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Sample records for analogues deplete androgen

  1. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells

    DEFF Research Database (Denmark)

    Griend, Donald J Vander; Antony, Lizamma; Dalrymple, Susan L;

    2009-01-01

    There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell......-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), approximately 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b, and......-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing...

  2. Antiandrogens and androgen depleting therapies in prostate cancer: novel agents for an established target

    OpenAIRE

    Chen, Yu; Clegg, Nicola J.; Scher, Howard I.

    2009-01-01

    Activation of the androgen receptor is critical for prostate cancer growth at all points in the illness. Currently therapies targeting the androgen receptor, including androgen depletion approaches and antiandrogens, do not completely inhibit androgen receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes such as AR overexpression that result in reactivation of the receptor. Based on understanding of these resistance mechanisms and androgen synthesis pa...

  3. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion

    OpenAIRE

    Harris, William P.; Mostaghel, Elahe A.; Peter S Nelson; Montgomery, Bruce

    2009-01-01

    Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data supports its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress...

  4. Androgens.

    Science.gov (United States)

    Iyer, Rakesh; Handelsman, David J

    2016-01-01

    Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed. PMID:27347677

  5. Asian trends in primar y androgen depletion therapy on prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hideyuki Akaza

    2013-01-01

    hTere are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy (ADT). Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization of ADT. ADT-related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer (CRPC) have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer.

  6. Pyridine analogues of curcumin exhibit high activity for inhibiting CWR-22Rv1 human prostate cancer cell growth and androgen receptor activation

    Science.gov (United States)

    ZHOU, DAI-YING; ZHAO, SU-QING; DU, ZHI-YUN; ZHENG, XI; ZHANG, KUN

    2016-01-01

    The concentrations required for curcumin to exert its anticancer activity (IC50, 20 µM) are difficult to achieve in the blood plasma of patients, due to the low bioavailability of the compound. Therefore, much effort has been devoted to the development of curcumin analogues that exhibit stronger anticancer activity and a lower IC50 than curcumin. The present study investigated twelve pyridine analogues of curcumin, labeled as groups AN, BN, EN and FN, to determine their effects in CWR-22Rv1 human prostate cancer cells. The inhibitory effects of these compounds on testosterone (TT)-induced androgen receptor (AR) activity was determined by performing an AR-linked luciferase assay and by TT-induced expression of prostate-specific antigen. The results of the current study suggested that the FN group of analogues had the strongest inhibitory effect of growth on CWR-22Rv1 cultured cells, and were the most potent inhibitor of AR activity compared with curcumin, and the AN, BN and EN analogues. Thus, the results of the present study indicate the inhibition of the AR pathways as a potential mechanism for the anticancer effect of curcumin analogues in human prostate cancer cells. Furthermore, curcumin analogues with pyridine as a distal ring and tetrahydrothiopyran-4-one as a linker may be good candidates for the development of novel drugs for the treatment of prostate cancer, by targeting the AR signaling pathway. PMID:27313760

  7. Novel agmatine analogue, γ-guanidinooxypropylamine (GAPA) efficiently inhibits proliferation of Leishmania donovani by depletion of intracellular polyamine levels

    International Nuclear Information System (INIS)

    The efficacy of γ-guanidinooxypropylamine (GAPA), a novel agmatine analogue against protozoan parasite, Leishmaniadonovani was evaluated. Wild-type and ornithine decarboxylase-overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. GAPA inhibited the growth of both promastigotes and amastigotes. Ornithine decarboxylase (ODC) activity and polyamine levels were markedly lower in cells treated with GAPA and proliferation was rescued by addition of putrescine or spermidine. GAPA inhibited L. donovani recombinant ODC with Ki value of ∼60 μM. The ODC-overexpressors showed significant resistance to GAPA. GAPA has pKa 6.71 and at physiological pH the analogue can mimic protonated state of putrescine and can probably use putrescine transport system. Transport of putrescine in wild-type L. donovani promastigotes was inhibited by GAPA. We for the first time report that GAPA is a potential antileishmanial lead compound and it possibly inhibits L. donovani growth by depletion of intracellular polyamine levels

  8. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    OpenAIRE

    Shtutman Michael; Tanner Matthew J; Carkner Richard D; Baghel Prateek S; Levina Elina; Feuerstein Michael A; Chen Mengqian; Vacherot Francis; Terry Stéphane; de la Taille Alexandre; Buttyan Ralph

    2010-01-01

    Abstract Background Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC....

  9. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Shtutman Michael

    2010-04-01

    Full Text Available Abstract Background Castration resistant prostate cancer (CRPC develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI prostate cancer cells. Results Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881 restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to

  10. Spontaneous parametric down conversion with a depleted pump as an analogue for black hole evaporation/particle production

    CERN Document Server

    Alsing, Paul M

    2015-01-01

    We present an analytical formulation of the recent one-shot decoupling model of Br\\`adler and Adami [arXiv:1505.0284] and compute the resulting "Page Information" curves, for the reduced density matrices for the evaporating black hole internal degrees of freedom, and emitted Hawking radiation pairs entangled across the horizon. We argue that black hole evaporation/particle production has a very close analogy to the laboratory process of spontaneous parametric down conversion, when the pump is allowed to deplete.

