because of the scarcity of studies in this area. Large-scale, longer-term randomized controlled trials will be required before the use of fasting can be recommended for the prevention and treatment of metabolic diseases.

  2. Intermittency Statistics in the Expanding Solar Wind

    Science.gov (United States)

    Cuesta, M. E.; Parashar, T. N.; Matthaeus, W. H.

    2017-12-01

    The solar wind is observed to be turbulent. One of the open questions in solar wind research is how the turbulence evolves as the solar wind expands to great distances. Some studies have focused on evolution of the outer scale but not much has been done to understand how intermittency evolves in the expanding wind beyond 1 AU (see [1,2]). We use magnetic field data from Voyager I spacecraft from 1 to 10AU to study the evolution of statistics of magnetic discontinuities. We perform various statistical tests on these discontinuities and make connections to the physical processes occurring in the expanding wind.[1] Tsurutani, Bruce T., and Edward J. Smith. "Interplanetary discontinuities: Temporal variations and the radial gradient from 1 to 8.5 AU." Journal of Geophysical Research: Space Physics 84.A6 (1979): 2773-2787.[2] Greco, A., et al. "Evidence for nonlinear development of magnetohydrodynamic scale intermittency in the inner heliosphere." The Astrophysical Journal 749.2 (2012): 105.

  3. Chronic intermittent hypoxia predisposes to liver injury.

    Science.gov (United States)

    Savransky, Vladimir; Nanayakkara, Ashika; Vivero, Angelica; Li, Jianguo; Bevans, Shannon; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

    2007-04-01

    Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). OSA is associated with nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of obesity. Lean C57BL/6J mice (n = 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n = 15). CIH caused liver injury with an increase in serum ALT (224 +/- 39 U/l versus 118 +/- 22 U/l in the IA group, P fasting serum insulin levels, and mild elevation of fasting serum total cholesterol and triglycerides (TG). Liver TG content was unchanged, whereas cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a malondialdehyde (MDA)/free fatty acids (FFA) ratio of 0.54 +/- 0.07 mmol/mol versus 0.30 +/- 0.01 mmol/mol in control animals (P obesity, CIH leads to mild liver injury via oxidative stress and excessive glycogen accumulation in hepatocytes and sensitizes the liver to a second insult, whereas NASH does not develop.

  4. Intermittent preventive treatment of malaria in pregnancy

    DEFF Research Database (Denmark)

    Mbonye, A.K.; Bygbjerg, Ib Christian; Magnussen, Pascal

    2008-01-01

    OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non-randomized comm......OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive-health workers, or adolescent peer mobilizers could administer intermittent preventive treatment (IPTp) for malaria with sulfadoxine-pyrimethamine to pregnant women. METHODS: A non......-randomized community trial was implemented in 21 community clusters (intervention) and four clusters where health units provided routine IPTp (control). The primary outcome measures were access and adherence to IPTp, number of malaria episodes, prevalence of anaemia, and birth weight. Numbers of live births, abortions......, still births, and maternal and child deaths were secondary endpoints. FINDINGS: 1404 (67.5%) of 2081 with the new delivery system received two doses of sulfadoxine-pyrimethamine versus 281 (39.9%) of 704 with health units (P malaria episodes decreased from 906 (49...

  5. Intermittent hyperthyreosis. A heat stress syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Sulman, F G; Tal, E; Pfeifer, Y; Superstine, E [Hebrew Univ., Jerusalem (Israel). Dept. of Applied Pharmacology

    1975-09-01

    Intermittent hyperthyreosis occurs under various forms of stress, especially heat stress. The clinician may diagnose such cases as masked or apathetic hyperthyroidism or 'forme fruste' hyperthyreosis or thyroid autonomy. As most routine and standard tests may here yield inconsistent results, it is the patients' anamnesis which may provide the clue. Our Bioclimatology Unit has now seen over 100 cases in which thyroid hypersensitivity towards heat was the most prominent syndrome: 10-15% of weather-sensitive patients are affected. The patients complain before or during heat spells of such contradictory symptoms as insomnia, irritability, tension, tachycardia, palpitations, precordial pain, dyspnoe, flushes with sweating or chills, tremor, abdominal pain or diarrhea, polyuria or pollakisuria, weight loss in spite of ravenous appetite, fatigue, exhaustion, depression, adynamia, lack of concentration and confusion. Determination of urinary neurohormones allows a differential diagnosis, intermittent hyperthyreosis being characterized by three cardinal symptoms: tachycardia - every case with more than 80 pulse beats being suspect (not specific); urinary histamine - every case excreting more than 90 ..mu..g/day being suspect. Again the drawback of this test is its lack of specificity, as histamine may also be increased in cases of allergy and spondylitis; urinary thyroxine - every case excreting more than 20 ..mu..g/day T-4 being suspect. This is the only specific test. Therapy should make use of lithium carbonate and betablockers. Propyl thiouracil is rarely required.

  6. Specific interaction of radioactive anti-androgen TSAA-291 with androgen receptor in rat prostates

    International Nuclear Information System (INIS)

    Sudo, K.; Yoshida, K.; Nakayama, R.

    1982-01-01

    A steroidal anti-androgen TSSA-291 (16β-ethyl-17β-hydroxy-4-oestren-3-one) bound to a macromolecular component in the cytosol of rat ventral prostates with high affinity (Kdsub(d) = 5.0 x 10 -9 M) and in a saturable manner. The number of binding sites was comparable to that for 5α-dihydrotestosterone (5α-DHT). [ 3 H]TSAA-291 binding was effectively displaced by unlabelled 5α-DHT, 19-nortestosterone and cyproterone acetate but to a lesser degree by corticosterone. Glycerol density-gradient centrifugation analysis revealed that the sedimentation coefficient of the [ 3 H]-TSAA-291-macromolecule complex was 3-4.5 S. However, when the unlabelled cytosol was fractionated by glycerol density-gradient centrifugation before the binding of [ 3 H]TSAA-291 was examined, specific binding of [ 3 H]TSAA-291 was observed in fractions corresponding to 8-10 S. Binding of the [ 3 H]TSAA-291-macromolecules comples to prostatic nuclei and DNA-cellulose was considerably less than binding by the [ 3 H]5α-DHT-macromolecule complex. Instability of the TSAA-291 binding coponent on heat treatment before and after complex formation was also revealed and the results are discussed in terms of the anti-androgenic activity of TSAA-291. (author)

  7. The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer

    NARCIS (Netherlands)

    Jongen, V. H. W. M.; Sluijmer, A. V.; Heineman, M. J.

    2002-01-01

    Postmenopausal estrogens originate from the peripheral conversion of androgens, which are produced by the adrenal glands and the ovaries. Estrogens are considered to contribute to the neoplastic development of endometrium. Hyperplasia of ovarian stroma is associated with an increased androgen

  8. Interaction Between a Novel p21 Activated Kinase (PAK6) and Androgen Receptor in Prostate Cancer

    National Research Council Canada - National Science Library

    Sun, Zijie

    2005-01-01

    The effects of androgens are mediated by the androgen receptor (AR), which plays a critical role in inducing normal differentiation of tissues of the reproductive organs and in the development and progression of prostate cancer...

  9. Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

    National Research Council Canada - National Science Library

    Wang, Zhou

    2001-01-01

    .... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

  10. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigsby, James

    2004-01-01

    .... Our major hypothesis is the patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  11. Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

    National Research Council Canada - National Science Library

    Grigaby, James

    2003-01-01

    .... Our major hypothesis is that patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

  12. Increased Androgen Response to Follicle-Stimulating Hormone Administration in Women with Polycystic Ovary Syndrome

    OpenAIRE

    Wachs, Deborah S.; Coffler, Mickey S.; Malcom, Pamela J.; Shimasaki, Shunichi; Chang, R. Jeffrey

    2008-01-01

    Context: In women with polycystic ovary syndrome (PCOS), excess ovarian androgen production is driven by increased LH secretion. Studies conducted in animals suggest that the granulosa cell may influence LH-stimulated theca cell androgen production.

  13. Additive effects of dietary glycotoxins and androgen excess on the kidney of a female rat model

    Directory of Open Access Journals (Sweden)

    Sotiria Palimeri

    2016-06-01

    Conclusions: The above mentioned data suggest that dietary glycotoxins, in combination with increased androgen exposure, exert a more profound negative impact on the kidney of an androgenized female rat model that mimics the metabolic characteristics of polycystic ovary syndrome.

  14. Adequacy in dialysis: intermittent versus continuous therapies.

    Science.gov (United States)

    Misra, M; Nolph, K D

    2000-01-01

    A vital conceptual difference between intermittent and continuous dialysis therapies is the difference in the relationship between Kt/V urea and dietary protein intake. For a given level of protein intake the intermittent therapies require a higher Kt/V urea due to the reasons mentioned above. The recently released adequacy guidelines by DOQI for intermittent and continuous therapies are based on these assumptions. The link between adequacy targets and patient survival is well documented for an intermittent therapy like HD. For a continuous therapy like CAPD however, the evidence linking improved peritoneal clearance to better survival is not as direct. However, present consensus allows one to extrapolate results based on HD. The concept of earlier and healthier initiation of dialysis is gaining hold and incremental dialysis forms an integral aspect of the whole concept. Tools like urea kinetic modeling give us valuable insight in making mathematical projections about the timing as well as dosing of dialysis. Daily home hemodialysis is still an underutilized modality despite offering best survival figures. Hopefully, with increasing availability of better and simpler machines its use will increase. Still several questions remain unanswered. Despite availability of data in hemodialysis patients suggesting that an increased dialysis prescription leads to a better survival, optimal dialysis dose is yet to be defined. Concerns regarding methodology of such studies and conclusions thereof has been raised. Other issues relating to design of the studies, variation in dialysis delivery, use of uncontrolled historical standards and lack of patient randomization etc also need to be considered when designing such trials. Hopefully an ongoing prospective randomized trial, namely the HEMO study, looking at two precisely defined and carefully maintained dialysis prescriptions will provide some insight into adequacy of dialysis dose and survival. In diabetic patients, the

  15. Acute Effects of Carbohydrate Supplementation on Intermittent Sports Performance.

    Science.gov (United States)

    Baker, Lindsay B; Rollo, Ian; Stein, Kimberly W; Jeukendrup, Asker E

    2015-07-14

    Intermittent sports (e.g., team sports) are diverse in their rules and regulations but similar in the pattern of play; that is, intermittent high-intensity movements and the execution of sport-specific skills over a prolonged period of time (~1-2 h). Performance during intermittent sports is dependent upon a combination of anaerobic and aerobic energy systems, both of which rely on muscle glycogen and/or blood glucose as an important substrate for energy production. The aims of this paper are to review: (1) potential biological mechanisms by which carbohydrate may impact intermittent sport performance; (2) the acute effects of carbohydrate ingestion on intermittent sport performance, including intermittent high-intensity exercise capacity, sprinting, jumping, skill, change of direction speed, and cognition; and (3) what recommendations can be derived for carbohydrate intake before/during exercise in intermittent sports based on the available evidence. The most researched intermittent sport is soccer but some sport-specific studies have also been conducted in other sports (e.g., rugby, field hockey, basketball, American football, and racquet sports). Carbohydrate ingestion before/during exercise has been shown in most studies to enhance intermittent high-intensity exercise capacity. However, studies have shown mixed results with regards to the acute effects of carbohydrate intake on sprinting, jumping, skill, change of direction speed, and cognition. In most of these studies the amount of carbohydrate consumed was ~30-60 g/h in the form of a 6%-7% carbohydrate solution comprised of sucrose, glucose, and/or maltodextrin. The magnitude of the impact that carbohydrate ingestion has on intermittent sport performance is likely dependent on the carbohydrate status of the individual; that is, carbohydrate ingestion has the greatest impact on performance under circumstances eliciting fatigue and/or hypoglycemia. Accordingly, carbohydrate ingestion before and during a game

  16. Acute Effects of Carbohydrate Supplementation on Intermittent Sports Performance

    Directory of Open Access Journals (Sweden)

    Lindsay B. Baker

    2015-07-01

    Full Text Available Intermittent sports (e.g., team sports are diverse in their rules and regulations but similar in the pattern of play; that is, intermittent high-intensity movements and the execution of sport-specific skills over a prolonged period of time (~1–2 h. Performance during intermittent sports is dependent upon a combination of anaerobic and aerobic energy systems, both of which rely on muscle glycogen and/or blood glucose as an important substrate for energy production. The aims of this paper are to review: (1 potential biological mechanisms by which carbohydrate may impact intermittent sport performance; (2 the acute effects of carbohydrate ingestion on intermittent sport performance, including intermittent high-intensity exercise capacity, sprinting, jumping, skill, change of direction speed, and cognition; and (3 what recommendations can be derived for carbohydrate intake before/during exercise in intermittent sports based on the available evidence. The most researched intermittent sport is soccer but some sport-specific studies have also been conducted in other sports (e.g., rugby, field hockey, basketball, American football, and racquet sports. Carbohydrate ingestion before/during exercise has been shown in most studies to enhance intermittent high-intensity exercise capacity. However, studies have shown mixed results with regards to the acute effects of carbohydrate intake on sprinting, jumping, skill, change of direction speed, and cognition. In most of these studies the amount of carbohydrate consumed was ~30–60 g/h in the form of a 6%–7% carbohydrate solution comprised of sucrose, glucose, and/or maltodextrin. The magnitude of the impact that carbohydrate ingestion has on intermittent sport performance is likely dependent on the carbohydrate status of the individual; that is, carbohydrate ingestion has the greatest impact on performance under circumstances eliciting fatigue and/or hypoglycemia. Accordingly, carbohydrate ingestion before

  17. The clinical and molecular spectrum of androgen insensitivity syndromes

    Energy Technology Data Exchange (ETDEWEB)

    Hiort, O.; Sinnecker, G.H.G.; Holterhus, P.M.; Nitsche, E.M.; Kruse, K. [Medical Univ. of Luebeck (Germany)

    1996-05-03

    Androgen insensitivity syndromes (AIS) are due to end-organ resistance to androgenic steroids in males leading to defective virilization of the external genitalia. The phenotype encompasses a wide array of genital ambiguity and may range from completely female to undervirilized but unequivocally male with infertility. This disorder is caused by mutations of the androgen receptor and is an X-linked recessive trait. We have studied 47 patients with AIS and have characterized the underlying molecular abnormality in the androgen receptor gene. Twenty patients had complete AIS and twenty-seven had partial AIS. Of the latter, 11 were of predominantly female phenotypic appearance and gender was assigned accordingly, while 16 were raised as males. Within the group of complete AIS, two patients had gross deletions within the gene, one had a small deletion, and one had an insertion. In the other patients with complete AIS, as well as all individuals with partial AIS, single nucleotide substitutions within the coding region were detected, each leading to an amino acid alteration. Seven codons were involved in more than one mutation in different cases. In addition, in one patient with spinal and bulbar muscular atrophy, an elongation of a glutamine-repeat was characterized. We conclude that mutations in the androgen receptor gene may be present throughout the whole coding region. However, our study provides evidence that several mutational hot spots exist. 18 refs., 2 figs.

  18. An Update on Plant Derived Anti-Androgens

    Science.gov (United States)

    Grant, Paul; Ramasamy, Shamin

    2012-01-01

    Anti-androgens are an assorted group of drugs and compounds that reduce the levels or activity of androgen hormones within the human body. Disease states in which this is relevant include polycystic ovarian syndrome, hirsutism, acne, benign prostatic hyperplasia, and endocrine related cancers such as carcinoma of the prostate. We provide an overview and discussion of the use of anti-androgen medications in clinical practice and explore the increasing recognition of the benefits of plant-derived anti-androgens, for example, spearmint tea in the management of PCOS, for which some evidence about efficacy is beginning to emerge. Other agents covered include red reishi, which has been shown to reduce levels 5-alpha reductase, the enzyme that facilitates conversion of testosterone to dihydrotestosterone (DHT); licorice, which has phytoestrogen effects and reduces testosterone levels; Chinese peony, which promotes the aromatization of testosterone into estrogen; green tea, which contains epigallocatechins and also inhibits 5-alpha reductase, thereby reducing the conversion of normal testosterone into the more potent DHT; black cohosh, which has been shown to kill both androgenresponsive and non-responsive human prostate cancer cells; chaste tree, which has a reduces prolactin from the anterior pituitary; and saw palmetto extract, which is used as an anti-androgen although it shown no difference in comparison to placebo in clinical trials. PMID:23843810

  19. Partial androgen deficiency, depression and testosterone treatment in aging men.

    Science.gov (United States)

    Amore, Mario; Scarlatti, Fabiano; Quarta, Antonio Lucio; Tagariello, Pietro

    2009-02-01

    This study provides a critical review of the literature on depressive symptoms of partial androgen deficiency (PADAM) and their treatment with Testosterone (T). PADAM in aging males is responsible for a variety of behavioral symptoms, such as weakness, decreased libido and erectile dysfunction, lower psychological vitality, depressive mood, anxiety, insomnia, difficulty in concentrating, and memory impairment. The psychological and behavioural aspects of PADAM may overlap with signs and symptoms of major depression. Evidence of the relationship between androgen deficiency and male depression comes from studies that have assessed depression in hypogonadal subjects, the association between low T level and male depressive illness, and the antidepressant action of androgen replacement. The etiology of depressive symptoms of PADAM is multifactorial, and results from the interaction of the biological and psychosocial changes that take place during the mid-life transition. Although data derived from androgen treatment trials and androgen replacement do not support T treatment or replacement as more efficacious than placebo for major depressive disorder (MDD), the clinical impression is that, in some sub-threshold depressive syndromes, T may lead to antidepressant benefits.

  20. Evolution of the androgen-induced male phenotype.

    Science.gov (United States)

    Fuxjager, Matthew J; Miles, Meredith C; Schlinger, Barney A

    2018-01-01

    The masculine reproductive phenotype varies significantly across vertebrates. As a result, biologists have long recognized that many of the mechanisms that support these phenotypes-particularly the androgenic system-is evolutionarily labile, and thus susceptible to the effects of selection for different traits. However, exactly how androgenic signaling systems vary in a way which results in dramatically different functional outputs, remain largely unclear. We explore this topic here by outlining four key-but non-mutually exclusive-hypotheses that propose how the mechanisms of androgenic signaling might change over time to potentiate the emergence of phenotypical variation in masculine behavior and physiology. We anchor this framework in a review of our own studies of a tropical bird called the golden-collared manakin (Manacus vitellinus), which has evolved an exaggerated acrobatic courtship display that is heavily androgen-dependent. The result is an example of how the cellular basis of androgenic action can be modified to support a unique reproductive repertoire. We end this review by highlighting a broad pathway forward to further pursue the intricate ways by which the mechanisms of hormone action evolve to support processes of adaptation and animal design.