  11. Chemical-mechanical coupling observed for depleted oil reservoirs subjected to long-term CO2-exposure - A case study of the Werkendam natural CO2 analogue field

    Science.gov (United States)

    Hangx, Suzanne; Bakker, Elisenda; Bertier, Pieter; Nover, Georg; Busch, Andreas

    2015-10-01

    Geological storage of CO2 is one of the most promising technologies to rapidly reduce anthropogenic emissions of carbon dioxide. In order to ensure storage integrity, it is important to understand the effect of long-term CO2/brine/rock interactions on the mechanical behaviour of a storage complex. As most of these reactions are too slow to reproduce on laboratory timescales, we studied a natural CO2 analogue reservoir (the Röt Fringe Sandstone, Werkendam field, the Netherlands; 125-135 Ma of CO2-exposure) and its unreacted counterpart. We focused on CO2-induced mineralogical and porosity-permeability changes, and their effect on mechanical behaviour of both intact rock and simulated fault gouge. Overall, CO2-exposure did not lead to drastic mineralogical changes. The CO2-exposed material shows a stronger dependence of permeability on porosity, which is attributed to differences in diagenesis (closed-system diagenesis and hydrocarbon emplacement) taking place before CO2 charging. The limited extent of reaction was in part the result of bitumen coatings protecting specific mineral phases from reaction. In local, mm-sized zones displaying significant anhydrite cement dissolution, enhanced porosity was observed. For most of the reservoir the long-term mechanical behaviour after CO2-exposure could be described by the behaviour of the unreacted sandstone, while these more 'porous' zones had a lower rock strength. In addition, CO2-exposure did not affect the fault friction behaviour, and slip is expected to result in stable sliding. Simple stress path calculations predict that reservoir failure due to depletion and injection is unlikely, even for the 'porous' zones, nor will fault reactivation occur for realistic injection scenarios.

  12. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients

    NARCIS (Netherlands)

    Westerhof, GR; Ploemacher, RE; Boudewijn, A; Blokland, [No Value; Dillingh, JH; McGown, AT; Hadfield, JA; Dawson, MJ; Down, JD

    2000-01-01

    Busulfan (1,4-butanediol dimethanesulfonate, BU) is relatively unique among other standard chemotherapy compounds in its ability to deplete noncycling primitive stem cells in the host and consequently to allow for high levels of long-term, donor-type engraftment after bone marrow transplantation (BM

  13. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients

    NARCIS (Netherlands)

    G.R. Westerhof; R.E. Ploemacher (Robert); A. Boudewijn (Adrie); I. Blokland (Irene); J.H. Dillingh; A.T. McGown; J.A. Hadfield; M.J. Dawson; J.D. Down

    2000-01-01

    textabstractBusulfan (1,4-butanediol dimethanesulfonate, BU) is relatively unique among other standard chemotherapy compounds in its ability to deplete noncycling primitive stem cells in the host and consequently to allow for high levels of long-term, donor-type engraft

  14. Androgen receptor mutations

    OpenAIRE

    Brinkmann, Albert; Jenster, Guido; Ris-Stalpers, Carolyn; Korput, J. A G M; Brüggenwirth, Hennie; Boehmer, A.L.; Trapman, Jan

    1995-01-01

    textabstractMale 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. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syn...

  15. Androgen insensitivity syndrome: gonadal androgen receptor activity

    International Nuclear Information System (INIS)

    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

  16. Androgen insensitivity syndrome

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/001180.htm Androgen insensitivity syndrome To use the sharing features on this page, please enable JavaScript. Androgen insensitivity syndrome (AIS) is when a person who ...

  17. Noninvasive monitoring of androgens in male Amazonian manatee (Trichechus inunguis): biologic validation.

    Science.gov (United States)

    Amaral, Rodrigo de Souza; Rosas, Fernando Cesar Weber; Viau, Priscila; d'Affonsêca Neto, José Anselmo; da Silva, Vera Maria Ferreira; de Oliveira, Cláudio Alvarenga

    2009-09-01

    The Amazonian manatee (Trichechus inunguis) is endemic in the Amazonian basin and is the only exclusively fresh water sirenian. Historically hunted on a large scale, this species is now considered endangered, and studies on the reproductive physiology are critical for the improvement of reproductive management of captive and wild populations of manatees. The aim of this study was to verify the viability of androgen measurement in saliva, lacrimal, urine, and fecal samples of the Amazonian manatee by conducting a hormone challenge. Two adult male manatees (A-1 and A-2) were submitted to an experimentation protocol of 12 day (D1 to D10). On D0, the animals received an intramuscular injection of gonadotropin-releasing hormone (GnRH)-analogue. Salivary, lacrimal, urinary, and fecal samples were collected daily (between 0800 hours and 0900 hours) and frozen at -20 degrees C until assayed. Fecal samples were lyophilized, extracted with 80% methanol, and diluted in buffer before the radioimmunoassay (RIA). Urine samples underwent acid hydrolysis and were diluted in depleted bovine serum. Salivary and lacrimal samples were assayed without the extraction step. Hormonal assays were conducted with a commercial testosterone RIA kit. An androgen peak (> median + 2 interquartile range [IQR]) was observed in all matrices of both animals, although it was less prominent in the lacrimal samples of A-2. However, the fecal androgen peak (A-1 peak = 293.78 ng/g dry feces, median [IQR] = 143.58 [32.38] ng/g dry feces; A-2 peak = 686.72 ng/g dry feces, median [IQR] = 243.82 [193.16] ng/g dry feces) occurred later than urinary (A-1 peak = 648.16 ng/mg creatinine [Cr], median [IQR] = 23.88 [30.44] ng/mg Cr; A-2 peak = 370.44 ng/mg Cr, median [IQR] = 113.87 [117.73] ng/mg Cr) and salivary (A-1 peak = 678.89 pg/ml, median [IQR] = 103.69 [119.86] pg/ml; A-2 peak = 733.71 pg/ml, median [IQR] = 262.92 [211.44] pg/ml) androgen peaks. These intervals appear to be correlated with the long digesta

  18. Androgens and the breast.

    Science.gov (United States)

    Dimitrakakis, Constantine; Bondy, Carolyn

    2009-01-01

    Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.

  19. Androgen receptor abnormalities

    NARCIS (Netherlands)

    A.O. Brinkmann (Albert); G.G.J.M. Kuiper (George); C. Ris-Stalpers (Carolyn); H.C.J. van Rooij (Henri); G. Romalo (G.); G. Trifiro (Gianluca); E. Mulder (Eppo); L. Pinsky (L.); H.U. Schweikert (H.); J. Trapman (Jan)

    1991-01-01

    markdownabstract__Abstract__ The human androgen receptor is a member of the superfamily of steroid hormone receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human androgen receptor cDNA and the elucidation of t

  20. 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, these things can reduce symptoms caused by high ...

  1. Androgens and Bone

    OpenAIRE

    Clarke, Bart L.; Khosla, Sundeep

    2008-01-01

    Testosterone is the major gonadal sex steroid produced by the testes in men. Testosterone is also produced in smaller amounts by the ovaries in women. The adrenal glands produce the weaker androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. These androgens collectively affect skeletal homeostasis throughout life in both men and women, particularly at puberty and during adult life. Because testosterone can be metabolized to estradiol by the aromatase enzyme, ...

  2. Androgen regulation of the androgen receptor coregulators

    International Nuclear Information System (INIS)

    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

  3. Androgen regulation of the androgen receptor coregulators

    Directory of Open Access Journals (Sweden)

    Helenius Merja A

    2008-08-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusion 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.

  4. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate.

    Science.gov (United States)

    Akita, Kazumasa; Harada, Koichiro; Ichihara, Junji; Takata, Naoko; Takahashi, Yasuhiko; Saito, Koichi

    2013-11-15

    Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of β-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease. However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor. To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Aβ-degrading enzyme. These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease.

  5. Overexpression of Androgen Receptors in Target Musculature Confers Androgen Sensitivity to Motoneuron Dendrites

    OpenAIRE

    Huguenard, Anna L.; Fernando, Shannon M.; Monks, D. Ashley; Sengelaub, Dale R.

    2010-01-01

    Androgen sensitivity of motoneuron dendrites is conferred indirectly via the enrichment of androgen receptors in the musculature in transgenic rats overexpressing androgen receptors in skeletal muscle.

  6. One and the same androgen for all? towards designer androgens

    Institute of Scientific and Technical Information of China (English)

    LouisJGGooren; NhuThanhNguyen

    1999-01-01

    The introduction of designer oestrogens as a treatment medality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male honnone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment, To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to nestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on bichemical parameters of cardiovascular risks: the potentially negative effects of oestmgens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiolog~ is certainly not proven.For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement medalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems fur treatment modalities. ( Asian J Andro11999 Jun; 1:21 -28)

  7. Metabolic syndrome in androgenic alopecia

    OpenAIRE

    Hima Gopinath; Gatha M Upadya

    2016-01-01

    Background: Androgenic alopecia has been associated with an increased risk of coronary heart disease in various studies. The relationship between androgenic alopecia and metabolic syndrome, a known risk factor for atherosclerotic cardiovascular disease, is still poorly understood. Aim: To study the association between metabolic syndrome and early-onset androgenic alopecia. Methods: A hospital-based analytical cross-sectional study was done on men in the age group of 18–55 years. Eighty five c...