  1. Androgenic anabolic steroid use among male adolescents in Falkenberg.

    Science.gov (United States)

    Nilsson, S

    1995-01-01

    Recent reports show that androgenic anabolic steroids are used by many teenagers, not as a deliberate attempt to give them strength, better athletic performance, etc., but to improve their looks. The so-called macho cult among young boys tempts them into using androgenic anabolic steroids to give them bigger muscles and a more powerful appearance. This study was undertaken to investigate the prevalence of androgenic anabolic steroid use among teenagers in a small town and to create a platform for future work with the aim of decreasing the misuse of these drugs. In Falkenberg, a town in the county of Halland in the west of Sweden, the pupils at two high schools were investigated by means of an anonymous multiple-choice questionnaire. A total of 1383 students (688 males and 695 females) aged 14-19 years participated in the study, giving a participation rate of 96%. The number of answers completed was 99%. The use of androgenic anabolic steroids is a reality among male teenagers in Falkenberg, with 5.8% of them using the drugs. Among 15- to 16-year-old boys misuse of these drugs is as high as 10%, and of these 50% (5.0% of total) also inject ampoules of the drugs. This prevalence is alarming since the adverse effects of androgenic anabolic steroids are more serious in teenagers. Serious action must be taken to inform teenagers of the consequences of misusing drugs.

  2. Evidence That Androgens Modulate Human Thymic T Cell Output

    Science.gov (United States)

    Olsen, Nancy J.; Kovacs, William J.

    2010-01-01

    Background The thymus has long been recognized as a target for the actions of androgenic hormones, but it has only been recently recognized that alterations in circulating levels of gonadal steroids might affect thymic output of T cells. We had the opportunity to examine parameters of thymic cellular output in several hypogonadal men undergoing androgen replacement therapy. Methods Circulating naive (CD4+CD45RA+) T cells were quantitated by flow cytometric analysis of peripheral blood mononuclear cells (PBMCs). Cells bearing T cell receptor excision circles (TRECs) were quantitated using real-time PCR amplification of DNA isolated from PBMCs from normal men and from hypogonadal men before and after testosterone replacement therapy. Results CD4+CD45+ (“naïve”) T cells comprised 10.5% of lymphocytes in normal males; this proportion was greatly increased in two hypogonadal men (35.5% and 44.4%). One man was studied sequentially during treatment with physiologic doses of testosterone. CD4+CD45RA+ cells fell from 37.36% to 20.05% after one month and to 12.51% after 7 months of normalized androgen levels. In two hypogonadal patients TREC levels fell by 83% and 78% after androgen replacement therapy. Conclusions Our observations indicate that the hypogonadal state is associated with increased thymic output of T cells and that this increase in recent thymic emigrants in peripheral blood is reversed by androgen replacement. PMID:21218609

  3. A comparative study on androgen metabolism in three invertebrate species.

    Science.gov (United States)

    Janer, G; LeBlanc, G A; Porte, C

    2005-09-15

    A comparative approach was taken in this study to evaluate androgen (androstenedione and testosterone) metabolism in three invertebrate species: the gastropod Marisa cornuarietis, the amphipod Hyalella azteca, and the echinoderm Paracentrotus lividus. The existence of 17beta/3beta-hydroxysteroid dehydrogenase (HSD) and 5alpha-reductase catalyzed reactions was demonstrated in all three species. Androstenedione was primarily converted to 5alpha-androstanedione in M. cornuarietis, while it was primarily metabolized to testosterone in P. lividus and H. azteca. In addition, and consistent with vertebrate findings, tissue specific pathways and sexual dimorphism in androgen metabolism were observed. Namely, testosterone was metabolized to dihydrotestosterone in P. lividus gonads (via 5alpha-reductase), and metabolized to 4-androstene-3beta,17beta-diol in the digestive tube (via 3beta-hydroxysteroid dehydrogenase). Furthermore, the synthesis of 17beta-reduced metabolites of androstenedione (testosterone and dihydrotestosterone) was 3- to 4-fold higher in males of M. cornuarietis than in females. Organotin compounds, which have been shown to interfere with some aspects of androgen metabolism, had no major effect on testosterone metabolism in any of the three species. Fenarimol enhanced 5alpha-reductase-mediated catalysis in gonads of P. lividus. Overall, results demonstrate the ubiquity of some androgen biotransformation processes in invertebrates and reveals interphyla differences in androgen metabolic pathways, and different sensitivity of these pathways to some xenobiotics.

  4. Intermittent hormonal therapy in the treatment of post-irradiation residual/recurrent prostate cancer

    International Nuclear Information System (INIS)

    Williams, Aaron O; Kocherill, Paul G; Wallace, Michelle; Forman, Jeffrey D

    1996-01-01

    Purpose: To evaluate the efficacy and toxicity of intermittent hormonal therapy in the treatment of residual/recurrent prostate cancer. Materials and Methods: Seventeen patients with biochemical evidence of residual/recurrent prostate cancer were initially treated with radiation therapy (RT)(13), neo-adjuvant hormonal therapy and RT (3), or RT following prostatectomy (1). The mean follow-up time was 19.4 months from the initiation of hormonal therapy. Hormonal therapy consisted of an LH-RH agonist alone (7), an anti-androgen alone (1) or a combination of both (9). Hormonal therapy was continued until the prostatic specific antigen (PSA) level became undetectable. IHT was reinstituted when the PSA reached a pre-determined level, usually greater than or equal to 10ng/ml. Results: The mean time from completion of primary treatment to the initiation of hormonal therapy was 32.5 months. The mean PSA at the start of the first cycle of hormonal therapy was 43.9ng/ml, the second cycle, 11.9ng/ml and the third cycle, 24ng/ml. The mean PSA levels at the end of the first and second cycle of hormonal therapy were .48 and .42ng/ml, respectively. No patient has yet completed the third cycle of hormonal therapy. The average duration of hormonal therapy was 10 months for the first cycle and 4 months for the second cycle. The mean intermittent time off hormones were 9.3 months between cycles 1 and 2, and 10 months between cycles 2 and 3. No patient has yet become refractory to hormonal therapy. Currently all patients are alive. All patients experienced hot flashes and decreased libido at varying degrees during treatment. Thirty-five percent experienced gynecomastia. During the intervals between hormonal therapy, most patients reported a decrease in hot flashes. Conclusion: This analysis supplies preliminary evidence that intermittent hormonal therapy is a viable option in patients with biochemical evidence of disease following initial therapy. It is associated with less treatment

  5. High-dose phenobarbital with intermittent short-acting barbiturates for acute encephalitis with refractory, repetitive partial seizures.

    Science.gov (United States)

    Uchida, Takashi; Takayanagi, Masaru; Kitamura, Taro; Nishio, Toshiyuki; Numata, Yurika; Endo, Wakaba; Haginoya, Kazuhiro; Ohura, Toshihiro

    2016-08-01

    Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by repetitive seizures during the acute and chronic phases and has a poor neurological outcome. Burst-suppression coma via continuous i.v. infusion of a short-acting barbiturate is used to terminate refractory seizures, but the severe side-effects of short-acting barbiturates are problematic. We report on a 9-year-old boy with AERRPS who was effectively treated with very-high-dose phenobarbital (VHDPB) combined with intermittent short-acting barbiturates. VHDPB side-effects were mild, especially compared with those associated with continuous i.v. infusion of short-acting barbiturates (dosage, 40-75 mg/kg/day; maximum blood level, 290 μg/mL). Using VHDPB as the main treatment, short-acting barbiturates were used intermittently and in small amounts. This is the first report to show that VHDPB, combined with intermittent short-acting barbiturates, can effectively treat AERRPS. After treatment, convulsions were suppressed and daily life continued, but intellectual impairment and high-level dysfunction remained. © 2016 Japan Pediatric Society.

  6. Critical androgen-sensitive periods of rat penis and clitoris development

    OpenAIRE

    Welsh, M.; Macleod, D. J.; Walker, M.; Smith, L. B.; Sharpe, R. M.

    2010-01-01

    Androgen control of penis development/growth is unclear. In rats, androgen action in a foetal 'masculinisation programming window' (MPW; e15.5-e18.5)' predetermines penile length and hypospadias occurrence. This has implications for humans (e.g. micropenis). Our studies aimed to establish in rats when androgen action/administration affects development/growth of the penis and if deficits in MPW androgen action were rescuable postnatally. Thus, pregnant rats were treated with flutamide during t...

  7. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

    OpenAIRE

    Caldwell, Aimee S. L.; Edwards, Melissa C.; Desai, Reena; Jimenez, Mark; Gilchrist, Robert B.; Handelsman, David J.; Walters, Kirsty A.

    2017-01-01

    The cause of polycystic ovary syndrome (PCOS) is unknown, but androgen excess is a key feature. We combined a hyperandrogenized PCOS mouse model with global and tissue- and cell-specific androgen-resistant mouse lines to uncover the sites of androgen action that initiate PCOS. We demonstrate that direct androgen actions, particularly in neurons but less so in granulosa cells, are required for the development of key reproductive and metabolic PCOS features. These data highlight the previously ...

  8. Intermittent, Non Cyclic Severe Mechanical Aortic Valve Regurgitation

    Science.gov (United States)

    Choi, Jong Hyun; Song, Seunghwan; Lee, Myung-Yong

    2013-01-01

    Mechanical aortic prosthesis dysfunction can result from thrombosis or pannus formation. We describe an unusual case of intermittent, non cyclic mechanical aortic prosthesis dysfunction due to pannus formation with thrombus in the absence of systolic restriction of disk excursion, that presented with intermittent severe aortic regurgitation. PMID:24459568

  9. Intermittent versus Continuous Physiotherapy in Children with Cerebral Palsy

    Science.gov (United States)

    Christiansen, Annette Sandahl; Lange, Christa

    2008-01-01

    The aim of this study was to compare the effect of the delivery of the same amount of intermittent versus continuous physiotherapy given to children with cerebral palsy (CP). This was organized either in an intermittent regime four times a week for 4 weeks alternating with a 6-week treatment pause, or a continuous once or twice a week regime, both…

  10. Interlaboratory comparison of four in vitro assays for assessing androgenic and antiandrogenic activity of environmental chemicals

    DEFF Research Database (Denmark)

    Körner, Wolfgang; Vinggaard, Anne; Terouanne, B.

    2004-01-01

    steroidal androgens, two antiandrogens, an androgenic control, 5alpha-dihydrotestosterone (DHT), and an antiandrogenic control, bicalutamide (ICI 176,334). All laboratories correctly detected the androgenic activity of 4-androsten-3,17-dione and 17alpha-methyl-testosterone. For both compounds...

  11. Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-07-01

    Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

  12. Fetal programming of adrenal androgen excess: lessons from a nonhuman primate model of polycystic ovary syndrome.

    Science.gov (United States)

    Abbott, David H; Zhou, Rao; Bird, Ian M; Dumesic, Daniel A; Conley, Alan J

    2008-01-01

    Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

  13. Deconstructing continuous flash suppression.

    Science.gov (United States)

    Yang, Eunice; Blake, Randolph

    2012-03-08

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

  14. Stromal Androgen Receptor in Prostate Cancer Development and Progression

    Science.gov (United States)

    Leach, Damien A.; Buchanan, Grant

    2017-01-01

    Prostate cancer development and progression is the result of complex interactions between epithelia cells and fibroblasts/myofibroblasts, in a series of dynamic process amenable to regulation by hormones. Whilst androgen action through the androgen receptor (AR) is a well-established component of prostate cancer biology, it has been becoming increasingly apparent that changes in AR signalling in the surrounding stroma can dramatically influence tumour cell behavior. This is reflected in the consistent finding of a strong association between stromal AR expression and patient outcomes. In this review, we explore the relationship between AR signalling in fibroblasts/myofibroblasts and prostate cancer cells in the primary site, and detail the known functions, actions, and mechanisms of fibroblast AR signaling. We conclude with an evidence-based summary of how androgen action in stroma dramatically influences disease progression. PMID:28117763

  15. Prevalent flucocorticoid and androgen activity in US water sources

    Science.gov (United States)

    Stavreva, Diana A.; George, Anuja A.; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C.; Schiltz, R. Louis; Blazer, Vicki; Iwanowiczl, Luke R.; Hager, Gordon L.

    2012-01-01

    Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

  16. Prevalent glucocorticoid and androgen activity in US water sources.

    Science.gov (United States)

    Stavreva, Diana A; George, Anuja A; Klausmeyer, Paul; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C; Schiltz, R Louis; Blazer, Vicki S; Iwanowicz, Luke R; Hager, Gordon L

    2012-01-01

    Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations.

  17. High androgen levels protect against hypothyroidism.

    Science.gov (United States)

    Schmidt, Johanna; Dahlgren, Eva; Bryman, Inger; Berntorp, Kerstin; Trimpou, Penelope; Wilhelmsen, Lars; Landin-Wilhelmsen, Kerstin

    2017-01-01

    Hypothyroidism is a common disorder, appearing mainly in women although less frequently found in women with polycystic ovary syndrome (PCOS). The objective was to test the hypothesis that hyperandrogenism might protect against hypothyroidism. The data from three prospective follow-up studies (up to 21 years) and one register study were compared: women with PCOS (Rotterdam criteria), n = 25, women with Turner syndrome, n = 217, a random population sample of women, n = 315, and men, n = 95 (the WHO MONICA study). Findings were to be verified or rejected in all females, n = 553 716, from the same region. The proportion of hypothyroidism was calculated and thyroid peroxidase antibodies (TPO) in serum were measured. Hypothyroidism at >50 years of age was found in 8% of women with PCOS, 4% in men (PCOS vs. men; ns), 43% of women with Turner syndrome, irrespective of karyotype (p Hypothyroidism increased with age in all groups except PCOS women and men. In the register study, hypothyroidism was less common in women with PCOS >25 years (5.5%) than in women without PCOS (6.8%) from the same region (p Hypothyroidism was less frequently seen in women with PCOS and in men compared with women in the general population and among women with Turner syndrome. This was not explained by altered autoimmunity or the Y-chromosome. Androgens seem to protect against hypothyroidism. © 2016 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology.

  18. A reason for intermittent fasting to suppress the awakening of dormant breast tumors.

    NARCIS (Netherlands)

    Lankelma, J.; Kooi, B.W.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

  19. A reason for intermittent fasting to suppress the awakening of dormant breast tumors

    NARCIS (Netherlands)

    Lankelma, J.; Kooi, B.; Krab, K.; Dorsman, J.C.; Joenje, H.; Westerhoff, H.V.

    2015-01-01

    For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors

  20. The Relationship between Androgenic Alopecia and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ghasem Rahmatpour Rokni

    2016-07-01

    Full Text Available Prostate cancer (PC and Androgenic Alopecia (AGA i are both common diseases in elder men. It seems that androgen plays a crucial role in the growth and development of prostate cancer. Therefore, the current study intended to investigate the relationship between androgenic alopecia and prostate cancer. The present study is a case-control study conducted on 75 patients with prostate cancer (case group referring to Imam Khomeini Hospital in Sari, Iran. The case group was compared with the control group (75 healthy individuals. The intended questionnaire of the study included information such as the age, sex, duration of disease, stage of disease, level of PSA, time diagnosis and time of interview for all the participants. The results of interview and clinical examination along with the patient’s information all were filled in the questionnaire and were statistically analyzed by SPSS after data collection. The mean age of PC group and healthy group was respectively 69.08 ± 8.97 and 68 .45 ± 10.16 years. The average level of PSA was 10.86 ± 11.7 and 2.66 ± 2.7 ng/ml in PC and healthy group in turn. The average duration of cancer was 12.63 ± 9.19 months in PC group. Furthermore, about 6.7% of cancer patients were in stage I, 48% were stage II, 29.3% were in stage III and 16% were in stage IV of prostate cancer. Besides, the number of cancer patients who had both frontal and vertex alopecia (baldness altogether exceeded healthy individuals (P=0.002. According to the results of the present study, there was a significant relationship between prostate cancer and androgenic alopecia which might have been caused by the effect of androgens on both diseases. Consequently, androgenic alopecia can be considered as one of the risk factors associated with prostate cancer.

  1. Prenatal Androgen Exposure Causes Hypertension and Gut Microbiota Dysbiosis.

    Science.gov (United States)

    Sherman, Shermel; Sarsour, Nadeen; Salehi, Marziyeh; Schroering, Allen; Mell, Blair; Joe, Bina; Hill, Jennifer W

    2018-02-22

    Conditions of excess androgen in women, such as polycystic ovary syndrome (PCOS), often exhibit intergenerational transmission. One way in which the risk for PCOS may be increased in daughters of affected women is through exposure to elevated androgens in utero. Hyperandrogenemic conditions have serious health consequences, including increased risk for hypertension and cardiovascular disease. Recently, gut dysbiosis has been found to induce hypertension in rats, such that blood pressure can be normalized through fecal microbial transplant. Therefore, we hypothesized that the hypertension seen in PCOS has early origins in gut dysbiosis caused by in utero exposure to excess androgen. We investigated this hypothesis with a model of prenatal androgen (PNA) exposure and maternal hyperandrogenemia by single-injection of testosterone cypionate or sesame oil vehicle (VEH) to pregnant dams in late gestation. We then completed a gut microbiota and cardiometabolic profile of the adult female offspring. The metabolic assessment revealed that adult PNA rats had increased body weight and increased mRNA expression of adipokines: adipocyte binding protein 2, adiponectin, and leptin in inguinal white adipose tissue. Radiotelemetry analysis revealed hypertension with decreased heart rate in PNA animals. The fecal microbiota profile of PNA animals contained higher relative abundance of bacteria associated with steroid hormone synthesis, Nocardiaceae and Clostridiaceae, and lower abundance of Akkermansia, Bacteroides, Lactobacillus, Clostridium. The PNA animals also had an increased relative abundance of bacteria associated with biosynthesis and elongation of unsaturated short chain fatty acids (SCFAs). We found that prenatal exposure to excess androgen negatively impacted cardiovascular function by increasing systolic and diastolic blood pressure and decreasing heart rate. Prenatal androgen was also associated with gut microbial dysbiosis and altered abundance of bacteria involved in

  2. Intermittent metabolic switching, neuroplasticity and brain health

    Science.gov (United States)

    Mattson, Mark P.; Moehl, Keelin; Ghena, Nathaniel; Schmaedick, Maggie; Cheng, Aiwu

    2018-01-01

    During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease. PMID:29321682

  3. Compensatory mechanisms activated with intermittent energy restriction

    DEFF Research Database (Denmark)

    Coutinho, Sílvia Ribeiro; Halset, Eline Holli; Gåsbakk, Sigrid

    2018-01-01

    Background & aims: Strong compensatory responses, with reduced resting metabolic rate (RMR), increased exercise efficiency (ExEff) and appetite, are activated when weight loss (WL) is achieved with continuous energy restriction (CER), which try to restore energy balance. Intermittent energy...... restriction (IER), where short spells of energy restriction are interspaced by periods of habitual energy intake, may offer some protection in minimizing those responses. We aimed to compare the effect of IER versus CER on body composition and the compensatory responses induced by WL. Methods: 35 adults (age......: 39 ± 9 y) with obesity (BMI: 36 ± 4 kg/m2) were randomized to lose a similar weight with an IER (N = 18) or a CER (N = 17) diet over a 12 week period. Macronutrient composition and overall energy restriction (33% reduction) were similar between groups. Body weight/composition, RMR, fasting...