  8. Control of adrenal androgen production.

    Science.gov (United States)

    Odell, W D; Parker, L N

    The major adrenal androgens are dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and androstenedione (delta 4). Studies by Cutler et al in 1978 demonstrated that these androgens are detectable in blood of all domestic and laboratory animals studied, but that only 4 species show increase in one or more with sexual maturation: rabbit, dog, chimpanzee and man. Studies by Grover and Odell in 1975 show these androgens do not bind to the androgen receptor obtained from rat prostate and thus probably are androgens only by conversion to an active androgen in vivo. Thomas and Oake in 1974 showed human skin converted DHEA to testosterone. The control of adrenal androgen secretion is in part modulated by ACTH. However, other factors or hormones must exist also, for a variety of clinical observations show dissociation in adrenal androgen versus cortisol secretion. Other substances that have been said to be controllers of adrenal androgen secretion include estrogens, prolactin, growth hormone, gonadotropins and lipotropin. None of these appear to be the usual physiological modulator, although under some circumstances each may increase androgen production. Studies from our laboratory using in vivo experiments in the castrate dog and published in 1979 indicated that crude extracts of bovine pituitary contained a substance that either modified ACTH stimulation of adrenal androgen secretion, or stimulated secretion itself - Cortisol Androgen Stimulating Hormone. Parker et al in 1983 showed a 60,000 MW glycoprotein was extractable from human pituitaries, which stimulated DHA secretion by dispersed canine adrenal cells in vitro, but did not stimulate cortisol secretion. This material contained no ACTH by radioimmunoassay. In 1982 Brubaker et al reported a substance was also present in human fetal pituitaries, which stimulated DHA secretion, but did not effect cortisol. PMID:6100259

  9. ANDROGEN INSENSITIVITY SYNDROME

    OpenAIRE

    Kanan; Sonali

    2014-01-01

    The condition is inherited as X - linked recessive gene 1 . The underlying pathology is the inability of end organs to respond to androgens. These cases are phenotypically and psychologically female with adequate breast development , normal external genitalia , a vagina with variable depth , absent /sparse pubic hair and axillary hair. The exact incidence in India is not known but the reported incidence is 1 in 2 , 000 to 1 in 62 ,400 worldwi...

  10. Complete androgen insensitivity syndrome

    Directory of Open Access Journals (Sweden)

    Tančić-Gajić Milina

    2015-01-01

    Full Text Available Introduction. Androgen insensitivity syndrome (AIS belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY with normally developed testes and age-appropriate for males of serum testosterone concentration. Case Outline. A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years. The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multisliced computed tomography (MSCT showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. Conclusion. The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina. [Projekat Ministarstva nauke Republike Srbije, br. 175067

  11. Analogue computing methods

    CERN Document Server

    Welbourne, D

    1965-01-01

    Analogue Computing Methods presents the field of analogue computation and simulation in a compact and convenient form, providing an outline of models and analogues that have been produced to solve physical problems for the engineer and how to use and program the electronic analogue computer. This book consists of six chapters. The first chapter provides an introduction to analogue computation and discusses certain mathematical techniques. The electronic equipment of an analogue computer is covered in Chapter 2, while its use to solve simple problems, including the method of scaling is elaborat

  12. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  13. Metabolic syndrome in androgenic alopecia

    Directory of Open Access Journals (Sweden)

    Hima Gopinath

    2016-01-01

    Full Text Available Background: Androgenic alopecia has been associated with an increased risk of coronary heart disease in various studies. The relationship between androgenic alopecia and metabolic syndrome, a known risk factor for atherosclerotic cardiovascular disease, is still poorly understood. Aim: To study the association between metabolic syndrome and early-onset androgenic alopecia. Methods: A hospital-based analytical cross-sectional study was done on men in the age group of 18–55 years. Eighty five clinically diagnosed cases with early-onset (<35 years androgenic alopecia of Norwood grade III or above, and 85 controls without androgenic alopecia were included. Data collected included anthropometric measurements, arterial blood pressure and history of chronic diseases. Fasting blood and lipid profile were determined. Metabolic syndrome was diagnosed as per the new International Diabetes Federation criteria. Chi-square and Student's t-test were used for statistical analysis using Statistical Package for the Social Sciences (SPSS version 17.00. Results: Metabolic syndrome was seen in 19 (22.4% patients with androgenic alopecia and 8 (9.4% controls (P = 0.021. Abdominal obesity, hypertension and lowered high-density lipoprotein were significantly higher in patients with androgenic alopecia versus their respective controls. Limitations: The limitations of our study include small sample size in subgroups and the lack of evidence of a temporal relationship between metabolic syndrome and androgenic alopecia. Conclusion: A higher prevalence of metabolic syndrome is seen in men with early-onset androgenic alopecia. Early screening for metabolic syndrome and its components is beneficial in patients with early-onset androgenic alopecia.