  4. Towards an intermittency-friendly energy system

    DEFF Research Database (Denmark)

    Blarke, Morten

    2012-01-01

    Distributed cogeneration has played a key role in the implementation of sustainable energy policies for three decades. However, increasing penetration levels of intermittent renewables is challenging that position. The paradigmatic case of West Denmark indicates that distributed operators...... are capitulating as wind power penetration levels are moving above 25%; some operators are retiring cogeneration units entirely, while other operators are making way for heat-only boilers. This development is jeopardizing the system-wide energy, economic, and environmental benefits that distributed cogeneration...... still has to offer. The solution is for distributed operators to adapt their technology and operational strategies to achieve a better co-existence between cogeneration and wind power. Four options for doing so are analysed including a new concept that integrates a high pressure compression heat pump...

  5. Scale Dependence of Spatiotemporal Intermittence of Rain

    Science.gov (United States)

    Kundu, Prasun K.; Siddani, Ravi K.

    2011-01-01

    It is a common experience that rainfall is intermittent in space and time. This is reflected by the fact that the statistics of area- and/or time-averaged rain rate is described by a mixed distribution with a nonzero probability of having a sharp value zero. In this paper we have explored the dependence of the probability of zero rain on the averaging space and time scales in large multiyear data sets based on radar and rain gauge observations. A stretched exponential fannula fits the observed scale dependence of the zero-rain probability. The proposed formula makes it apparent that the space-time support of the rain field is not quite a set of measure zero as is sometimes supposed. We also give an ex.planation of the observed behavior in tenus of a simple probabilistic model based on the premise that rainfall process has an intrinsic memory.

  6. Beneficial effects of intermittent suction and pressure treatment in intermittent claudication

    DEFF Research Database (Denmark)

    Mehlsen, J; Himmelstrup, H; Himmelstrup, Bodil

    1993-01-01

    administration. The treatment caused significant increments in the ADP thresholds for platelet aggregation, while the effects on fibrinolysis were uncertain. It is concluded that intermittent suction and pressure treatment offers a new approach for conservative treatment of intermittent claudication....... participated in an open trial investigating the possible effects of the treatment on platelet aggregation and fibrinolysis. Pain-free and maximal walking distances were measured on a treadmill, and systolic blood pressure was measured on the upper limb, the ankle, and the first toe bilaterally. The threshold...... for adenosine diphosphate (ADP)-induced platelet aggregation was tested, and the fibrinolytic activity was estimated from the euglobulin clot lysis time. Active treatment resulted in significant improvements in pain-free and maximal walking distances, whereas no changes could be found during placebo...

  7. The Central Effects of Androgenic-anabolic Steroid Use.

    Science.gov (United States)

    Mędraś, Marek; Brona, Anna; Jóźków, Paweł

    : Millions of men use androgenic-anabolic steroids (AAS) to stimulate muscle growth and improve physical appearance. Although 1 out of 3 people who uses androgenic-anabolic steroids develops a steroid use disorder, the effects of the drugs on the central nervous system and the psyche are still not well understood. Although most addictive substances improve mood immediately after administration, AAS exert less pronounced euphoric effects. Instead, they are primarily taken for the delayed gratification of increased muscle mass. Withdrawal from AAS may lead to a range of somatic and psychiatric symptoms, and, in many cases, comprehensive treatment supervised by an endocrinologist and a psychiatrist is required.

  8. [Intermittent Explosive Disorder: A Controversial Diagnosis].

    Science.gov (United States)

    Zapata, Juan Pablo; Palacio, Juan David

    2016-01-01

    Intermittent explosive disorder (IED) is aan externalizing externalising disorder characterized characterised by recurrent aggression episodes. Even though this disorder was described several decades ago, and it carries personal and social consequences, there is little in the medical scientific literature on this. bibliographic production about it is scanty. To perform a conceptualization conceptualisation of this disorder, through the review and bibliometric analysis of the available scientific articles. A search was performed in databases with the english English terms intermittent explosive disorder, impulse disorders control [MeSH], in combination with other terms. A bibliometric analysis in the GoPubMed® search engineer was also performed using all data obtained in the search. was also perfomed. IED prevalence ranges from 1.4% to 7%, it presents more frequently during middle adolescence, and with more noticeable repercussions in men males than in womenfemales. The psychopathological core of IED is the impulsive aggressive behaviour that presents in the form of «attacks» that occurs in response to a lower precipitating stimulus. Scientific publications about IED are few and relatively recent, and the vast majority is provided bycomes from the United States (56.56%), and headed by a single author. This fact highlights the need to replicate the findings described about the IED in order to demonstrate the validity and reliability of its diagnostic criteria. It is possible that doubts about the existence of a diagnosis lead have led to such a scant literature about the IED. Available studies about IED allow have allowed characterizing a group of subjects with episodes of impulsive aggression to be characterised, but this description requires replication in different latitudesneeds to be repeated in different areas. Copyright © 2015 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  9. Managing server clusters on intermittent power

    Directory of Open Access Journals (Sweden)

    Navin Sharma

    2015-12-01

    Full Text Available Reducing the energy footprint of data centers continues to receive significant attention due to both its financial and environmental impact. There are numerous methods that limit the impact of both factors, such as expanding the use of renewable energy or participating in automated demand-response programs. To take advantage of these methods, servers and applications must gracefully handle intermittent constraints in their power supply. In this paper, we propose blinking—metered transitions between a high-power active state and a low-power inactive state—as the primary abstraction for conforming to intermittent power constraints. We design Blink, an application-independent hardware–software platform for developing and evaluating blinking applications, and define multiple types of blinking policies. We then use Blink to design both a blinking version of memcached (BlinkCache and a multimedia cache (GreenCache to demonstrate how application characteristics affect the design of blink-aware distributed applications. Our results show that for BlinkCache, a load-proportional blinking policy combines the advantages of both activation and synchronous blinking for realistic Zipf-like popularity distributions and wind/solar power signals by achieving near optimal hit rates (within 15% of an activation policy, while also providing fairer access to the cache (within 2% of a synchronous policy for equally popular objects. In contrast, for GreenCache, due to multimedia workload patterns, we find that a staggered load proportional blinking policy with replication of the first chunk of each video reduces the buffering time at all power levels, as compared to activation or load-proportional blinking policies.

  10. Intermittency in the Scrape-off Layer of the National Spherical Torus Experiment During H-mode Confinement

    International Nuclear Information System (INIS)

    Maqueda, R.J.; Stotler, D.P.; Zweben, S.J.

    2010-01-01

    A gas puff imaging diagnostic is used in the National Spherical Tokamak Experiment (M. Ono, et al., Nucl. Fusion 40, 557 (2000)) to study the edge turbulence and intermittency present during H-mode discharges. In the case of low power Ohmic H-modes the suppression of turbulence/blobs is maintained through the duration of the (short lived) H-modes. Similar quiescent edges are seen during the early stages of H-modes created with the use of neutral beam injection. Nevertheless, as time progresses following the L-H transition, turbulence and blobs reappear although at a lower level than that typically seen during L-mode confinement. It is also seen that the time-averaged SOL emission profile broadens, as the power loss across the separatrix increases. These broad profiles are characterized by a large level of fluctuations and intermittent events.

  11. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Congcong Chen

    Full Text Available Androgen receptor (AR signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS, TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2 were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1 were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins

  12. The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats

    International Nuclear Information System (INIS)

    Wang, Chao; Luo, Fei; Zhou, Ying; Du, Xiaoling; Shi, Jiandang; Zhao, Xiaoling; Xu, Yong; Zhu, Yan; Hong, Wei; Zhang, Ju

    2016-01-01

    Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression. - Highlights: • Seal oil prevents oestradiol/testosterone (E2/T)-induced BPH in castrated rats. • Seal oil downregulates the expression of oestrogen receptor α(ERα) and androgen receptor (AR) in rat BPH tissues. • DHA inhibits the growth of human prostate stromal and epithelial cells in vitro. • DHA arrests human prostate stromal and epithelial cells in the G2/M phase and downregulates the expression of cyclin B1. • DHA inhibits the expression of ERα and AR in human prostate stromal and epithelial cells.

  13. Treatment of Anabolic-Androgenic Steroid Dependence: Emerging Evidence and Its Implications

    Science.gov (United States)

    Kanayama, Gen; Brower, Kirk J.; Wood, Ruth I.; Hudson, James I.; Pope, Harrison G.

    2010-01-01

    Currently, few users of anabolic-androgenic steroids (AAS) seek substance-abuse treatment. But this picture may soon change substantially, because illicit AAS use did not become widespread until the 1980s, and consequently the older members of this AAS-using population—those who initiated AAS as youths in the 1980s—are only now reaching middle age. Members of this group, especially those who have developed AAS dependence, may therefore be entering the age of risk for cardiac and psychoneuroendocrine complications sufficient to motivate them for substance-abuse treatment. We suggest that this treatment should address at least three etiologic mechanisms by which AAS dependence might develop. First, individuals with body-image disorders such as “muscle dysmorphia” may become dependent on AAS for their anabolic effects; these body-image disorders may respond to psychological therapies or pharmacologic treatments. Second, AAS suppress the male hypothalamic-pituitary-gonadal axis via their androgenic effects, potentially causing hypogonadism during AAS withdrawal. Men experiencing prolonged dysphoric effects or frank major depression from hypogonadism may desire to resume AAS, thus contributing to AAS dependence. AAS-induced hypogonadism may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function, and may necessitate antidepressant treatments in cases of depression inadequately responsive to endocrine therapies alone. Third, human and animal evidence indicates that AAS also possess hedonic effects, which likely promote dependence via mechanisms shared with classical addictive drugs, especially opioids. Indeed, the opioid antagonist naltrexone blocks AAS dependence in animals. By inference, pharmacological and psychosocial treatments for human opioid dependence might also benefit AAS-dependent individuals. PMID:20188494

  14. Treatment of anabolic-androgenic steroid dependence: Emerging evidence and its implications.

    Science.gov (United States)

    Kanayama, Gen; Brower, Kirk J; Wood, Ruth I; Hudson, James I; Pope, Harrison G

    2010-06-01

    Currently, few users of anabolic-androgenic steroids (AAS) seek substance abuse treatment. But this picture may soon change substantially, because illicit AAS use did not become widespread until the 1980s, and consequently the older members of this AAS-using population - those who initiated AAS as youths in the 1980s - are only now reaching middle age. Members of this group, especially those who have developed AAS dependence, may therefore be entering the age of risk for cardiac and psychoneuroendocrine complications sufficient to motivate them for substance abuse treatment. We suggest that this treatment should address at least three etiologic mechanisms by which AAS dependence might develop. First, individuals with body image disorders such as "muscle dysmorphia" may become dependent on AAS for their anabolic effects; these body image disorders may respond to psychological therapies or pharmacological treatments. Second, AAS suppress the male hypothalamic-pituitary-gonadal axis via their androgenic effects, potentially causing hypogonadism during AAS withdrawal. Men experiencing prolonged dysphoric effects or frank major depression from hypogonadism may desire to resume AAS, thus contributing to AAS dependence. AAS-induced hypogonadism may require treatment with human chorionic gonadotropin or clomiphene to reactivate neuroendocrine function, and may necessitate antidepressant treatments in cases of depression inadequately responsive to endocrine therapies alone. Third, human and animal evidence indicates that AAS also possess hedonic effects, which likely promote dependence via mechanisms shared with classical addictive drugs, especially opioids. Indeed, the opioid antagonist naltrexone blocks AAS dependence in animals. By inference, pharmacological and psychosocial treatments for human opioid dependence might also benefit AAS-dependent individuals. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  15. The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Chao [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China); Luo, Fei [Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211 (China); Zhou, Ying; Du, Xiaoling; Shi, Jiandang; Zhao, Xiaoling [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China); Xu, Yong [Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211 (China); Zhu, Yan [Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193 (China); Hong, Wei, E-mail: hongwei@tijmu.edu.cn [Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070 (China); Zhang, Ju, E-mail: zhangju@nankai.edu.cn [Department of Biochemistry and Molecular Biology, College of Life Sciences, Bioactive Materials Key Lab of Ministry of Education, Nankai University, Tianjin 300071 (China)

    2016-07-15

    Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression of androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression. - Highlights: • Seal oil prevents oestradiol/testosterone (E2/T)-induced BPH in castrated rats. • Seal oil downregulates the expression of oestrogen receptor α(ERα) and androgen receptor (AR) in rat BPH tissues. • DHA inhibits the growth of human prostate stromal and epithelial cells in vitro. • DHA arrests human prostate stromal and epithelial cells in the G2/M phase and downregulates the expression of cyclin B1. • DHA inhibits the expression of ERα and AR in human prostate stromal and epithelial cells.

  16. Investigation of patients with atypical or severe hyperandrogenaemia including androgen-secreting ovarian teratoma.

    LENUS (Irish Health Repository)

    Dennedy, Michael Conall

    2012-02-01

    Approximately 7% of women of reproductive age manifest polycystic ovary syndrome (PCOS) and <0.5% have other causes of hyperandrogenism including congenital adrenal hyperplasia (CAH), androgen-secreting tumour of an ovary or an adrenal gland, Cushing\\'s syndrome or hyperthecosis. The presence of features atypical of PCOS should prompt more extensive evaluation than that usually undertaken. Features atypical of PCOS include the onset of symptoms outside the decade of 15-25 years, rapid progression of symptoms, the development of virilization and a serum testosterone concentration in excess of twice the upper limit of the reference range. Ethnic background, family history and specific clinical findings, e.g. Cushingoid appearance, may inform a focused investigation. Otherwise, patients should have measurement of 17-hydroxyprogesterone (17-OHP) under basal conditions ideally in the early morning, and if abnormal, they should have measurement of 17-OHP one hour after the administration of synthetic ACTH, 250 microg i.v., to screen for CAH, which is present in approximately 2% of hyperandrogenic patients. The overnight cortisol suppression test employing 1 mg dexamethasone at midnight is a sensitive test for Cushing\\'s syndrome. Coronal tomographic (CT) scanning of the adrenals and transvaginal ultrasonography of the ovaries are the investigations of choice when screening for tumours in these organs. Less frequently required is catheterization and sampling from both adrenal and ovarian veins, which is a technically demanding procedure with potential complications which may provide definitive diagnostic information not available from other investigations. Illustrative case reports highlight some complexities in the investigation of hyperandrogenic patients presenting with features atypical of PCOS and include only the ninth case report of an androgen-secreting ovarian teratoma.

  17. Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats.

    Science.gov (United States)

    Yan, Xiaonan; Yuan, Chun; Zhao, Nannan; Cui, Yugui; Liu, Jiayin

    2014-07-01

    In adolescent girls with polycystic ovary syndrome (PCOS), neuroendocrine derangements manifest after the onset of puberty, characterized by rapid LH pulse frequency. The early mechanism underlying the pubertal regulation of the GNRH/LH pulsatile release in adolescents with PCOS remains uncertain. To determine the effects of prenatal androgen exposure on the activation of GNRH neurons and generation of LH pulse at puberty, we administrated 5α-dihydrotestosterone to pregnant rats and observed serum LH levels and expression of hypothalamic genes in female offspring from postnatal 4 to 8 weeks. The 6-week-old prenatally androgenized (PNA) female rats exhibited an increase in LH pulse frequency. The hypothalamic expression of neurokinin B (Nkb (Tac2)) and Lepr mRNA levels in PNA rats increased remarkably before puberty and remained high during puberty, whereas elevated Kiss1 mRNA levels were detected only after the onset of puberty. Exogenous kisspeptin, NK3R agonist, and leptin triggered tonic stimulation of GNRH neurons and increased LH secretion in 6-week-old PNA rats. Leptin upregulated Kiss1 mRNA levels in the hypothalamus of pubertal PNA rats; however, pretreatment with a kisspeptin antagonist failed to suppress the elevated serum LH stimulated by leptin, indicating that the stimulatory effects of leptin may be conveyed indirectly to GNRH neurons via other neural components within the GNRH neuronal network, rather than through the kisspeptin-GPR54 pathway. These findings validate the hypotheses that NKB and leptin play an essential role in the activation of GNRH neurons and initiation of increased LH pulse frequency in PNA female rats at puberty and that kisspeptin may coordinate their stimulatory effects on LH release. © 2014 Society for Endocrinology.

  18. Direct Regulation of Androgen Receptor Activity by Potent CYP17 Inhibitors in Prostate Cancer Cells*

    Science.gov (United States)

    Soifer, Harris S.; Souleimanian, Naira; Wu, Sijian; Voskresenskiy, Anatoliy M.; Kisaayak Collak, Filiz; Cinar, Bekir; Stein, Cy A.

    2012-01-01

    TOK-001 and abiraterone are potent 17-heteroarylsteroid (17-HAS) inhibitors of Cyp17, one of the rate-limiting enzymes in the biosynthesis of testosterone from cholesterol in prostate cancer cells. Nevertheless, the molecular mechanism underlying the prevention of prostate cell growth by 17-HASs still remains elusive. Here, we assess the effects of 17-HASs on androgen receptor (AR) activity in LNCaP and LAPC-4 cells. We demonstrate that both TOK-001 and abiraterone reduced AR protein and mRNA expression, and antagonized AR-dependent promoter activation induced by androgen. TOK-001, but not abiraterone, is an effective apparent competitor of the radioligand [3H]R1881 for binding to the wild type and various mutant AR (W741C, W741L) proteins. In agreement with these data, TOK-001 is a consistently superior inhibitor than abiraterone of R1881-induced transcriptional activity of both wild type and mutant AR. However, neither agent was able to trans-activate the AR in the absence of R1881. Our data demonstrate that phospho-4EBP1 levels are significantly reduced by TOK-001 and to a lesser extent by abiraterone alcohol, and suggest a mechanism by which cap-dependent translation is suppressed by blocking assembly of the eIF4F and eIF4G complex to the mRNA 5′ cap. Thus, the effects of these 17-HASs on AR signaling are complex, ranging from a decrease in testosterone production through the inhibition of Cyp17 as previously described, to directly reducing both AR protein expression and R1881-induced AR trans-activation. PMID:22174412

  19. Intermittent hypoxia increases insulin resistance in genetically obese mice.

    Science.gov (United States)

    Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

    2003-10-01

    Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P intermittent hypoxia is dependent on the disruption of leptin pathways.