  14. Analogue MIMO Detection

    Directory of Open Access Journals (Sweden)

    McNamara Darren

    2006-01-01

    Full Text Available In this contribution we propose an analogue receiver that can perform turbo detection in MIMO systems. We present the case for a receiver that is built from nonlinear analogue devices, which perform detection in a "free-flow" network (no notion of iterations. This contribution can be viewed as an extension of analogue turbo decoder concepts to include MIMO detection. These first analogue implementations report reductions of few orders of magnitude in the number of required transistors and in consumed energy, and the same order of improvement in processing speed. It is anticipated that such analogue MIMO decoder could bring about the same advantages, when compared to traditional digital implementations.

  15. ANDROGEN LEVELS IN PREECLAMPSIA

    Directory of Open Access Journals (Sweden)

    M. Valadan

    2006-08-01

    Full Text Available Preeclampsia is a major cause of morbidity and mortality during pregnancy. Several independent investigators have demonstrated the association of androgens with hypertension. The main purpose of this study was to determine whether maternal levels of sex hormones, especially testosterone, are higher in patients with preeclampsia than in matched normotensive control subjects. Serum levels of testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEA-S and estradiol were measured in 60 subjects in the 3rd trimester of pregnancy with documented preeclampsia (including 30 cases of mild and 30 cases of severe preeclampsia and 60 healthy normotensive women with similar maternal and gestational ages and body mass index (BMI and neonatal sex. All subjects were primigravid with singleton pregnancies. Cases of polycystic ovary (PCO, diabetes, chronic hypertension and chronic systemic diseases such as lupus and patients using steroid hormones and anti-hypertensive drugs were excluded. Levels of testosterone, DHEA-S and estradiol were not higher in primigravid women with preeclampsia than in normotensive women with similar gestational and maternal ages, BMI and neonatal sex. There were no significant differences in sex hormones measured between groups of mild and severe preeclampsia and normotensive women. There were also no significant differences in sex hormone levels according to neonatal sex. These findings are against the hypothesis of mediating or amplifying role of high androgen levels in pathophysiology of preeclampsia.

  16. Androgens and sexuality.

    Science.gov (United States)

    Hutchinson, K A

    1995-01-16

    A review of the literature reveals that the endocrine determinants of female sexuality are complex and difficult to characterize. In adolescent males, free testosterone directly affects sexual motivation, with social factors exerting little or no effect. In adolescent girls, by contrast, societal and peer pressure play a pivotal role in the appearance of certain sexual behaviors. Throughout a woman's life, hormonal and psychosocial factors are critical influences. It is possible that cyclic patterns of testosterone are less important for female sexual behavior than the "tonic" effect of overall testosterone levels. Although the estrogen dependence of the vaginal epithelium--important for postmenopausal women--has been clearly established, the role of other hormonal factors and treatments, particularly those involving androgens, in human female sexual behavior remains enigmatic. The search for an understanding of these relationships is not merely an interesting academic exercise but is necessary to determine what role, if any, androgens may play in the treatment of sexual dysfunction during the female reproductive years. PMID:7825630

  17. Androgen and prostatic stroma

    Institute of Scientific and Technical Information of China (English)

    Yuan-JieNIU; Teng-XiangMA; IuZHANG; YongXU; Rui-FaHAN; GuangSUN

    2003-01-01

    Aim:To investigate the effect of androgen on the proliferation,differentiation and regression of canine prostatic stromal cells in vivo and human stromal cells in vitro.Methods:Twenty-two dogs,including 15 normal prostate doge and 7 prostatic hyperplasia dogs,had their serum concentration of testosterone and estrodiol determined by radioimmunoassay before and after castration.The expression of androgen receptor(AR)and estrogen receptor(ER)in the prostate were analysed by immunohistochemistry and semi-quantitative RT-PCR before and after castration.Light microscopy,transmission electron microscopy and TUNEL assay were carried out successively before and after castration to evaluate the prostatic histomorphology.In vitro serum-free cell cultures from human prostatic stroma were established and exposed to dihydrotestosterone(DHT).The proliferation of the cell culture was detected by MTT assay.The expression of TGFβ bFGF,AR,and smooth muscle cell(SMC) specific proteins (myosin and/or smoothelin)were detected using immunohistochemistry and RT-PCR.The differentiation from fibroblasts to smooth muscle cells was deduced by measuring the expression of SMC specific proteins.Results:Before castration,the serum concentrations of testosterone and estrodiol were not statistically different between normal and hyperplasia groups.Following castration,the serum concentration of testerone decreased rapidly in 2 days,and the concentration of estrodiol had no significant change compared with the pre-castration data.In the prostate,AR was presented in both the epithelial and stromal cells and the AR mRNA level was higher in hyperplasia than in normal prostate tissues(P<0.05).While ER predominantly existed in the prostate stromal cells and the ER mRNA had no difference between the hyperplasia and the normal group.Within the early phase of castration(

  18. [Osteoporosis in men and androgen replacement therapy].