  20. Putting intelligent structured intermittent auscultation (ISIA) into practice.

    Science.gov (United States)

    Maude, Robyn M; Skinner, Joan P; Foureur, Maralyn J

    2016-06-01

    Fetal monitoring guidelines recommend intermittent auscultation for the monitoring of fetal wellbeing during labour for low-risk women. However, these guidelines are not being translated into practice and low-risk women birthing in institutional maternity units are increasingly exposed to continuous cardiotocographic monitoring, both on admission to hospital and during labour. When continuous fetal monitoring becomes routinised, midwives and obstetricians lose practical skills around intermittent auscultation. To support clinical practice and decision-making around auscultation modality, the intelligent structured intermittent auscultation (ISIA) framework was developed. The purpose of this discussion paper is to describe the application of intelligent structured intermittent auscultation in practice. The intelligent structured intermittent auscultation decision-making framework is a knowledge translation tool that supports the implementation of evidence into practice around the use of intermittent auscultation for fetal heart monitoring for low-risk women during labour. An understanding of the physiology of the materno-utero-placental unit and control of the fetal heart underpin the development of the framework. Intelligent structured intermittent auscultation provides midwives with a robust means of demonstrating their critical thinking and clinical reasoning and supports their understanding of normal physiological birth. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Effect of Intermittent Hypercapnia on Respiratory Control in Rat Pups

    Science.gov (United States)

    Steggerda, Justin A.; Mayer, Catherine A.; Martin, Richard J.; Wilson, Christopher G.

    2010-01-01

    Preterm infants are subject to fluctuations in blood gas status associated with immature respiratory control. Intermittent hypoxia during early postnatal life has been shown to increase chemoreceptor sensitivity and destabilize the breathing pattern; however, intermittent hypercapnia remains poorly studied. Therefore, to test the hypothesis that intermittent hypercapnia results in altered respiratory control, we examined the effects of daily exposure to intermittent hypercapnia on the ventilatory response to subsequent hypercapnic and hypoxic exposure in neonatal rat pups. Exposure cycles consisted of 5 min of intermittent hypercapnia (5% CO2, 21% O2, balance N2) followed by 10 min of normoxia. Rat pups were exposed to 18 exposure cycles each day for 1 week, from postnatal day 7 to 14. We analyzed diaphragm electromyograms (EMGs) from pups exposed to subsequent acute hypercapnic (5% CO2) and hypoxic (12% O2) challenges. In response to a subsequent hypercapnia challenge, there was no significant difference in the ventilatory response between control and intermittent hypercapnia-exposed groups. In contrast, intermittent hypercapnia-exposed rat pups showed an enhanced ventilatory response to hypoxic challenge with an increase in minute EMG to 118 ± 14% of baseline versus 107 ± 13% for control pups (p < 0.05). We speculate that prior hypercapnic exposure may increase peripheral chemoreceptor response to subsequent hypoxic exposures and result in perturbed neonatal respiratory control. PMID:19752577

  2. Atmospheric Pressure Photoionization Tandem Mass Spectrometry of Androgens in Prostate Cancer

    Science.gov (United States)

    Lih, Fred Bjørn; Titus, Mark A.; Mohler, James L.; Tomer, Kenneth B.

    2010-01-01

    Androgen deprivation therapy is the most common treatment option for advanced prostate cancer. Almost all prostate cancers recur during androgen deprivation therapy, and new evidence suggests that androgen receptor activation persists despite castrate levels of circulating androgens. Quantitation of tissue levels of androgens is critical to understanding the mechanism of recurrence of prostate cancer during androgen deprivation therapy. A liquid chromatography atmospheric pressure photoionization tandem mass spectrometric method was developed for quantitation of tissue levels of androgens. Quantitation of the saturated keto-steroids dihydrotestosterone and 5-α-androstanedione required detection of a novel parent ion, [M + 15]+. The nature of this parent ion was explored and the method applied to prostate tissue and cell culture with comparison to results achieved using electrospray ionization. PMID:20560527

  3. Role of Hsp90 in Androgen-Refractory Prostate Cancer

    Science.gov (United States)

    2010-03-01

    designed siRNA sequence using Intergrated DNA Technologies RNAi online software tool (IDT, Coralville, IA). The sequence of siRNA specific for...proliferation and production of prostate-specific antigen in androgen-sensitive pros- tatic cancer cells, LNCaP, by dihydrotestosterone. Endocrinology 136

  4. Prevalence and awareness of anabolic androgenic steroid use ...

    African Journals Online (AJOL)

    Purpose: To examine the prevalence and awareness of anabolic-androgenic steroid (AAS) use among male bodybuilders visiting gyms in Jazan region, Saudi Arabia. Methods: A cross-sectional survey was conducted among 500 male bodybuilders visiting gyms in the Jazan region of Saudi Arabia. Information on ...

  5. Hypercholesterolemia in Male Power Lifters Using Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Cohen, Jonathan C.; And Others

    1988-01-01

    Measurement of serum cholesterol concentrations in male power lifters who used anabolic-androgenic steroids for eight weeks, three years, or eight years indicated that mean serum cholesterol levels increased with drug use, but decreased promptly to near pre-steroid levels after steroid use ended. (Author/CB)

  6. Psychological and Behavioral Effects of Anabolic-Androgenic Steroids.

    Science.gov (United States)

    Bahrke, Michael S.

    This review of the literature on the psychological and behavioral effects of anabolic-androgenic steroids (AS) first looks at aspects of the history and prevalence of AS use in competitive sports. Research suggests that one-quarter to one-half million adolescents in the United States have used, or are currently using AS. Some effects of androgens…

  7. Baldness, benign prostate hyperplasia, prostate cancer and androgen levels.

    Science.gov (United States)

    Faydaci, Gökhan; Bilal, Eryildirim; Necmettin, Penpegül; Fatih, Tarhan; Asuman, Orçun; Uğur, Kuyumcuoğlu

    2008-12-01

    We evaluated the pattern of baldness and serum androgen levels in patients with benign prostate hyperplasia (BPH) and prostate cancer. BPH, prostate cancer and androgenic alopecia (AA) were somehow androgen dependent and affect large population of elderly men. A total of 152 patients, 108 patients with BPH and 44 patients with prostate cancer were included in the study. We measured serum total, free and bioavailable testosterone, FSH, LH, prolactin, estradiol, albumin and SHBG levels. Baldness classification was based on Norwood's classification and we categorised baldness as vertex and frontal baldness. The frequency of AA in BPH and prostate cancer groups were not different. We looked for some correlation between the two groups with respect to AA and hormone levels. We did not find any correlation between AA and total testosterone, free testosterone, bioavailable testosterone or SHBG levels in both groups. This prospective study with selected small group of patients showed that there is no difference of male pattern baldness in BPH and prostate cancer patients and also there is no correlation between pattern of baldness and serum androgen levels.

  8. Effect of Cuscuta reflexa Roxb on androgen-induced alopecia.

    Science.gov (United States)

    Pandit, Shweta; Chauhan, Nagendra Singh; Dixit, V K

    2008-09-01

    Alopecia is a psychologically distressing condition. Androgenetic alopecia, which affects millions of men and women, is an androgen-driven disorder. Here, Cuscuta reflexa Roxb is evaluated for hair growth activity in androgen-induced alopecia. Petroleum ether extract of C. reflexa was studied for its hair growth-promoting activity. Alopecia was induced in albino mice by testosterone administration for 20 days. Its inhibition by simultaneous administration of extract was evaluated using follicular density, anagen/telogen ratio, and microscopic observation of skin sections. To investigate the mechanism of observed activity, in vitro experiments were performed to study the effect of extract and its major component on activity of 5alpha-reductase enzyme. Petroleum ether extract of C. reflexa exhibited promising hair growth-promoting activity as reflected from follicular density, anagen/telogen ratio, and skin sections. Inhibition of 5alpha-reductase activity by extract and isolate suggest that the extract reversed androgen-induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone. The petroleum ether extract of C. reflexa and its isolate is useful in treatment of androgen-induced alopecia by inhibiting the enzyme 5alpha-reductase.

  9. Procoagulant State in Current and Former Anabolic Androgenic Steroid Abusers

    DEFF Research Database (Denmark)

    Chang, Simon; Rasmussen, Jon J; Frandsen, Mikkel N

    2018-01-01

    BACKGROUND:  Anabolic androgenic steroid (AAS) abusers are considered at increased risk of cardiovascular morbidity and mortality. We hypothesized that current and former AAS abuse would induce a procoagulant shift in the haemostatic balance. METHODS:  Men 18 to 50 years of age were included...

  10. Expression of androgen and estrogen receptors in the testicular ...

    African Journals Online (AJOL)

    enoh

    2012-04-10

    Apr 10, 2012 ... 66: 1161-1168. Oliveira CA, Mahecha GA, Carnes K, Prins GS, Saunders PT, Franca. LR, Hess RA (2004). Differential hormonal regulation of estrogen receptors ERα and ER and androgen receptor expression in rat efferent ductules. Reproduction, 128(1): 73-86. O'Shaughnessy PJ, Johnston H, Willerton L ...

  11. Environmental polycyclic aromatic hydrocarbons affect androgen receptor activation in vitro

    DEFF Research Database (Denmark)

    Vinggaard, Anne Marie; Hnida, Christina; Larsen, John Christian

    2000-01-01

    Nine structurally different polycyclic aromatic hydrocarbons (PAHs) were tested for their ability to either agonize or antagonize the human androgen receptor (hAR) in a sensitive reporter gene assay based on CHO cells transiently cotransfected with a hAR vector and an MMTV-LUC vector. Benz...

  12. Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

    Science.gov (United States)

    Thevis, Mario; Schänzer, Wilhelm

    2010-01-01

    The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

  13. Reduced fetal androgen exposure compromises Leydig cell function in adulthood

    NARCIS (Netherlands)

    Teerds, K.J.; Keijer, J.

    2015-01-01

    Disruption of normal fetal development can influence functioning of organs and cells in adulthood. Circumstantial evidence suggests that subtle reductions in fetal androgen production may be the cause of adult male reproductive disorders due to reduced testosterone production. The mechanisms through

  14. Unique Approaches to Androgen Effects on Prostate Cancer

    National Research Council Canada - National Science Library

    Rosner, W; Kahn, S. M

    2007-01-01

    Sex hormone-binding globulin (SHBG) is a plasma protein that binds andrngens and it acts as a transducer of androgen signaling at the plasma membrane of prostate cancer cells The human prostate cancer cell line LNCaP in addition...

  15. Premature adrenarche: novel lessons from early onset androgen excess.

    Science.gov (United States)

    Idkowiak, Jan; Lavery, Gareth G; Dhir, Vivek; Barrett, Timothy G; Stewart, Paul M; Krone, Nils; Arlt, Wiebke

    2011-08-01

    Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

  16. Photoluminescence intermittency of semiconductor quantum dots in dielectric environments

    Energy Technology Data Exchange (ETDEWEB)

    Isaac, A.

    2006-08-11

    The experimental studies presented in this thesis deal with the photoluminescence intermittency of semiconductor quantum dots in different dielectric environments. Detailed analysis of intermittency statistics from single capped CdSe/ZnS, uncapped CdSe and water dispersed CdSe/ZnS QDs in different matrices provide experimental evidence for the model of photoionization with a charge ejected into the surrounding matrix as the source of PL intermittency phenomenon. We propose a self-trapping model to explain the increase of dark state lifetimes with the dielectric constant of the matrix. (orig.)

  17. Intermittent fasting: a "new" historical strategy for controlling seizures?

    Science.gov (United States)

    Hartman, Adam L; Rubenstein, James E; Kossoff, Eric H

    2013-05-01

    In antiquity, fasting was a treatment for epilepsy and a rationale for the ketogenic diet (KD). Preclinical data indicate the KD and intermittent fasting do not share identical anticonvulsant mechanisms. We implemented an intermittent fasting regimen in six children with an incomplete response to a KD. Three patients adhered to the combined intermittent fasting/KD regimen for 2 months and four had transient improvement in seizure control, albeit with some hunger-related adverse reactions. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection

    NARCIS (Netherlands)

    Dybul, M; Nies-Kraske, E; Dewar, R; Maldarelli, F; Hallahan, CW; Daucher, M; Piscitelli, SC; Ehler, L; Weigand, A; Palmer, S; Metcalf, JA; Davey, RT; Kress, DMR; Powers, A; Beck, [No Value; Frenkel, L; Baseler, M; Coffin, J; Fauci, AS

    2004-01-01

    Background. We previously demonstrated that short-cycle structured intermittent therapy ( SIT; 7 days without therapy followed by 7 days with antiretroviral therapy [ART]) with a ritonavir-boosted, indinavir-based, twice-daily regimen maintained suppression of plasma HIV viremia while reducing serum

  19. Suppression of chaos via control of energy flow

    Science.gov (United States)

    Guo, Shengli; Ma, Jun; Alsaedi, Ahmed

    2018-03-01

    Continuous energy supply is critical and important to support oscillating behaviour; otherwise, the oscillator will die. For nonlinear and chaotic circuits, enough energy supply is also important to keep electric devices working. In this paper, Hamilton energy is calculated for dimensionless dynamical system (e.g., the chaotic Lorenz system) using Helmholtz's theorem. The Hamilton energy is considered as a new variable and then the dynamical system is controlled by using the scheme of energy feedback. It is found that chaos can be suppressed even when intermittent feedback scheme is applied. This scheme is effective to control chaos and to stabilise other dynamical systems.

  20. Intermittent Renewable Management Pilot Phase 2

    Energy Technology Data Exchange (ETDEWEB)

    Kiliccote, Sila [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Homan, Gregory [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Anderson, Robert [Olivine, Inc., San Ramon, CA (United States); Hernandez, John [Pacific Gas & Electric Company, San Francisco, CA (United States)

    2015-04-01

    The Intermittent Renewable Management Pilot - Phase 2 (IRM2) was designed to study the feasibility of demand-side resources to participate into the California Independent System Operator (CAISO) wholesale market as proxy demand resources (PDR). The pilot study focused on understanding the issues related with direct participation of third-parties and customers including customer acceptance; market transformation challenges (wholesale market, technology); technical and operational feasibility; and value to the rate payers, DR resource owners and the utility on providing an enabling mechanism for DR resources into the wholesale markets. The customer had the option of committing to either three contiguous hour blocks for 24 days or six contiguous hours for 12 days a month with day-ahead notification that aligned with the CAISO integrated forward market. As a result of their being available, the customer was paid $10/ kilowatt (kW)-month for capacity in addition to CAISO energy settlements. The participants were limited to no more than a 2 megawatt (MW) capacity with a six-month commitment. Four participants successfully engaged in the pilot. In this report, we provide the description of the pilot, participant performance results, costs and value to participants as well as outline some of the issues encountered through the pilot. Results show that participants chose to participate with storage and the value of CAISO settlements were significantly lower than the capacity payments provided by the utility as incentive payments. In addition, this pilot revealed issues both on the participant side and system operations side. These issues are summarized in the report.The Intermittent Renewable Management Pilot - Phase 2 (IRM2) was designed to study the feasibility of demand-side resources to participate into the California Independent System Operator (CAISO) wholesale market as proxy demand resources (PDR). The pilot study focused on understanding the issues related with

  1. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

    Science.gov (United States)

    Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Azuma, Haruhito; Lee, Gwo-Shu Mary; Kantoff, Philip W.; Sweeney, Christopher J.

    2016-01-01

    The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. PMID:27185910

  2. Androgen deficiency and dry eye syndrome in the aging male.

    Science.gov (United States)

    Azcarate, Patrick M; Venincasa, Vincent D; Feuer, William; Stanczyk, Frank; Schally, Andrew V; Galor, Anat

    2014-07-03

    To evaluate the relationship between androgen levels and subjective and objective measures of dry eye syndrome (DES). A total of 263 male patients from the Miami Veterans Affairs Medical Center eye clinic aged ≥50 were recruited for this prospective cross-sectional study. Patients completed Dry Eye Questionnaire 5, underwent tear film evaluation, and had serum androgen levels measured. The correlations between androgen levels, DES composite scores, DES symptoms, and global, lipid, and aqueous tear film parameters were evaluated. Two hundred sixty-three patients with a mean age of 69 (50-95) were examined. There was no linear association between composite DES scores (generated using latent class analysis) and androgen levels. However, eyes with high DES scores (0.95-1.0) had higher levels of sex hormone-binding globulin (P = 0.03) and lower levels of dehydroepiandrosterone sulfate (DHEAS) (P = 0.02), androstenedione (A) (P = 0.02), and androstane-3α,17β-diol glucuronide (P = 0.03) compared to eyes with intermediate (0.05-0.95) or low (0-0.05) scores. There were no strong correlations between tear film measures and androgen levels. Regarding global parameters, a weak inverse correlation was found between corneal staining and A (r = -0.17, P = 0.009). For lipid parameters, a weak correlation existed between tear breakup time (TBUT) and A (r = 0.15, P = 0.02). When considering aqueous and lipid deficiency independently, the association between TBUT and A existed only with aqueous tear deficiency (r = 0.66, P = 0.002). Regarding aqueous parameters, a weak correlation existed between Schirmer test and DHEAS (r = 0.13, P = 0.047) and A (r = 0.21, P = 0.001). There was a weak correlation between higher levels of androstenedione and healthier global, lipid, and aqueous tear film parameters. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  3. Leuprolide acetate-stimulated androgen response during female puberty.