    Science.gov (United States)

    Tsujimura, Akira; Okuyama, Akihiko

    2003-11-01

    Androgen plays an important role in bone maturation and maintenance of bone mass. Androgen deficiency associated with aging causes osteoporosis for men. With respect to this disease, androgen replacement treatment has been performed for aging male. However, available preparations of androgen are limited in Japan and each of them has both merit and demerit. Establishment of guideline for androgen replacement treatment including criteria of serum testosterone concentration is the problem, which now confronts us. PMID:15775234

  19. In vivo modulation of androgen receptor by androgens

    Institute of Scientific and Technical Information of China (English)

    V·L·Kumar; V·Kumar

    2002-01-01

    Aim:To study the effect of androgen and antiandrogen on the level of androgen receptor(AR)mRNA.Methods:The totalRNA was extracted from the prostate and analyzed by slot blot analysis,The blots were hybrid-ized with ARcDNA probe and 1Aprobe(internal control)and autoradionraphy was performed.The intensity of signal was measured with a densitometer and the ratio of AR RNAand1ARNAwas calculated.Results:Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of ARmRNA.Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of ARmRNA.Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels of AR mRNA.Conclusion:Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.

  20. Li depletion in solar analogues with exoplanets: Extending the sample

    CERN Document Server

    Mena, E Delgado; Hernández, J I González; Sousa, S G; Mortier, A; Santos, N C; Adibekyan, V Zh; Fernandes, J; Rebolo, R; Udry, S; Mayor, M

    2013-01-01

    We want to study the effects of the formation of planets and planetary systems on the atmospheric Li abundance of planet host stars. In this work we present new determinations of lithium abundances for 326 Main Sequence stars with and without planets in the T$_\\mathrm{eff}$ range 5600-5900 K. 277 stars come from the HARPS sample, the remaining targets have been observed with a variety of high resolution spectrographs. We confirm significant differences in the Li distribution of solar twins (T$_\\mathrm{eff}$ = T$_{\\odot} \\pm$ 80 K, log g = log g$_{\\odot}$ $\\pm$ 0.2 and [Fe/H] = [Fe/H]$_{\\odot} \\pm$ 0.2): the full sample of planet host stars (22) shows Li average values lower than "single" stars with no detected planets (60). If we focus in subsamples with narrower ranges in metallicity and age, we observe indications of a similar result though it is not so clear for some of the studied subsamples. Furthermore, we compare the observed spectra of several couples of stars with very similar parameters which show d...

  1. Role of androgen receptor in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    HiroyoshiSuzuki; HaruoIto

    1999-01-01

    The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. "Ilais article focusedon the role of AR in the progression of prostate cancer.

  2. DEPLETED URANIUM TECHNICAL WORK

    Science.gov (United States)

    The Depleted Uranium Technical Work is designed to convey available information and knowledge about depleted uranium to EPA Remedial Project Managers, On-Scene Coordinators, contractors, and other Agency managers involved with the remediation of sites contaminated with this mater...

  3. Survey of analogue spacetimes

    CERN Document Server

    Visser, Matt

    2013-01-01

    Analogue spacetimes, (and more boldly, analogue models both of and for gravity), have attracted significant and increasing attention over the last decade and a half. Perhaps the most straightforward physical example, which serves as a template for most of the others, is Bill Unruh's model for a dumb hole, (mute black hole, acoustic black hole), wherein sound is dragged along by a moving fluid --- and can even be trapped behind an acoustic horizon. This and related analogue models for curved spacetimes are useful in many ways: Analogue spacetimes provide general relativists with extremely concrete physical models to help focus their thinking, and conversely the techniques of curved spacetime can sometimes help improve our understanding of condensed matter and/or optical systems by providing an unexpected and countervailing viewpoint. In this introductory chapter, I shall provide a few simple examples of analogue spacetimes as general background for the rest of the contributions.

  4. N-Aryl-oxazolidin-2-imine Muscle Selective Androgen Receptor Modulators Enhance Potency through Pharmacophore Reorientation

    Energy Technology Data Exchange (ETDEWEB)

    Nirschl, Alexandra A.; Zou, Yan; Krystek, Jr., Stanley R.; Sutton, James C.; Simpkins, Ligaya M.; Lupisella, John A.; Kuhns, Joyce E.; Seethala, Ramakrishna; Golla, Rajasree; Sleph, Paul G.; Beehler, Blake C.; Grover, Gary J.; Egan, Donald; Fura, Aberra; Vyas, Viral P.; Li, Yi-Xin; Sack, John S.; Kish, Kevin F.; An, Yongmi; Bryson, James A.; Gougoutas, Jack Z.; DiMarco, John; Zahler, Robert; Ostrowski, Jacek; Hamann, Lawrence G.; (BMS)

    2010-11-09

    A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.