    Science.gov (United States)

    Hernandez, María Isabel; Martinez-Aguayo, Alejandro; Cavada, Gabriel; Avila, Alejandra; Iñiguez, German; Mericq, Veronica

    2015-08-01

    A physiological increase in androgen levels occurs during adolescence. Measuring androgen concentrations is the best method to distinguish normal evolution processes from hyperandrogenic disorders. The increase in circulating androgens during puberty is inversely associated with insulin sensitivity in normal weight girls. To assess circulating levels of ovarian androgens and anti-Müllerian hormone (AMH) at baseline and after GnRH analogue (GnRH-a) stimulation in normal pubertal girls across different Tanner stages. We also studied the association between this response and insulin sensitivity. Prospective study of healthy girls (6-12 years) from the local community (n = 63). Tanner I (n = 23) subjects were assessed cross-sectionally, and Tanner II girls (n = 40) were evaluated every 6 months until they reached Tanner V. Early morning dehydroepiandrosterone sulphate (DHEA-S), AMH, sex hormone-binding globulin (SHBG), androstenedione, glucose and insulin levels were measured. A GnRH-a test (500 μg/m(2) ; sc) and oral glucose intolerance test (OGTT) were performed. Differences throughout puberty were evaluated. Basal and/or stimulated Testosterone DHEA-S and 17-hydroxyprogesterone (17OHP) were inversely associated with insulin sensitivity (WIBSI) from the beginning of puberty, whereas androstenedione was directly associated with gonadotrophins. AMH was inversely associated with basal and stimulated gonadotrophins and directly with insulin area under the curve (AUC) only in the early stages of puberty. 17OHP and testosterone responsiveness increased significantly during puberty in all subjects, whereas testosterone levels changed less consistently. This pattern of ovarian-steroidogenic response was most evident during mid- and late puberty. Moreover, during late puberty only, basal 17OHP, testosterone and DHEA-S were positively associated with gonadotrophins. In normal nonobese girls born appropriate for gestational age, androgen synthesis was associated with

  4. Androgenic signaling systems and their role in behavioral evolution.

    Science.gov (United States)

    Fuxjager, Matthew J; Schuppe, Eric R

    2018-06-05

    Sex steroids mediate the organization and activation of masculine reproductive phenotypes in diverse vertebrate taxa. However, the effects of sex steroid action in this context vary tremendously, in that steroid action influences reproductive physiology and behavior in markedly different ways (even among closely related species). This leads to the idea that the mechanisms underlying sex steroid action similarly differ across vertebrates in a manner that supports diversification of important sexual traits. Here, we highlight the Evolutionary Potential Hypothesis as a framework for understanding how androgen-dependent reproductive behavior evolves. This idea posits that the cellular mechanisms underlying androgenic action can independently evolve within a given target tissue to adjust the hormone's functional effects. The result is a seemingly endless number of permutations in androgenic signaling pathways that can be mapped onto the incredible diversity of reproductive phenotypes. One reason this hypothesis is important is because it shifts current thinking about the evolution of steroid-dependent traits away from an emphasis on circulating steroid levels and toward a focus on molecular mechanisms of hormone action. To this end, we also provide new empirical data suggesting that certain cellular modulators of androgen action-namely, the co-factors that dynamically adjust transcritpional effects of steroid action either up or down-are also substrates on which evolution can act. We then close the review with a detailed look at a case study in the golden-collared manakin (Manacus vitellinus). Work in this tropical bird shows how androgenic signaling systems are modified in specific parts of the skeletal muscle system to enhance motor performance necessary to produce acrobatic courtship displays. Altogether, this paper seeks to develop a platform to better understand how steroid action influences the evolution of complex animal behavior. Copyright © 2018 Elsevier Ltd

  5. Nonsteroidal selective androgen receptor modulators enhance female sexual motivation.

    Science.gov (United States)

    Jones, Amanda; Hwang, Dong Jin; Duke, Charles B; He, Yali; Siddam, Anjaiah; Miller, Duane D; Dalton, James T

    2010-08-01

    Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

  6. Is acne a sign of androgen excess disorder or not?

    Science.gov (United States)

    Uysal, Gulsum; Sahin, Yılmaz; Unluhizarci, Kursad; Ferahbas, Ayten; Uludag, Semih Zeki; Aygen, Ercan; Kelestimur, Fahrettin

    2017-04-01

    Acne is not solely a cosmetic problem. The clinical importance of acne in the estimation of androgen excess disorders is controversial. Recently, the Amsterdam ESHRE/ASRM-sponsored third PCOS Consensus Workshop Group suggested that acne is not commonly associated with hyperandrogenemia and therefore should not be regarded as evidence of hyperandrogenemia. Our aim was to investigate whether acne is a sign of androgen excess disorder or not. This is a cross sectional study that was performed in a university hospital involving 207 women, aged between 18 and 45 years, suffering mainly from acne. The women were assigned as polycystic ovary syndrome (PCOS), idiopathic hirsutism (IH), idiopathic hyperandrogenemia (IHA). Women with acne associated with any of the androgen excess disorders mentioned above were named as hyperandrogenemia associated acne (HAA). Women with acne but without hirsutism and hyperandrogenemia and having ovulatory cycles were named as "isolated acne". Serum luteinizing hormone, follicle stimulating hormone, estradiol, progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone-sulfate (DHEAS), androstenedione, total testosterone and lipid levels were measured. Acne score was similar between the women with isolated acne and HAA. The most common cause for acne was PCOS and only 28% of the women had isolated acne. 114 (55%) women had at least one raised serum androgen level. In this study, 72% of acneic women had clinical and/or biochemical hyperandrogenemia. In contrast to the suggestion of ESHRE/ASRM-sponsored third PCOS Consensus Workshop Group, our data indicate that the presence of androgen excess disorders should be evaluated in women presenting with acne. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Excess androgen during puberty disrupts circadian organization in female rats.

    Science.gov (United States)

    Sellix, Michael T; Murphy, Zachary C; Menaker, Michael

    2013-04-01

    Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes.

  8. Factors predisposing to consecutive esotropia after surgery to correct intermittent exotropia.

    Science.gov (United States)

    Jang, Jung Hyun; Park, Jung Min; Lee, Soo Jung

    2012-10-01

    To investigate the incidence of and factors predisposing to consecutive esotropia after intermittent exotropia surgery, and to prevent the onset of consecutive esotropia. We retrospectively surveyed 226 patients who had been followed up for more than 1 year after surgery for intermittent exotropia conducted between February 2005 and September 2010. Consecutive esotropia was defined as an esotropia of at least 10 prism diopters (PD) at distance or near at least once in 2 weeks after surgery. Presumed risk factors for consecutive esotropia were analyzed. Gender, age at surgery, average binocular spherical equivalent, anisometropia, high myopia, amblyopia, preoperative angle of deviation, vertical deviation, A-V pattern strabismus, exotropia type, type of surgery, stereopsis, and suppression were investigated to evaluate factors influencing the onset of consecutive esotropia. Consecutive esotropia occurred in 22 patients (9.7 %). Significant correlations with occurrence of the condition were found with high myopia (P = 0.013), amblyopia (P = 0.047), preoperative angle of deviation of 25-40 PD at distance (P = 0.016), deviation at distance - deviation at near > 10 PD (P = 0.041), lateral incomitance (P = 0.007), tenacious proximal convergence fusion type (P = 0.001), unilateral lateral rectus muscle recession and medial rectus muscle resection (P = 0.001). High myopia, amblyopia, and lateral incomitance were predisposing factors for consecutive esotropia. Furthermore, the preoperative angle of deviation at distance, differences between the angle of deviation at near and at distance, the type of intermittent exotropia, and the type of surgery affected the incidence of consecutive esotropia. More attention must be paid to patients with such factors.

  9. Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.

    Science.gov (United States)

    Olson, Brian M; Gamat, Melissa; Seliski, Joseph; Sawicki, Thomas; Jeffery, Justin; Ellis, Leigh; Drake, Charles G; Weichert, Jamey; McNeel, Douglas G

    2017-12-01

    Androgen deprivation is the primary therapy for recurrent prostate cancer, and agents targeting the androgen receptor (AR) pathway continue to be developed. Because androgen-deprivation therapy (ADT) has immmunostimulatory effects as well as direct antitumor effects, AR-targeted therapies have been combined with other anticancer therapies, including immunotherapies. Here, we sought to study whether an antigen-specific mechanism of resistance to ADT (overexpression of the AR) may result in enhanced AR-specific T-cell immune recognition, and whether this might be strategically combined with an antitumor vaccine targeting the AR. Androgen deprivation increased AR expression in human and murine prostate tumor cells in vitro and in vivo The increased expression persisted over time. Increased AR expression was associated with recognition and cytolytic activity by AR-specific T cells. Furthermore, ADT combined with vaccination, specifically a DNA vaccine encoding the ligand-binding domain of the AR, led to improved antitumor responses as measured by tumor volumes and delays in the emergence of castrate-resistant prostate tumors in two murine prostate cancer models (Myc-CaP and prostate-specific PTEN-deficient mice). Together, these data suggest that ADT combined with AR-directed immunotherapy targets a major mechanism of resistance, overexpression of the AR. This combination may be more effective than ADT combined with other immunotherapeutic approaches. Cancer Immunol Res; 5(12); 1074-85. ©2017 AACR . ©2017 American Association for Cancer Research.

  10. Sex differences associated with intermittent swim stress.

    Science.gov (United States)

    Warner, Timothy A; Libman, Matthew K; Wooten, Katherine L; Drugan, Robert C

    2013-11-01

    Various animal models of depression have been used to seek a greater understanding of stress-related disorders. However, there is still a great need for novel research in this area, as many individuals suffering from depression are resistant to current treatment methods. Women have a higher rate of depression, highlighting the need to investigate mechanisms of sex differences. Therefore, we employed a new animal model to assess symptoms of depression, known as intermittent swim stress (ISS). In this model, the animal experiences 100 trials of cold water swim stress. ISS has already been shown to cause signs of behavioral depression in males, but has yet to be assessed in females. Following ISS exposure, we looked at sex differences in the Morris water maze and forced swim test. The results indicated a spatial learning effect only in the hidden platform task between male and female controls, and stressed and control males. A consistent spatial memory effect was only seen for males exposed to ISS. In the forced swim test, both sexes exposed to ISS exhibited greater immobility, and the same males and females also showed attenuated climbing and swimming, respectively. The sex differences could be due to different neural substrates for males and females. The goal of this study was to provide the first behavioral examination of sex differences following ISS exposure, so the stage of estrous cycle was not assessed for the females. This is a necessary future direction for subsequent experiments. The current article highlights the importance of sex differences in response to stress.

  11. Treatment of variable and intermittently flowing wastewaters.

    Science.gov (United States)

    Kocasoy, Günay

    1993-11-01

    The biological treatment of wastewaters originating from hotels and residential areas of seasonal use, flowing intermittently, is difficult due to the fact that bacteria cannot survive during periods of no-flow. An investigation has been conducted in order to develop a system which will be able to overcome the difficulties encountered. After a long investigation the following system has given satisfactory results. The wastewater was taken initially into an aeration tank operating as a sequential batch reactor. Waste was taken after the sedimentation phase of the reactor into a coagulation-flocculation tank where it was treated by chemical means, and then settled in order to separate the floes. When the population of bacteria in the aeration tank reached the required level, the physico-chemical treatment was terminated and the tank used for chemical treatment has been started to be used as an equalization tank while the aeration and sedimentation tanks have been used as an activated sludge unit. This system has been proved to be a satisfactory method for the above mentioned wastes.

  12. Mesoscopic fluctuations and intermittency in aging dynamics

    Science.gov (United States)

    Sibani, P.

    2006-01-01

    Mesoscopic aging systems are characterized by large intermittent noise fluctuations. In a record dynamics scenario (Sibani P. and Dall J., Europhys. Lett., 64 (2003) 8) these events, quakes, are treated as a Poisson process with average αln (1 + t/tw), where t is the observation time, tw is the age and α is a parameter. Assuming for simplicity that quakes constitute the only source of de-correlation, we present a model for the probability density function (PDF) of the configuration autocorrelation function. Beside α, the model has the average quake size 1/q as a parameter. The model autocorrelation PDF has a Gumbel-like shape, which approaches a Gaussian for large t/tw and becomes sharply peaked in the thermodynamic limit. Its average and variance, which are given analytically, depend on t/tw as a power law and a power law with a logarithmic correction, respectively. Most predictions are in good agreement with data from the literature and with the simulations of the Edwards-Anderson spin-glass carried out as a test.

  13. Long-range forecasting of intermittent streamflow

    Science.gov (United States)

    van Ogtrop, F. F.; Vervoort, R. W.; Heller, G. Z.; Stasinopoulos, D. M.; Rigby, R. A.

    2011-11-01

    Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a statistical model to forecast streamflow up to 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS) to determine the probability of flow occurring in any of the systems. We then use the same regression framework in combination with a right-skewed distribution, the Box-Cox t distribution, to model the intensity (depth) of the non-zero streamflows. Time, seasonality and climate indices, describing the Pacific and Indian Ocean sea surface temperatures, are tested as covariates in the GAMLSS model to make probabilistic 6 and 12-month forecasts of the occurrence and intensity of streamflow. The output reveals that in the study region the occurrence and variability of flow is driven by sea surface temperatures and therefore forecasts can be made with some skill.

  14. Acute intermittent porphyria in Argentina: an update.

    Science.gov (United States)

    Cerbino, Gabriela Nora; Gerez, Esther Noemí; Varela, Laura Sabina; Melito, Viviana Alicia; Parera, Victoria Estela; Batlle, Alcira; Rossetti, María Victoria

    2015-01-01

    Porphyrias are a group of metabolic diseases that arise from deficiencies in the heme biosynthetic pathway. A partial deficiency in hydroxymethylbilane synthase (HMBS) produces a hepatic disorder named Acute Intermittent Porphyria (AIP); the acute porphyria is more frequent in Argentina. In this paper we review the results obtained for 101 Argentinean AIP families and 6 AIP families from foreign neighbour countries studied at molecular level at Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP). Thirty-five different mutations were found, of which 14 were described for the first time in our population. The most prevalent type of mutations was the missense mutations (43%) followed by splice defects (26%) and small deletions (20%). An odd case of a double heterozygous presentation of AIP in a foreign family from Paraguay is discussed. Moreover, it can be noted that 38 new families were found carrying the most frequent mutation in Argentina (p.G111R), increasing to 55.66% the prevalence of this genetic change in our population and adding further support to our previous hypothesis of a founder effect for this mutation in Argentina. Identification of patients with an overt AIP is important because treatment depends on an accurate diagnosis, but more critical is the identification of asymptomatic relatives to avoid acute attacks which may progress to death.

  15. Long-range forecasting of intermittent streamflow

    Directory of Open Access Journals (Sweden)

    F. F. van Ogtrop

    2011-11-01

    Full Text Available Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a statistical model to forecast streamflow up to 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS to determine the probability of flow occurring in any of the systems. We then use the same regression framework in combination with a right-skewed distribution, the Box-Cox t distribution, to model the intensity (depth of the non-zero streamflows. Time, seasonality and climate indices, describing the Pacific and Indian Ocean sea surface temperatures, are tested as covariates in the GAMLSS model to make probabilistic 6 and 12-month forecasts of the occurrence and intensity of streamflow. The output reveals that in the study region the occurrence and variability of flow is driven by sea surface temperatures and therefore forecasts can be made with some skill.

  16. Androgen deprivation therapy impact on quality of life and cardiovascular health, monitoring therapeutic replacement.

    Science.gov (United States)

    Trost, Landon W; Serefoglu, Ege; Gokce, Ahmet; Linder, Brian J; Sartor, Alton O; Hellstrom, Wayne J G

    2013-02-01

    Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy. © 2013 International Society for Sexual Medicine.

  17. Sodium fire suppression

    Energy Technology Data Exchange (ETDEWEB)

    Malet, J C [DSN/SESTR, Centre de Cadarache, Saint-Paul-lez-Durance (France)

    1979-03-01

    Ignition and combustion studies have provided valuable data and guidelines for sodium fire suppression research. The primary necessity is to isolate the oxidant from the fuel, rather than to attempt to cool the sodium below its ignition temperature. Work along these lines has led to the development of smothering tank systems and a dry extinguishing powder. Based on the results obtained, the implementation of these techniques is discussed with regard to sodium fire suppression in the Super-Phenix reactor. (author)

  18. Sodium fire suppression

    International Nuclear Information System (INIS)

    Malet, J.C.

    1979-01-01

    Ignition and combustion studies have provided valuable data and guidelines for sodium fire suppression research. The primary necessity is to isolate the oxidant from the fuel, rather than to attempt to cool the sodium below its ignition temperature. Work along these lines has led to the development of smothering tank systems and a dry extinguishing powder. Based on the results obtained, the implementation of these techniques is discussed with regard to sodium fire suppression in the Super-Phenix reactor. (author)

  19. Effects of Intermittent Fasting on Experimental Autoimune Encephalomyelitis in C57BL/6 Mice.

    Science.gov (United States)

    Razeghi Jahromi, Soodeh; Ghaemi, Amir; Alizadeh, Akram; Sabetghadam, Fatemeh; Moradi Tabriz, Hedieh; Togha, Mansoureh

    2016-06-01

    Several religions recommend periods of fasting. One of the most frequently asked questions of MS patients before the holy month of Ramadan is weather fasting might have an unfavorable effect on their disease course. This debate became more challenging after the publication of experimental studies suggesting that calorie restriction prior to disease induction attenuates disease severity. We conducted this study to assess early and late effects of fasting on the animal model of MS, known as autoimmune encephalomyelitis. EAE was induced in the C57BL/6 mice, using Myelin Oligodendrocyte Glycopeptide  (MOG) 35-55 and they fasted every other day either after the appearance of the first clinical sign or 30 days after disease induction for ten days. Thereafter, the mice were sacrificed for further histological and immunological evaluations. Intermittent fasting after the establishment of EAE did not have any unfavorable effect on the course of disease. Moreover, fasting at the early phase of disease alleviated EAE severity by ameliorating spinal cord demyelination. Fasting suppressed the secretion of IFN-γ, TNF-α and raised IL-10 production in splenocytes. Fasting was also associated with a lower percent of cytotoxicity. Intermittent fasting not only had no unfavorable effect on EAE but also reduced EAE severity if started at early phase of disease.

  20. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects.

    Science.gov (United States)

    Faris, Mo'ez Al-Islam E; Kacimi, Safia; Al-Kurd, Ref'at A; Fararjeh, Mohammad A; Bustanji, Yasser K; Mohammad, Mohammad K; Salem, Mohammad L

    2012-12-01

    Intermittent fasting and caloric restriction have been shown to extend life expectancy and reduce inflammation and cancer promotion in animal models. It was hypothesized that intermittent prolonged fasting practiced during the month of Ramadan (RIF) could positively affect the inflammatory state. To investigate this hypothesis, a cross-sectional study was designed to investigate the impact of RIF on selected inflammatory cytokines and immune biomarkers in healthy subjects. Fifty (21 men and 29 women) healthy volunteers who practiced Ramadan fasting were recruited for the investigation of circulating proinflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor α), immune cells (total leukocytes, monocytes, granulocytes, and lymphocytes), and anthropometric and dietary assessments. The investigations were conducted 1 week before Ramadan fasting, at the end of the third week of Ramadan, and 1 month after the cessation of Ramadan month. The proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α; systolic and diastolic blood pressures; body weight; and body fat percentage were significantly lower (P fasting. Immune cells significantly decreased during Ramadan but still remained within the reference ranges. These results indicate that RIF attenuates inflammatory status of the body by suppressing proinflammatory cytokine expression and decreasing body fat and circulating levels of leukocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Intermittency in multiparticle production analyzed by means of stochastic theories

    International Nuclear Information System (INIS)

    Bartl, A.; Suzuki, N.

    1990-01-01

    Intermittency in multiparticle production is described by means of probability distributions derived from pure birth stochastic equations. The UA1, TASSO, NA22 and cosmic ray data are analyzed. 24 refs., 1 fig. (Authors)

  2. Factors Relevant to Utility Integration of Intermittent Renewable Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Y.; Parsons, B.

    1993-08-24

    This study assesses factors that utilities must address when they integrate intermittent renewable technologies into their power-supply systems; it also reviews the literature in this area and has a bibliography containing more than 350 listings. Three topics are covered: (1) interface (hardware and design-related interconnection), (2) operability/stability, and (3) planning. This study finds that several commonly held perceptions regarding integration of intermittent renewable energy technologies are not valid. Among fmdings of the study are the following: (1) hardware and system design advances have eliminated most concerns about interface, (2) cost penalties have not occurred at low to moderate penetration levels (and high levels am feasible); and (3) intermittent renewable energy technologies can have capacity values. Obstacles still interfering with intermittent renewable technologies are also indentified.