  5. Anti-androgen treatments.

    Science.gov (United States)

    Bachelot, Anne; Chabbert-Buffet, Nathalie; Salenave, Sylvie; Kerlan, Véronique; Galand-Portier, Marie-Béatrice

    2010-02-01

    1. Estrogen plus progestin contraceptives (EPP) are the first-line treatment of moderate hirsutism and acne in women of child bearing age (grade C). 2. CPA, 50mg/day, 20 days out of 28, associated with estrogen is the first-line treatment of "moderate to severe hirsutism" in women of childbearing age (grade C). 3. Spironolactone, given as a contraceptive, can be proposed as a second-line treatment in case of side effects or counter-indications to CPA in moderate to severe hirsutism (grade C) in women of childbearing age. No market authorization in this indication. 4. Flutamide or Finasteride are "only" to be used under the guise of contraception as a "thirdline therapy" in cases of severe hirsutism, the presence of side effects or counter-indications to EPP, CPA 50mg/day or spironolactone (grade C). No market authorization in this indication 5. There is no indication for GnRH analogs as an anti-androgen treatment in women of childbearing age given the current therapeutic alternatives (grade C) 6. Only long-term hair removal treatments can be proposed (grade C): electrolysis or laser hair removal. PMID:20096826

  6. ANDROGEN INSENSITIVITY SYNDROME

    Directory of Open Access Journals (Sweden)

    Kanan

    2014-01-01

    Full Text Available The condition is inherited as X - linked recessive gene 1 . The underlying pathology is the inability of end organs to respond to androgens. These cases are phenotypically and psychologically female with adequate breast development , normal external genitalia , a vagina with variable depth , absent /sparse pubic hair and axillary hair. The exact incidence in India is not known but the reported incidence is 1 in 2 , 000 to 1 in 62 ,400 worldwide . These patients have male karyotyping (XY wi th negative sex chromatin with undescended gonads. These cases are rarely diagnosed before puberty. Though rare , these are extremely distressing to the concerned individuals requiring expert handling. Management should include psychological counseling not only to determine the sexual mentation but also to help those individuals to cope with their problems. The chance of malignancy developing in the gonad with Y chromosome are about 20%.Surgical removal of the gonad is mandatory but can be delayed till 18 ye ars to permit breast development and epiphyseal closure. The aim of presenting this case is to develop awareness regarding this rare syndrome X - linked genetic disorder which runs in families

  7. 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....

  8. 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...

  9. Androgen deficiency and aging in men.

    OpenAIRE

    Swerdloff, R S; Wang, C

    1993-01-01

    Androgen levels decrease with age in men. Androgen deficiency in men older than 65 years leads to asthenia, a decrease in muscle mass, osteoporosis, and a decrease in sexual activity. Androgen deficiency has been reported to cause changes in mood and cognitive function. The combination of these factors results in impaired quality of life in older men. Androgen replacement therapy in hypogonadal men increases bone and muscle mass, enhances muscle and cardiovascular function, and improves sexua...

  10. Androgen Receptors, Sex Behaviour, and Aggression

    OpenAIRE

    Cunningham, Rebecca L; Lumia, Augustus R.; McGinnis, Marilyn Y.

    2012-01-01

    Androgens are intricately involved in reproductive and aggressive behaviours, but the role of the androgen receptor in mediating these behaviours is less defined. Further, activity of the hypothalamic-pituitary-gonadal (HPG) axis and hypothalamic-pituitary-adrenal (HPA) axis can influence each other at the level of the androgen receptor. Knowledge of the mechanisms for androgens’ effects on behaviours through the androgen receptor will guide future studies in elucidating male reproductive and...

  11. 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 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...... 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...

  12. Depleted Uranium Management

    International Nuclear Information System (INIS)

    The paper considers radiological and toxic impact of the depleted uranium on the human health. Radiological influence of depleted uranium is less for 60 % than natural uranium due to the decreasing of short-lived isotopes uranium-234 and uranium-235 after enrichment. The formation of radioactive aerosols and their impact on the human are mentioned. Use of the depleted uranium weapons has also a chemical effect on intake due to possible carcinogenic influence on kidney. Uranium-236 in the substance of the depleted uranium is determined. The fact of beta-radiation formation in the uranium-238 decay is regarded. This effect practically is the same for both depleted and natural uranium. Importance of toxicity of depleted uranium, as the heavier chemical substance, has a considerable contribution to the population health. The paper analyzes risks regarding the use of the depleted uranium weapons. There is international opposition against using weapons with depleted uranium. Resolution on effects of the use of armaments and ammunitions containing depleted uranium was five times supported by the United Nations (USA, United Kingdom, France and Israel did not support). The decision for banning of depleted uranium weapons was supported by the European Parliament

  13. Synthesis of Tonghaosu Analogues

    Institute of Scientific and Technical Information of China (English)

    SUN Hai; LIN Yingjie; WU Yulin; WU Yikang

    2009-01-01

    Several new analogues of natural antifeedant tonghaosu were synthesized via m-CPBA (m-chloroperoxybenzoic acid) oxidation of corresponding 3-(a-furyl)propanols, Luche reduction of the resulting enone, epoxidation, acid-mediated spiroketalization, and radical mediated dehydration.