  3. Factors relevant to utility integration of intermittent renewable technologies

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Yih-huei; Parsons, B.K.

    1993-08-01

    This study assesses factors that utilities must address when they integrate intermittent renewable technologies into their power-supply systems; it also reviews the literature in this area and has a bibliography containing more than 350 listings. Three topics are covered: (1) interface (hardware and design-related interconnection), (2) operability/stability, and (3) planning. This study finds that several commonly held perceptions regarding integration of intermittent renewable energy technologies are not valid. Among findings of the study are the following: (1) hardware and system design advances have eliminated most concerns about interface; (2) cost penalties have not occurred at low to moderate penetration levels (and high levels are feasible); and (3) intermittent renewable energy technologies can have capacity values. Obstacles still interfering with intermittent renewable technologies are also identified.

  4. Isolated intermittent vertigo: A presenting feature of persistent trigeminal artery

    Directory of Open Access Journals (Sweden)

    Rajsrinivas Parthasarathy

    2016-01-01

    Full Text Available Embryonic carotid – basilar anastomosis when persistent in adult life can present with a variety of neurological symptoms. We present a patient with isolated intermittent vertigo attributable to the embryonic anastomosis and describe the different types of persistent trigeminal artery. A 76-year-old Caucasian man presented with isolated intermittent vertigo and symptoms suggestive of anterior and posterior circulation strokes. Impaired vasomotor reactivity was demonstrated on insonation of the anterior and posterior cerebral arteries in this patient with a persistent left trigeminal artery and 75% stenosis of the left internal carotid artery (ICA. The symptom of intermittent vertigo resolved with carotid endarterectomy. Decreased flow across the stenotic segment of the ICA which subserved the posterior circulation resulted in basilar insufficiency. Hypoperfusion to the flocculonodular lobe supplied by the anterior inferior cerebellar artery is a likely cause for the intermittent vertigo.

  5. Composeable Chat over Low-Bandwidth Intermittent Communication Links

    National Research Council Canada - National Science Library

    Wilcox, D. R

    2007-01-01

    Intermittent low-bandwidth communication environments, such as those encountered in U.S. Navy tactical radio and satellite links, have special requirements that do not pertain to commercial applications...

  6. Sliding Intermittent Control for BAM Neural Networks with Delays

    Directory of Open Access Journals (Sweden)

    Jianqiang Hu

    2013-01-01

    Full Text Available This paper addresses the exponential stability problem for a class of delayed bidirectional associative memory (BAM neural networks with delays. A sliding intermittent controller which takes the advantages of the periodically intermittent control idea and the impulsive control scheme is proposed and employed to the delayed BAM system. With the adjustable parameter taking different particular values, such a sliding intermittent control method can comprise several kinds of control schemes as special cases, such as the continuous feedback control, the impulsive control, the periodically intermittent control, and the semi-impulsive control. By using analysis techniques and the Lyapunov function methods, some sufficient criteria are derived for the closed-loop delayed BAM neural networks to be globally exponentially stable. Finally, two illustrative examples are given to show the effectiveness of the proposed control scheme and the obtained theoretical results.

  7. Computing moving and intermittent queue propagation in highway work zones.

    Science.gov (United States)

    2012-07-01

    Drivers may experience intermittent congestion and moving queue conditions in work zones due to several reasons such as presence of lane closure, roadway geometric changes, higher demand, lower speed, and reduced capacity. The congestion and queue ha...

  8. Sensing and characterization of EMI during intermittent connector anomalies

    Data.gov (United States)

    National Aeronautics and Space Administration — This paper presents a new on-line methodology for detecting intermittent disconnection failures. The detection principle operates on the fundamental Lorentz Law that...

  9. Prostate specific antigen in boys with precocious puberty before and during gonadal suppression by GnRH agonist treatment

    DEFF Research Database (Denmark)

    Juul, A; Müller, J; Skakkebaek, N E

    1997-01-01

    antigen (PSA) is a marker of the androgen-dependent prostatic epithelial cell activity and it is used in the diagnosis and surveillance of adult patients with prostatic cancer. We have measured PSA concentrations in serum from boys with precocious puberty before and during gonadal suppression with Gn......RH agonists to evaluate the effect of normal and precocious puberty on PSA levels and to study the correlation between testosterone and PSA in boys....

  10. Boldness and intermittent locomotion in the bluegill sunfish, Lepomis macrochirus

    OpenAIRE

    Alexander D.M. Wilson; Jean-Guy J. Godin

    2009-01-01

    Intermittent locomotion, characterized by moves interspersed with pauses, is a common pattern of locomotion in animals, but its ecological and evolutionary significance relative to continuous locomotion remains poorly understood. Although many studies have examined individual differences in both intermittent locomotion and boldness separately, to our knowledge, no study to date has investigated the relationship between these 2 traits. Characterizing and understanding this relationship is impo...

  11. Intermittent Hypoxic Episodes in Preterm Infants: Do They Matter?

    OpenAIRE

    Martin, Richard J.; Wang, Katherine; Köroğlu, Özge; Di Fiore, Juliann; Kc, Prabha

    2011-01-01

    Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks 6–8. Such episodic hypoxi...

  12. Mobility and cloud: operating in intermittent, austere network conditions

    OpenAIRE

    Wee, Toon Joo; Ling, Yu Xian Eldine

    2014-01-01

    Approved for public release; distribution is unlimited Cloud computing is emerging as the mainstream platform for a range of on-demand applications, services, and infrastructure. Before the benefits of cloud computing are realized, several technology challenges must be addressed. Operating in intermittent and austere network conditions is one of such challenges, which navy ships face when communicating with land-based cloud computing environments. Given limited bandwidth and intermittent c...

  13. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor.

    Science.gov (United States)

    Liao, Yuning; Liu, Ningning; Hua, Xianliang; Cai, Jianyu; Xia, Xiaohong; Wang, Xuejun; Huang, Hongbiao; Liu, Jinbao

    2017-02-02

    Androgen receptor (AR) is frequently over-expressed and plays a critical role in the growth and progression of human prostate cancer. The therapy attempting to target AR signalling was established in decades ago but the treatment of prostate cancer is far from being satisfactory. The assignable cause is that our understanding of the mechanism of AR regulation and re-activation remains incomplete. Increasing evidence suggests that deubiquitinases are involved in the regulation of cancer development and progression but the specific underlying mechanism often is not elucidated. In the current study, we have identified ubiquitin-specific protease 14 (USP14) as a novel regulator of AR, inhibiting the degradation of AR via deubiquitinating this oncoprotein in the androgen-responsive prostate cancer cells. We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells. Hence, we conclude that USP14 promotes prostate cancer progression likely through stabilization of AR, suggesting that USP14 could be a promising therapeutic target for prostate cancer.

  14. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

    Science.gov (United States)

    Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

    2017-09-01

    Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

  15. ANDROGENS REGULATE T47D CELLS MOTILITY AND INVASION THROUGH ACTIN CYTOSKELETON REMODELLING

    Directory of Open Access Journals (Sweden)

    Maria Magdalena Montt-Guevara

    2016-09-01

    Full Text Available The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgens receptor (AR is expressed in approximately 70% to 90% of invasive breast carcinomas, which has prognostic relevance in basal-like cancers and in triple negative breast cancers. Recent studies have associated the actin-binding proteins of the Ezrin-Radixin-Moesin (ERM family with metastasis in endocrine-sensitive cancers. We studied on T47D breast cancer cells whether androgens with different characteristics, such as testosterone (T, dihydrotestosterone (DHT and dehydroepiandrosterone (DHEA may regulate breast cancer cell motility and invasion through the control of actin remodelling. We demonstrate that androgens promote migration and invasion in T47D via Moesin activation. We show that T and DHEA exert their actions via the AR and estrogen receptor (ER, while the non aromatizable androgen – DHT only recruits AR. We further report that androgen induced significant changes in actin organization with pseudopodia along with membrane ruffles formation, and this process is mediated by Moesin. Our work identifies novel mechanisms of action of androgens on breast cancer cells. Through the modulation of Moesin, androgens alter the architecture of cytoskeleton in T47D breast cancer cell and promote cell migration and invasion. These results could help to understand the biological actions of androgens on breast cancer, and eventually to develop new strategies for treatment of breast cancer.

  16. Profiling of androgen response in rainbow trout pubertal testis: relevance to male gonad development and spermatogenesis.

    Directory of Open Access Journals (Sweden)

    Antoine D Rolland

    Full Text Available The capacity of testicular somatic cells to promote and sustain germ cell differentiation is largely regulated by sexual steroids and notably androgens. In fish species the importance of androgens is emphasized by their ability to induce sex reversal of the developing fries and to trigger spermatogenesis. Here we studied the influence of androgens on testicular gene expression in trout testis using microarrays. Following treatment of immature males with physiological doses of testosterone or 11-ketotestosterone, 418 genes that exhibit changes in expression were identified. Interestingly, the activity of testosterone appeared stronger than that of 11-ketotestosterone. Expression profiles of responsive genes throughout testis development and in isolated germ cells confirmed androgens to mainly affect gene expression in somatic cells. Furthermore, specific clusters of genes that exhibit regulation coincidently with changes in the natural circulating levels of androgens during the reproductive cycle were highlighted, reinforcing the physiological significance of these data. Among somatic genes, a phylogenetic footprinting study identified putative androgen response elements within the proximal promoter regions of 42 potential direct androgen target genes. Finally, androgens were also found to alter the germ line towards meiotic expression profiles, supporting the hypothesis of a role for the somatic responsive genes in driving germ cell fate. This study significantly increases our understanding of molecular pathways regulated by androgens in vertebrates. The highly cyclic testicular development in trout together with functions associated with regulated genes reveal potential mechanisms for androgen actions in tubule formation, steroid production, germ cell development and sperm secretion.

  17. Androgen deficiency in the aging male and chronic prostatitis: clinical and diagnostic comparative analysis

    Directory of Open Access Journals (Sweden)

    Spirin Р.V.

    2013-03-01

    Full Text Available The research goal is to study probability, period of development and characteristics of a clinical course of chronic prostatitis against the background of androgen deficiency in the aging male. Materials and methods: The Aging Male Symptoms (AMS rating scale has been applied for androgen deficiency evaluation and the International Prostate Symptom Score (IPSS — for chronic prostatitis evaluation. 57 men with chronic prostatitis in combination with androgen deficiency in the aging male have been examined. Results: It has been concluded that the development of chronic prostatitis against the background of androgen deficiency in the aging male occurs in a shorter time period and about 1.5 times more frequently compared to androgen deficiency in the aging male at the background of chronic prostatitis. The analysis of time periods between the onset of chronic prostatitis symptoms against the background of androgen deficiency in the aging male and androgen deficiency in the aging male symptoms against the background of chronic prostatitis showed that androgen deficiency in the aging male symptoms have been revealed 1-2 years earlier than the onset of chronic prostatitis. The development of androgen deficiency in the aging male against the background of chronic prostatitis has showed a backward tendency. Signs of chronic prostatitis have been more frequently occurred in a period of four-five years earlier the androgen deficiency in the aging male development. Conclusion: The risk of development of chronic prostatitis against the background of androgen deficiency in the aging male during the next two years is actually four times higher in comparison with the development of androgen deficiency in the aging male against the background of chronic prostatitis. According to the International Prostate Symptom Score (IPSS, patients with chronic prostatitis in combination with androgen deficiency in the aging male showed higher degree of severity than

  18. 11-Oxygenated C19 Steroids Are the Predominant Androgens in Polycystic Ovary Syndrome.

    Science.gov (United States)

    O'Reilly, Michael W; Kempegowda, Punith; Jenkinson, Carl; Taylor, Angela E; Quanson, Jonathan L; Storbeck, Karl-Heinz; Arlt, Wiebke

    2017-03-01

    Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), but the exact origin of hyperandrogenemia remains a matter of debate. Recent studies have highlighted the importance of the 11-oxygenated C19 steroid pathway to androgen metabolism in humans. In this study, we analyzed the contribution of 11-oxygenated androgens to androgen excess in women with PCOS. One hundred fourteen women with PCOS and 49 healthy control subjects underwent measurement of serum androgens by liquid chromatography-tandem mass spectrometry. Twenty-four-hour urinary androgen excretion was analyzed by gas chromatography-mass spectrometry. Fasting plasma insulin and glucose were measured for homeostatic model assessment of insulin resistance. Baseline demographic data, including body mass index, were recorded. As expected, serum concentrations of the classic androgens testosterone (P PCOS. Mirroring this, serum 11-oxygenated androgens 11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone, and 11-ketotestosterone were significantly higher in PCOS than in control subjects, as was the urinary 11-oxygenated androgen metabolite 11β-hydroxyandrosterone. The proportionate contribution of 11-oxygenated to total serum androgens was significantly higher in patients with PCOS compared with control subjects [53.0% (interquartile range, 48.7 to 60.3) vs 44.0% (interquartile range, 32.9 to 54.9); P PCOS had significantly increased 11-oxygenated androgens. Serum 11β-hydroxyandrostenedione and 11-ketoandrostenedione correlated significantly with markers of insulin resistance. We show that 11-oxygenated androgens represent the majority of circulating androgens in women with PCOS, with close correlation to markers of metabolic risk.

  19. Randomized trial of intermittent or continuous amnioinfusion for variable decelerations.

    Science.gov (United States)

    Rinehart, B K; Terrone, D A; Barrow, J H; Isler, C M; Barrilleaux, P S; Roberts, W E

    2000-10-01

    To determine whether continuous or intermittent bolus amnioinfusion is more effective in relieving variable decelerations. Patients with repetitive variable decelerations were randomized to an intermittent bolus or continuous amnioinfusion. The intermittent bolus infusion group received boluses of 500 mL of normal saline, each over 30 minutes, with boluses repeated if variable decelerations recurred. The continuous infusion group received a bolus infusion of 500 mL of normal saline over 30 minutes and then 3 mL per minute until delivery occurred. The ability of the amnioinfusion to abolish variable decelerations was analyzed, as were maternal demographic and pregnancy outcome variables. Power analysis indicated that 64 patients would be required. Thirty-five patients were randomized to intermittent infusion and 30 to continuous infusion. There were no differences between groups in terms of maternal demographics, gestational age, delivery mode, neonatal outcome, median time to resolution of variable decelerations, or the number of times variable decelerations recurred. The median volume infused in the intermittent infusion group (500 mL) was significantly less than that in the continuous infusion group (905 mL, P =.003). Intermittent bolus amnioinfusion is as effective as continuous infusion in relieving variable decelerations in labor. Further investigation is necessary to determine whether either of these techniques is associated with increased occurrence of rare complications such as cord prolapse or uterine rupture.

  20. Sinusoidal visuomotor tracking: intermittent servo-control or coupled oscillations?

    Science.gov (United States)

    Russell, D M; Sternad, D

    2001-12-01

    In visuomotor tasks that involve accuracy demands, small directional changes in the trajectories have been taken as evidence of feedback-based error corrections. In the present study variability, or intermittency, in visuomanual tracking of sinusoidal targets was investigated. Two lines of analyses were pursued: First, the hypothesis that humans fundamentally act as intermittent servo-controllers was re-examined, probing the question of whether discontinuities in the movement trajectory directly imply intermittent control. Second, an alternative hypothesis was evaluated: that rhythmic tracking movements are generated by entrainment between the oscillations of the target and the actor, such that intermittency expresses the degree of stability. In 2 experiments, participants (N = 6 in each experiment) swung 1 of 2 different hand-held pendulums, tracking a rhythmic target that oscillated at different frequencies with a constant amplitude. In 1 line of analyses, the authors tested the intermittency hypothesis by using the typical kinematic error measures and spectral analysis. In a 2nd line, they examined relative phase and its variability, following analyses of rhythmic interlimb coordination. The results showed that visually guided corrective processes play a role, especially for slow movements. Intermittency, assessed as frequency and power components of the movement trajectory, was found to change as a function of both target frequency and the manipulandum's inertia. Support for entrainment was found in conditions in which task frequency was identical to or higher than the effector's eigenfrequency. The results suggest that it is the symmetry between task and effector that determines which behavioral regime is dominant.

  1. Uncoupling of Vascular Nitric Oxide Synthase Caused by Intermittent Hypoxia

    Directory of Open Access Journals (Sweden)

    Mohammad Badran

    2016-01-01

    Full Text Available Objective. Obstructive sleep apnea (OSA, characterized by chronic intermittent hypoxia (CIH, is often present in diabetic (DB patients. Both conditions are associated with endothelial dysfunction and cardiovascular disease. We hypothesized that diabetic endothelial dysfunction is further compromised by CIH. Methods. Adult male diabetic (BKS.Cg-Dock7m +/+ Leprdb/J (db/db mice (10 weeks old and their heterozygote littermates were subjected to CIH or intermittent air (IA for 8 weeks. Mice were separated into 4 groups: IA (intermittent air nondiabetic, IH (intermittent hypoxia nondiabetic, IADB (intermittent air diabetic, and IHDB (intermittent hypoxia diabetic groups. Endothelium-dependent and endothelium-independent relaxation and modulation by basal nitric oxide (NO were analyzed using wire myograph. Plasma 8-isoprostane, interleukin-6 (IL-6, and asymmetric dimethylarginine (ADMA were measured using ELISA. Uncoupling of eNOS was measured using dihydroethidium (DHE staining. Results. Endothelium-dependent vasodilation and basal NO production were significantly impaired in the IH and IADB group compared to IA group but was more pronounced in IHDB group. Levels of 8-isoprostane, IL-6, ADMA, and eNOS uncoupling were ≈2-fold higher in IH and IADB groups and were further increased in the IHDB group. Conclusion. Endothelial dysfunction is more pronounced in diabetic mice subjected to CIH compared to diabetic or CIH mice alone. Oxidative stress, ADMA, and eNOS uncoupling were exacerbated by CIH in diabetic mice.

  2. Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

    Science.gov (United States)

    Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

    2012-01-01

    The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

  3. Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.

    Science.gov (United States)

    Kumagai, Jinpei; Hofland, Johannes; Erkens-Schulze, Sigrun; Dits, Natasja F J; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H; van Weerden, Wytske M

    2013-11-01

    Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. © 2013 Wiley Periodicals, Inc.

  4. Development of an androgen reporter gene assay (AR-LUX) utilizing a human cell line with an endogenously regulated androgen receptor

    NARCIS (Netherlands)

    Blankvoort, B.M.G.; Groene, E.M. de; Meeteren-Kreikamp, A.P. van; Witkamp, R.F.; Rodenburg, R.J.T.; Aarts, J.M.M.J.G.

    2001-01-01

    The aim of the work described in this report is to develop and characterize a cell-based androgen reporter assay. For this purpose, the androgen receptor (AR) expressing human breast cancer cell line T47D was stably transfected with a luciferase gene under transcriptional control of the PB-ARE-2

  5. Giant Suppression of the Activation Rate in Dynamical Systems Exhibiting Chaotic Transitions

    Science.gov (United States)

    Gac, J. M.; Xafebrowski, J. J.

    2008-05-01

    The phenomenon of giant suppression of activation, when two or more correlated noise signals act on the system, was found a few years ago in dynamical bistable or metastable systems. When the correlation between these noise signals is strong enough and the amplitudes of the noise are chosen correctly --- the life time of the metastable state may be longer than in the case of the application of only a single noise even by many orders of magnitude. In this paper, we investigate similar phenomena in systems exhibiting several chaotic transitions: Pomeau--Manneville intermittency, boundary crisis and interior crisis induced intermittency. Our goal is to show that, in these systems the application of two noise components with the proper choice of the parameters in the case of intermittency can also lengthen the mean laminar phase length or, in the case of boundary crisis, lengthen the time the trajectory spends on the pre-crisis attractor. In systems with crisis induced intermittency, we introduce a new phenomenon we called quasi-deterministic giant suppression of activation in which the lengthening of the laminar phase lengths is caused not by the action of two correlated noise signals but by a single noise term which is correlated with one of the chaotic variables of the system.

  6. EEG Suppression Associated with Apneic Episodes in a Neonate

    Directory of Open Access Journals (Sweden)

    Evonne Low

    2012-01-01

    Full Text Available We describe the EEG findings from an ex-preterm neonate at term equivalent age who presented with intermittent but prolonged apneic episodes which were presumed to be seizures. A total of 8 apneic episodes were captured (duration 23–376 seconds during EEG monitoring. The baseline EEG activity was appropriate for corrected gestational age and no electrographic seizure activity was recorded. The average baseline heart rate was 168 beats per minute (bpm and the baseline oxygen saturation level was in the mid-nineties. Periods of complete EEG suppression lasting 68 and 179 seconds, respectively, were recorded during 2 of these 8 apneic episodes. Both episodes were accompanied by bradycardia less than 70 bpm and oxygen saturation levels of less than 20%. Short but severe episodes of apnea can cause complete EEG suppression in the neonate.

  7. Intermittent hypoxia induces hyperlipidemia in lean mice.

    Science.gov (United States)

    Li, Jianguo; Thorne, Laura N; Punjabi, Naresh M; Sun, Cheuk-Kwan; Schwartz, Alan R; Smith, Philip L; Marino, Rafael L; Rodriguez, Annabelle; Hubbard, Walter C; O'Donnell, Christopher P; Polotsky, Vsevolod Y

    2005-09-30

    Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.

  8. Intermittency and Topology of Shock Induced Mixing

    Science.gov (United States)

    Tellez, Jackson; Redondo, Jose M.; Ben Mahjoub, Otman; Malik, Nadeem; Vila, Teresa

    2016-04-01

    The advance of a Rayleigh-Taylor front is described in Linden & Redondo (1991),[1-3] and may be shown to follow a quadratic law in time where the width of the growing region of instability depends on the local mixing efficiency of the different density fluids that accelerate against each other g is the acceleration and A is the Atwood number defined as the diference of densities divided by their sum. This results show the independence of the large amplitude structures on the initial conditions the width of the mixing region depends also on the intermittency of the turbulence. Then dimensional analysis may also depend on the relevant reduced acceleration driven time and the molecular reactive time akin to Damkholer number and the fractal structure of the contact zone [2,4]. Detailed experiments and simulations on RT and RM shock induced fronts analized with respect to structure functions are able to determine which mechanisms are most effective in local mixing which increase the effective fractal dimension, as well as the effect of higher order geometrical parameters, such as the structure functions, in non-homogeneous fluids (Mahjoub et al 1998)[5]. The structure of a Mixing blob shows a relatively sharp head with most of the mixing taking place at the sides due to what seems to be shear instability very similar to the Kelvin-Helmholtz instabilities, but with sideways accelerations. The formation of the blobs and spikes with their secondary instabilities produces a turbulent cascade, evident just after about 1 non-dimensional time unit, from a virtual time origin that takes into account the linear growth phase, as can be seen by the growth of the fractal dimension for different volume fractions. Two-dimensional cuts of the 3D flow also show that vortex flows have closed or spiral streamlines around their core. Examples of such flows can be also seen in the laboratory, for example at the interface of atwo-layer stratified fluid in a tank in which case streamlines

  9. A new dawn for androgens: Novel lessons from 11-oxygenated C19 steroids.

    Science.gov (United States)

    Pretorius, Elzette; Arlt, Wiebke; Storbeck, Karl-Heinz

    2017-02-05

    The abundant adrenal C19 steroid 11β-hydroxyandrostenedione (11OHA4) has been written off as a dead-end product of adrenal steroidogenesis. However, recent evidence has demonstrated that 11OHA4 is the precursor to the potent androgenic 11-oxygenated steroids, 11-ketotestosterone and 11-ketodihydrotestosterone, that bind and activate the human androgen receptor similarly to testosterone and DHT. The significance of this discovery becomes apparent when considering androgen dependent diseases such as castration resistant prostate cancer and diseases associated with androgen excess, e.g. congenital adrenal hyperplasia and polycystic ovary syndrome. In this review we describe the production and metabolism of 11-oxygenated steroids. We subsequently discuss their androgenic activity and highlight the putative role of these androgens in disease states. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Complete androgen insensitivity syndrome with paratesticular leiomyoma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hoon; Oh, Hyung Woo; Lee, Mi Ja; Lim, Dong Hoon [Chosun University College of Medicine, Gwangju (Korea, Republic of)

    2017-03-15

    Complete androgen insensitivity syndrome (AIS) is a rare, X-linked recessive disorder. Patients with AIS may develop primary amenorrhea due to androgen receptor resistance, resulting in a normal female phenotype and male (XY) karyotype. We report a case of a 30-year-old woman who was diagnosed with complete AIS. Ultrasonography and magnetic resonance imaging revealed bilateral inguinal cryptorchidism and no ovaries and uterus. After gonadectomy, the inguinal mass was confirmed as testicular atrophy with hamartomatous proliferation of Leydig cells and paratesticular leiomyoma. Although these tumors have been reported in association with AIS, this is the first case of paratesticular leiomyoma with hamartomatous proliferation of Leydig cells in atrophic testes being reported in Korea.

  11. Complete androgen insensitivity syndrome with paratesticular leiomyoma: A case report

    International Nuclear Information System (INIS)

    Lee, Ji Hoon; Oh, Hyung Woo; Lee, Mi Ja; Lim, Dong Hoon

    2017-01-01

    Complete androgen insensitivity syndrome (AIS) is a rare, X-linked recessive disorder. Patients with AIS may develop primary amenorrhea due to androgen receptor resistance, resulting in a normal female phenotype and male (XY) karyotype. We report a case of a 30-year-old woman who was diagnosed with complete AIS. Ultrasonography and magnetic resonance imaging revealed bilateral inguinal cryptorchidism and no ovaries and uterus. After gonadectomy, the inguinal mass was confirmed as testicular atrophy with hamartomatous proliferation of Leydig cells and paratesticular leiomyoma. Although these tumors have been reported in association with AIS, this is the first case of paratesticular leiomyoma with hamartomatous proliferation of Leydig cells in atrophic testes being reported in Korea

  12. Optimised deconjugation of androgenic steroid conjugates in bovine urine

    DEFF Research Database (Denmark)

    Pedersen, Mikael; Frandsen, Henrik Lauritz; Andersen, Jens Hinge

    2017-01-01

    and glucuronidase resulting in free steroids in the extract. It is well known that some sulphates are not deconjugated using aryl sulphatase; instead, for example, solvolysis can be used for deconjugation of these aliphatic sulphates. The effectiveness of solvolysis on androgenic steroid sulphates was tested......After administration of steroids to animals the steroids are partially metabolised in the liver and kidney to phase 2 metabolites, i.e., glucuronic acid or sulphate conjugates. During analysis these conjugated metabolites are normally deconjugated enzymatically with aryl sulphatase...... with selected aliphatic steroid sulphates (boldenone sulphate, nortestosteron sulphate and testosterone sulphate), and the method was validated for analysis of androgenic steroids in bovine urine using free steroids, steroid sulphates and steroid glucuronides as standards. Glucuronidase and sulphuric acid...

  13. Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Claire [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France); Lafosse, Jean-Michel [CHU Toulouse, Hopital Rangueil, Service d' orthopedie et Traumatologie, Toulouse F-31000 (France); Malavaud, Bernard [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France); CHU Toulouse, Hopital Rangueil, Service d' Urologie et de Transplantation Renale, Toulouse F-31000 (France); Cuvillier, Olivier, E-mail: olivier.cuvillier@ipbs.fr [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France)

    2010-01-01

    Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.

  14. Rutting behavior and androgen variation in reindeer (Rangifer tarandus L.).

    Science.gov (United States)

    Mossing, T; Damber, J E

    1981-03-01

    The rutting behavior of captive reindeer was studied during three rutting seasons. Blood samples from three males were taken for androgen analysis before, during, and afterthe rut. The amount of androgen increased at the end of August to a peak during late September-early October and decreased thereafter. Flehmen, urinating on the hindlegs, and two different low-stretch displays emerged during the prerut period. The preorbital gland enlarged and secretion occurred at the rim of the pocket. A conspicuous breath odor appeared very abruptly during the most intense period of rutting. A few days later a strong odor also appeared in the urine. The urination behavior and the two odors were confined to a brief period during the rut, while other behavior persisted afterwards.

  15. Selective androgen receptor modulators in preclinical and clinical development.

    Science.gov (United States)

    Narayanan, Ramesh; Mohler, Michael L; Bohl, Casey E; Miller, Duane D; Dalton, James T

    2008-01-01

    Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.

  16. Cortical venous thrombosis following exogenous androgen use for bodybuilding.

    Science.gov (United States)

    Sveinsson, Olafur; Herrman, Lars

    2013-02-05

    There are only a few reports of patients developing cerebral venous sinus thrombosis (CVST) after androgen therapy. We present a young man who developed cortical venous thrombosis after using androgens to increase muscle mass. He was hospitalised for parasthesia and dyspraxia in the left hand followed by a generalised tonic-clonic seizure. At admission, he was drowsy, not fully orientated, had sensory inattention, pronation drift and a positive extensor response, all on the left side. The patient had been using anabolic steroids (dainabol 20 mg/day) for the last month for bodybuilding. CT angiography showed a right cortical venous thrombosis. Anticoagulation therapy was started with intravenous heparin for 11 days and oral anticoagulation (warfarin) thereafter. A control CT angiography 4 months later showed resolution of the thrombosis. He recovered fully.

  17. Serum 11 beta-hydroxyandrostenedione as an indicator of the source of excess androgen production in women with polycystic ovaries.

    Science.gov (United States)

    Polson, D W; Reed, M J; Franks, S; Scanlon, M J; James, V H

    1988-05-01

    Serum 11 beta-hydroxyandrostenedione levels (11-OHA) were measured in normal women and women with polycystic ovaries (PCO) to assess their value in localizing the source of excessive androgen production in women with PCO. Serum 11-OHA was undetectable (less than 1.5 nmol/L) in an adrenalectomized woman, a woman with 11-hydroxylase deficiency, and a woman receiving chronic dexamethasone therapy, confirming the specificity of the antiserum used in this study. Serum 11-OHA concentrations were similar in normal women [mean, 5.0 +/- 2.3 (+/- SD) nmol/L] and women with PCO (5.0 +/- 2.1 nmol/L); serum androstenedione concentrations were increased in women with PCO. Thus, the ratio of androstenedione to 11-OHA was significantly higher (P less than 0.001) in women with PCO (2.0 +/- 0.7) than in normal women (1.1 +/- 0.5). Serum 11-OHA levels after adrenal suppression or stimulation were similar in women with PCO who had an ovulatory response and those who failed to ovulate after clomiphene administration. Administration of dexamethasone (1 mg) and injection of ACTH (250 micrograms) were associated with marked suppression and subsequent stimulation of serum 11-OHA levels in both normal women and women with PCO, and the responses were similar in the two groups. Also, the hour to hour and diurnal variations in serum 11-OHA were similar to those of androstenedione and cortisol during a 24-h period, indicating the adrenal origin of 11-OHA. Our finding of similar serum 11-OHA levels in the presence of increased serum androstenedione levels in women with PCO supports the concept that the ovary is the major source of excess androgen production in women with PCO.

  18. Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation.

    Science.gov (United States)

    Kobayashi, Takashi; Shimizu, Yosuke; Terada, Naoki; Yamasaki, Toshinari; Nakamura, Eijiro; Toda, Yoshinobu; Nishiyama, Hiroyuki; Kamoto, Toshiyuki; Ogawa, Osamu; Inoue, Takahiro

    2010-06-01

    Ras homolog-enriched in brain (Rheb), a small GTP-binding protein, is associated with prostate carcinogenesis through activating mammalian target of rapamycin (mTOR) signaling pathway. This study aimed to elucidate whether Rheb promotes proliferation of prostate cancer cells and can act as a potent therapeutic target in prostate cancer. Prostate cancer cell lines and human prostatic tissues were examined for the expression of Rheb. The effects of forced expression or knockdown of Rheb on cell proliferation were also examined. Semi-quantitative and quantitative RT-PCR were performed to evaluate mRNA expression. Western blotting was used to examine protein expression. Cell count and WST-1 assay were used to measure cell proliferation. Fluorescence-activated cell sorting was used to assess the cell cycle. Rheb mRNA and protein expression was higher in more aggressive, androgen-independent prostate cancer cell lines PC3, DU145, and C4-2, compared with the less aggressive LNCaP. Rheb expression was higher in cancer tissues than in benign prostatic epithelia. Forced expression of Rheb in LNCaP cells accelerated proliferation without enhancing androgen receptor transactivity. Attenuation of Rheb expression or treatment with the mTOR inhibitor rapamycin decreased proliferation of PC3 and DU145 cells, with a decrease in the activated form of p70S6 kinase, one of the main targets of mTOR. Rheb potentiates proliferation of prostate cancer cells and inhibition of Rheb or mTOR can lead to suppressed proliferation of aggressive prostate cancer cell lines in vitro. Rheb and the mTOR pathway are therefore probable targets for suppressing prostate cancer.

  19. Pressure suppression device

    International Nuclear Information System (INIS)

    Mizumachi, Wataru; Fukuda, Akira; Kitaguchi, Hidemi; Shimizu, Toshiaki.

    1976-01-01

    Object: To relieve and absorb impact wave vibrations caused by steam and non-condensed gases releasing into the pressure suppression chamber at the time of an accident. Structure: The reactor container is filled with inert gases. A safety valve attached main steam pipe is provided to permit the excessive steam to escape, the valve being communicated with the pressure suppression chamber through an exhaust pipe. In the pressure suppression chamber, a doughnut-like cylindrical outer wall is filled at its bottom with pool water to condense the high temperature vapor released through the exhaust pipe. A head portion of a vent tube which leads the exhaust pipe is positioned at the top, and a down comer and an exhaust vent tube are locked by means of steady rests. At the bottom is mounted a pressure adsorber device which adsorbs a pressure from the pool water. (Kamimura, M.)

  20. Identification of Androgen Receptor-Specific Enhancer RNAs

    Science.gov (United States)

    2017-08-01

    SUPPLEMENTARY NOTES 14. ABSTRACT The major goal of this application is to determine whether prostate cancer cells express enhancer RNAs in response to...androgen treatment such that these enhancer RNAs may serve as novel biomarkers for prostate cancer diagnosis and prognosis. There are two Tasks in...biomarkers or therapeutic targets for prostate cancer , especially for castration resistant prostate cancer . 15. SUBJECT TERMS lncRNA, eRNA, biomarker

  1. Evaluation of androgenic activity of Mucuna pruriens in male rats ...

    African Journals Online (AJOL)

    Methanolic extract of Mucuna pruriens seed was tested for their possible androgenic activity in Wister male albino rats. The methanolic extract of M. pruriens plant was gavaged separately into 2 group of rat at similar doses of 1000 mg/kg b.wt and 1500 mg/kg b.wt for 30 days. At the end of the treatment, the animals were ...

  2. Cardiometabolic Features of Polycystic Ovary Syndrome: Role of Androgens.

    Science.gov (United States)

    Yanes Cardozo, Licy L; Romero, Damian G; Reckelhoff, Jane F

    2017-09-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects reproductive-age women. Hyperandrogenemia is present in a significant fraction (~80%) of women with PCOS. Increased prevalence of cardiometabolic risk factors is frequently observed in PCOS women. The present review aims to highlight the key role of androgens in mediating the negative cardiometabolic profile observed in PCOS women. Copyright © 2017 the American Physiological Society.

  3. Increased C-C chemokine receptor 2 gene expression in monocytes of severe obstructive sleep apnea patients and under intermittent hypoxia.

    Science.gov (United States)

    Chuang, Li-Pang; Chen, Ning-Hung; Lin, Shih-Wei; Chang, Ying-Ling; Liao, Hsiang-Ruei; Lin, Yu-Sheng; Chao, I-Ju; Lin, Yuling; Pang, Jong-Hwei S

    2014-01-01

    Obstructive sleep apnea (OSA) is known to be a risk factor of coronary artery disease. The chemotaxis and adhesion of monocytes to the endothelium in the early atherosclerosis is important. This study aimed to investigate the effect of intermittent hypoxia, the hallmark of OSA, on the chemotaxis and adhesion of monocytes. Peripheral blood was sampled from 54 adults enrolled for suspected OSA. RNA was prepared from the isolated monocytes for the analysis of C-C chemokine receptor 2 (CCR2). The effect of intermittent hypoxia on the regulation and function of CCR2 was investigated on THP-1 monocytic cells and monocytes. The mRNA and protein expression levels were investigated by RT/real-time PCR and western blot analysis, respectively. Transwell filter migration assay and cell adhesion assay were performed to study the chemotaxis and adhesion of monocytes. Monocytic CCR2 gene expression was found to be increased in severe OSA patients and higher levels were detected after sleep. Intermittent hypoxia increased the CCR2 expression in THP-1 monocytic cells even in the presence of TNF-α and CRP. Intermittent hypoxia also promoted the MCP-1-mediated chemotaxis and adhesion of monocytes to endothelial cells. Furthermore, inhibitor for p42/44 MAPK or p38 MAPK suppressed the activation of monocytic CCR2 expression by intermittent hypoxia. This is the first study to demonstrate the increase of CCR2 gene expression in monocytes of severe OSA patients. Monocytic CCR2 gene expression can be induced under intermittent hypoxia which contributes to the chemotaxis and adhesion of monocytes.

  4. Pressure Autoregulation Measurement Techniques in Adult Traumatic Brain Injury, Part I: A Scoping Review of Intermittent/Semi-Intermittent Methods.

    Science.gov (United States)

    Zeiler, Frederick A; Donnelly, Joseph; Calviello, Leanne; Menon, David K; Smielewski, Peter; Czosnyka, Marek

    2017-12-01

    The purpose of this study was to perform a systematic, scoping review of commonly described intermittent/semi-intermittent autoregulation measurement techniques in adult traumatic brain injury (TBI). Nine separate systematic reviews were conducted for each intermittent technique: computed tomographic perfusion (CTP)/Xenon-CT (Xe-CT), positron emission tomography (PET), magnetic resonance imaging (MRI), arteriovenous difference in oxygen (AVDO 2 ) technique, thigh cuff deflation technique (TCDT), transient hyperemic response test (THRT), orthostatic hypotension test (OHT), mean flow index (Mx), and transfer function autoregulation index (TF-ARI). MEDLINE ® , BIOSIS, EMBASE, Global Health, Scopus, Cochrane Library (inception to December 2016), and reference lists of relevant articles were searched. A two tier filter of references was conducted. The total number of articles utilizing each of the nine searched techniques for intermittent/semi-intermittent autoregulation techniques in adult TBI were: CTP/Xe-CT (10), PET (6), MRI (0), AVDO 2 (10), ARI-based TCDT (9), THRT (6), OHT (3), Mx (17), and TF-ARI (6). The premise behind all of the intermittent techniques is manipulation of systemic blood pressure/blood volume via either chemical (such as vasopressors) or mechanical (such as thigh cuffs or carotid compression) means. Exceptionally, Mx and TF-ARI are based on spontaneous fluctuations of cerebral perfusion pressure (CPP) or mean arterial pressure (MAP). The method for assessing the cerebral circulation during these manipulations varies, with both imaging-based techniques and TCD utilized. Despite the limited literature for intermittent/semi-intermittent techniques in adult TBI (minus Mx), it is important to acknowledge the availability of such tests. They have provided fundamental insight into human autoregulatory capacity, leading to the development of continuous and more commonly applied techniques in the intensive care unit (ICU). Numerous methods of

  5. Thyroxin hormone suppression treatment

    International Nuclear Information System (INIS)

    Samuel, A.M.

    1999-01-01

    One of the important modalities of treatment of thyroid cancer (TC) after surgery is the administration of thyroxin as an adjuvant treatment. The analysis supports the theory that thyroid suppression plays an important role in patient management. 300 μg of thyroxin, as this is an adequate dose for suppression is given. Ideally the dose should be tailored by testing s-TSH levels. However, since a large number of the patients come from out station cities and villages this is impractical. We therefore depend on clinical criteria of hyperthyroid symptoms and adjust the dose. Very few patients need such adjustment

  6. Prenatal androgen exposure and children's aggressive behavior and activity level.

    Science.gov (United States)

    Spencer, Debra; Pasterski, Vickie; Neufeld, Sharon; Glover, Vivette; O'Connor, Thomas G; Hindmarsh, Peter C; Hughes, Ieuan A; Acerini, Carlo L; Hines, Melissa

    2017-11-01

    Some human behaviors, including aggression and activity level, differ on average for males and females. Here we report findings from two studies investigating possible relations between prenatal androgen and children's aggression and activity level. For study 1, aggression and activity level scores for 43 girls and 38 boys, aged 4 to 11years, with congenital adrenal hyperplasia (CAH, a genetic condition causing increased adrenal androgen production beginning prenatally) were compared to those of similarly-aged, unaffected relatives (41 girls, 31 boys). Girls with CAH scored higher on aggression than unaffected girls, d=0.69, and unaffected boys scored higher on activity level than unaffected girls, d=0.50. No other group differences were significant. For study 2, the relationship of amniotic fluid testosterone to aggression and activity level was investigated in typically-developing children (48 girls, 44 boys), aged 3 to 5years. Boys scored higher than girls on aggression, d=0.41, and activity level, d=0.50. However, amniotic fluid testosterone was not a significant predictor of aggression or activity level for either sex. The results of the two studies provide some support for an influence of prenatal androgen exposure on children's aggressive behavior, but not activity level. The within-sex variation in amniotic fluid testosterone may not be sufficient to allow reliable assessment of relations to aggression or activity level. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Spatial memory performance in androgen insensitive male rats.

    Science.gov (United States)

    Jones, Bryan A; Watson, Neil V

    2005-06-02

    Masculinization of the developing rodent brain critically depends on the process of aromatization of circulating testosterone (T) to its estrogenic metabolite 17beta-estradiol, which subsequently interacts with estrogen receptors to permanently masculinize the brain. However, it remains unclear what role other androgenic mechanisms may play in the process of masculinization. A novel way of examining this is through the study of male rats that express the tfm mutation of the androgen receptor (AR) gene; such males are fully androgen insensitive and manifest a female phenotype due to a failure of AR-mediated masculinization of peripheral structures. Because tfm-affected males develop secretory testes and have near-normal T titers during development, aromatization would be expected to proceed normally, and brain mechanisms may be developmentally masculinized despite the feminized periphery. We compared tfm-affected males (X(tfm)Y) with normal males and females in the Morris Water Maze, a task in which males typically perform better than females. Performance of tfm-affected males was intermediate between that of normal males and females. While an overall male superiority was found in the task, the X(tfm)Y group reached male-typical escape latencies faster than females. Furthermore, in the X(tfm)Y group, the granule cell layer of the dentate gyrus was significantly larger than in females. These results support the suggestion that that AR mediated mechanisms contribute to the masculinization of spatial behaviours and hippocampal morphology, and this may be independent of estrogenic processes.

  8. Vitamin D, PCOS and androgens in men: a systematic review

    Directory of Open Access Journals (Sweden)

    Christian Trummer

    2018-03-01

    Full Text Available Background: Accumulating evidence from animal and human studies suggests that vitamin D is involved in many functions of the reproductive system in both genders. Aim: The aim of this review was to provide an overview on the effects of vitamin D on polycystic ovary syndrome (PCOS in women and androgen metabolism in men. Methods: We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017. Results and discussion: The vitamin D receptor and vitamin D-metabolizing enzymes are found in reproductive tissues of women and men. In women, vitamin D status has been associated with several features of PCOS. In detail, cross-sectional data suggest a regulatory role of vitamin D in PCOS-related aspects such as ovulatory dysfunction, insulin resistance as well as hyperandrogenism. Moreover, results from randomized controlled trials (RCTs suggest that vitamin D supplementation may be beneficial for metabolic, endocrine and fertility aspects in PCOS. In men, vitamin D status has been associated with androgen levels and hypogonadism. Further, there is some evidence for a favorable effect of vitamin D supplementation on testosterone concentrations, although others failed to show a significant effect on testosterone levels. Conclusion: In summary, vitamin D deficiency is associated with adverse fertility outcomes including PCOS and hypogonadism, but the evidence is insufficient to establish causality. High-quality RCTs are needed to further evaluate the effects of vitamin D supplementation in PCOS women as well as on androgen levels in men.

  9. Free androgen index and Irisin in polycystic ovary syndrome.

    Science.gov (United States)

    Li, H; Xu, X; Wang, X; Liao, X; Li, L; Yang, G; Gao, L

    2016-05-01

    PCOS is associated with hyperandrogenism and insulin resistance (IR). Recent studies have shown that circulating Irisin levels increase in PCOS women. However, no report has demonstrated a relationship between Irisin and hyperandrogenism in PCOS women. The purpose of the study was to compare interrelationship between Irisin or androgen excess with IR in PCOS and normal subjects. 166 PCOS and 103 control women were prospectively studied. Euglycemic- hyperinsulinemic clamps were preformed to assess their insulin sensitivity, which was expressed as M value. Circulating Irisin was determined by ELISA kit. Circulating androgens were measured using ultrasensitive assays. PCOS women with high FAI had significantly higher BMI, FAT%, TC, DHEA-S and HOMA-IR, and significantly lower levels of M values and SHBG than PCOS women with low FAI or the controls. Pearson correlations showed that in the entire population, FAI correlated positively with BMI, WHR, FAT%, blood pressure, TG, DHEA-S, LH/FSH, AUCinsulin, HOMA-IR and Irisin, and negatively with M values. In multiple stepwise regression analysis, only FAT%, DHEA-S and LH/FSH were independent related factors with FAI. The elevated Irisin levels in PCOS women were associated with androgen excess. Circulating Irisin is a primary predictor of hyperandrogenism, MetS and IR in PCOS women.

  10. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse.

    Science.gov (United States)

    Nair, Deepti; Ramesh, Vijay; Li, Richard C; Schally, Andrew V; Gozal, David

    2013-11-01

    Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development, and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here, we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-hydroxydeoxyguanosine, and increases in hypoxia inducible factor-1α DNA binding and up-regulation of insulin growth factor-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction. Sleep apnea, characterized by chronic intermittent hypoxia (IH), is associated with substantial cognitive and behavioral deficits. Here, we show that administration of a GHRH agonist (JI-34) reduces oxidative stress, increases both HIF-1α nuclear binding and downstream expression of IGF1 and erythropoietin (EPO) in hippocampus and cortex, and markedly attenuates water maze performance deficits in mice exposed to intermittent hypoxia during sleep. © 2013 International Society for Neurochemistry.

  11. Complete Androgen Insensitivity Syndrome: A Rare Case of Disorder of Sex Development

    Directory of Open Access Journals (Sweden)

    Alfonsa Pizzo

    2013-01-01

    Full Text Available Androgen Insensitivity Syndrome (AIS could be considered as a disease that causes resistance to androgens actions, influencing both the morphogenesis and differentiation of the body structures, and systems in which this hormone exerts its effects. It depends on an X-linked mutations in the Androgen Receptor (AR gene that express a variety of phenotypes ranging from male infertility to completely normal female external genitalia. The clinical phenotypes of AIS could vary and be classified into three categories, as complete (CAIS, partial (PAIS, and mild (MAIS forms, according to the severity of androgen resistance. We will describe a case of CAIS in a 16-year-old patient.

  12. Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

    Directory of Open Access Journals (Sweden)

    Satwant Kaur

    Full Text Available Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT, under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment.

  13. Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery.

    Science.gov (United States)

    Segal, Scott; Narayanan, Ramesh; Dalton, James T

    2006-04-01

    Selective androgen receptor modulators (SARMS) bind to the androgen receptor and demonstrate anabolic activity in a variety of tissues; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents are able to induce bone and muscle growth, as well as shrinking the prostate. The potential of SARMS is to maximise the positive attributes of steroidal androgens as well as minimising negative effects, thus providing therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, end-stage renal disease, osteoporosis, frailty and hypogonadism. This review summarises androgen physiology, the current status of the R&D of SARMS and potential therapeutic indications for this emerging class of drugs.

  14. Intermittent single point machining of brittle materials

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, E

    1999-12-07

    A series of tests were undertaken to explore diamond tool wear in the intermittent cutting of brittle materials, specifically silicon. The tests were carried out on a plain way No. 3 Moore machine base equipped as a flycutter with a motorized Professional Instruments 4R air bearing spindle. The diamond tools were made by Edge Technologies with known crystal orientation and composition and sharpened with either an abrasive or chemical process, depending on the individual test. The flycutting machine configuration allowed precise control over the angle at which the tool engages the anisotropic silicon workpiece. In contrast, the crystallographic orientation of the silicon workpiece changes continuously during on-axis turning. As a result, it is possible to flycut a workpiece in cutting directions that are known to be easy or hard. All cuts were run in the 100 plane of the silicon, with a slight angle deliberately introduced to ensure that the 100 plane is engaged in ''up-cutting'' which lengthens the tool life. A Kistler 9256 dynamometer was used to measure the cutting forces in order to gain insight into the material removal process and tool wear during testing. The dynamometer provides high bandwidth force measurement with milli-Newton resolution and good thermal stability. After many successive passes over the workpiece, it was observed that the cutting forces grow at a rate that is roughly proportional to the degradation of the workpiece surface finish. The exact relationship between cutting force growth and surface finish degradation was not quantified because of the problems associated with measuring surface finish in situ. However, a series of witness marks were made during testing in an aluminum sample that clearly show the development of wear flats on the tool nose profile as the forces grow and the surface finish worsens. The test results show that workpieces requiring on the order of two miles of track length can be made with low tool

  15. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use

    Directory of Open Access Journals (Sweden)

    J Abram McBride

    2016-01-01

    Full Text Available The use of testosterone replacement therapy (TRT for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids (AAS within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal (HPG axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

  16. Regulation of uterine progesterone receptors by the nonsteroidal anti-androgen hydroxyflutamide

    International Nuclear Information System (INIS)

    Chandrasekhar, Y.; Armstrong, D.T.

    1991-01-01

    The authors have recently reported that the anti-androgen hydroxyflutamide causes delayed implantation and exhibits antideciduogenic activity in the rat. The present experiments were conducted to examine whether hydroxyflutamide binds to the uterine progesterone receptors and/or alters the progesterone binding sites in the uterus. Cytosol and nuclear fractions from decidualized rat uterus were incubated with [3H]-R5020 without or with increasing concentrations of radioinert R5020, RU486, dihydrotestosterone, or hydroxyflutamide. From the log-dose inhibition curves, the relative binding affinity of both hydroxyflutamide and dihydrotestosterone was less than 0.1% and 2%, compared with R5020 (100%) for displacing [3H]-R5020 bound to uterine cytosol and nuclear fractions, respectively. Injection of estradiol-17 beta (1 microgram/rat) to ovariectomized prepubertal rats induced a 1.85-fold increase in uterine weight by 24 h. Hydroxyflutamide at 2.5 or 5.0 mg did not significantly alter the estrogen-induced increase in uterine weight. Compared to vehicle alone, estrogen induced an approximately 5-fold increase in uterine cytosolic progesterone binding sites. Hydroxyflutamide at both 2.5- and 5.0-mg doses significantly attenuated the estrogen-induced elevation in uterine progesterone binding sites. These studies demonstrate that hydroxyflutamide does not bind with high affinity to progesterone receptors, but suppresses the estrogen-induced elevation in progesterone receptor levels in the uterus

  17. Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

    Science.gov (United States)

    Chua, Chee Wai; Epsi, Nusrat J; Leung, Eva Y; Xuan, Shouhong; Lei, Ming; Li, Bo I; Bergren, Sarah K; Hibshoosh, Hanina; Mitrofanova, Antonina

    2018-01-01

    Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer. PMID:29334357

  18. Computerized cognitive training in prostate cancer patients on androgen deprivation therapy: a pilot study.

    Science.gov (United States)

    Wu, Lisa M; Amidi, Ali; Tanenbaum, Molly L; Winkel, Gary; Gordon, Wayne A; Hall, Simon J; Bovbjerg, Katrin; Diefenbach, Michael A

    2018-06-01

    Prostate cancer patients who have undergone androgen deprivation therapy (ADT) may experience cognitive impairment, yet there is an unmet need for nonpharmacological interventions to address cognitive impairment in this population. This study examines the feasibility, acceptability, and preliminary efficacy of a home-based computerized cognitive training (CCT) program to treat cancer-related cognitive impairment. Sixty men who had received ≥ 3 months of ADT were screened for at least mild cognitive or neurobehavioral impairment and randomized to 8 weeks of CCT or usual care. Follow-up assessments occurred immediately post-intervention or equivalent (T2) and 8 weeks later (T3). The acceptability of CCT was also assessed. Feasibility:A priori feasibility thresholds were partially met (i.e., randomization rate > 50%, retention rate > 70% excluding CCT drop-outs, but cognitive functioning, neurobehavioral functioning, nor quality of life. This study provides tentative support for the feasibility and acceptability of CCT to treat mild cognitive impairment in ADT patients. CCT had a beneficial effect on reaction time, but temporarily suppressed memory. CCT's benefits may be limited to a narrow area of functioning. Larger-scale studies are needed.

  19. Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Sahashi, Kentaro; Katsuno, Masahisa; Hung, Gene; Adachi, Hiroaki; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Iida, Madoka; Bennett, C Frank; Sobue, Gen

    2015-11-01

    Spinal and bulbar muscular atrophy (SBMA), an adult-onset neurodegenerative disease that affects males, results from a CAG triplet repeat/polyglutamine expansions in the androgen receptor (AR) gene. Patients develop progressive muscular weakness and atrophy, and no effective therapy is currently available. The tissue-specific pathogenesis, especially relative pathological contributions between degenerative motor neurons and muscles, remains inconclusive. Though peripheral pathology in skeletal muscle caused by toxic AR protein has been recently reported to play a pivotal role in the pathogenesis of SBMA using mouse models, the role of motor neuron degeneration in SBMA has not been rigorously investigated. Here, we exploited synthetic antisense oligonucleotides to inhibit the RNA levels of mutant AR in the central nervous system (CNS) and explore its therapeutic effects in our SBMA mouse model that harbors a mutant AR gene with 97 CAG expansions and characteristic SBMA-like neurogenic phenotypes. A single intracerebroventricular administration of the antisense oligonucleotides in the presymptomatic phase efficiently suppressed the mutant gene expression in the CNS, and delayed the onset and progression of motor dysfunction, improved body weight gain and survival with the amelioration of neuronal histopathology in motor units such as spinal motor neurons, neuromuscular junctions and skeletal muscle. These findings highlight the importance of the neurotoxicity of mutant AR protein in motor neurons as a therapeutic target. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Adverse effects of doping with anabolic androgenic steroids (AAS) in competitive athletics, recreational sports and bodybuilding.

    Science.gov (United States)

    Vorona, Elena; Nieschlag, Eberhard

    2018-02-19

    Despite the fact that sports organizations and legislators have introduced various mechanisms to discourage athletes from using performance and appearance enhancing substances a high percentage of athletes admits to their unabated application. In competitive athletics, bodybuilding and in recreational sports anabolic androgenic steroids (AAS) continue to be the substances most abused. This review summarizes the side effects of AAS abuse on organs and system functions in both sexes. High doses of AAS cause a significant increase of erythrocytes und haemoglobin concentration, which may lead to thromboembolism, intracardiac thrombosis and stroke. Long-term AAS abusers have a higher incidence of arrhythmias, atherosclerosis, concentric left-ventricular myocardial hypertrophy with impaired diastolic function and also sudden cardiac death. Changes of liver function and structure, up to hepatocellular carcinoma, have been described, mainly in cases of chronic misuse of 17α-alkylated AAS. Sleeplessness, increased irritability, depressive mood status are often observed in AAS abuse. In former AAS abusers depression, anxiety and melancholy may persist for many years. Due to negative feedback in the regulation of the hypothalamic-pituitary-gonadal axis AAS can cause reversible suppression of spermatogenesis up to azoospermia. In women the changes most often caused by AAS abuse are hirsutism, irreversible deepening of voice, dysmenorrhoea, secondary amenorrhoea with anovulation and infertility. AAS abuse notwithstanding, under clinical conditions testosterone remains the most important hormone for substitution therapy of male hypogonadism.