  14. Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome

    OpenAIRE

    Bhaskararao, G.; Himabindu, Y.; Samir Ranjan Nayak; Sriharibabu, M.

    2014-01-01

    Complete Androgen insensitivity syndrome is a disorder of hormone resistance characterized by a female phenotype in an individual with an XY karyotype. The pathogenesis of CAIS involves a defective androgen receptor gene located on X-chromosome at Xq11-12and end organ insensitivity to androgens, although androgen concentrations are appropriate for the age of the patient. There are three major types of androgen insensitivity syndrome: Complete androgen insensitivity syndrome, minimal androgen ...

  15. Androgen-Responsive MicroRNAs in Mouse Sertoli Cells

    OpenAIRE

    Subbarayalu Panneerdoss; Yao-Fu Chang; Kalyan C Buddavarapu; Hung-I Harry Chen; Gunapala Shetty; Huizhen Wang; Yidong Chen; T Rajendra Kumar; Rao, Manjeet K.

    2012-01-01

    Although decades of research have established that androgen is essential for spermatogenesis, androgen's mechanism of action remains elusive. This is in part because only a few androgen-responsive genes have been definitively identified in the testis. Here, we propose that microRNAs – small, non-coding RNAs – are one class of androgen-regulated trans-acting factors in the testis. Specifically, by using androgen suppression and androgen replacement in mice, we show that androgen regulates the ...

  16. Targeting intratumoral androgens: statins and beyond.

    Science.gov (United States)

    Schweizer, Michael T; Yu, Evan Y

    2016-09-01

    While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). PMID:27583031

  17. 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...

  18. Yolk androgens reduce offspring survival.

    Science.gov (United States)

    Sockman, K W; Schwabl, H

    2000-07-22

    Females may favour some offspring over others by differential deposition of yolk hormones. In American kestrels (Falco sparverius), we found that yolks of eggs laid late in the sequence of a clutch had more testosterone (T) and androstenedione (A4) than yolks of first-laid eggs. To investigate the effects of these yolk androgens on nestling 'fitness', we injected both T and A4 into the yolks of first-laid eggs and compared their hatching time, nestling growth and nestling survival with those of first-laid eggs in which we injected vehicle as a control. Compared to controls, injection of T and A4 at a dose intended to increase their levels to those of later-laid eggs delayed hatching and reduced nestling growth and survival rates. Yolk androgen treatment of egg 1 had no effect on survival of siblings hatching from subsequently laid eggs. The adverse actions of yolk androgen treatment in the kestrel are in contrast to the favourable actions of yolk T treatment found previously in canaries (Serinus canaria). Additional studies are necessary in order to determine whether the deposition of yolk androgens is an adaptive form of parental favouritism or an adverse by-product of endocrine processes during egg formation. Despite its adaptive significance, such 'transgenerational' effects of steroid hormones may have helped to evolutionarily shape the hormonal mechanisms regulating reproduction. PMID:10983830

  19. Depleted uranium in Japan

    International Nuclear Information System (INIS)

    In Japan, depleted uranium ammunition is regarded as nuclear weapons and meets with fierce opposition. The fact that US Marines mistakenly fired bullets containing depleted uranium on an island off Okinawa during training exercises in December 1995 and January 1996, also contributes. The overall situation in this area in Japan is outlined. (P.A.)

  20. Management of depleted uranium

    International Nuclear Information System (INIS)

    Large stocks of depleted uranium have arisen as a result of enrichment operations, especially in the United States and the Russian Federation. Countries with depleted uranium stocks are interested in assessing strategies for the use and management of depleted uranium. The choice of strategy depends on several factors, including government and business policy, alternative uses available, the economic value of the material, regulatory aspects and disposal options, and international market developments in the nuclear fuel cycle. This report presents the results of a depleted uranium study conducted by an expert group organised jointly by the OECD Nuclear Energy Agency and the International Atomic Energy Agency. It contains information on current inventories of depleted uranium, potential future arisings, long term management alternatives, peaceful use options and country programmes. In addition, it explores ideas for international collaboration and identifies key issues for governments and policy makers to consider. (authors)

  1. Water Depletion Threatens Agriculture

    Science.gov (United States)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  2. Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells

    OpenAIRE

    Burton, Dominick G. A.; Giribaldi, Maria G.; Anisleidys Munoz; Katherine Halvorsen; Asmita Patel; Merce Jorda; Carlos Perez-Stable; Priyamvada Rai

    2013-01-01

    Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refra...

  3. A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells

    OpenAIRE

    Li, Tzu-Huey; Zhao, Hongjuan; Peng, Yue; Beliakoff, Jason; James D Brooks; Sun, Zijie

    2007-01-01

    Although the vital role of the androgen receptor (AR) has been well demonstrated in primary prostate cancers, its role in the androgen-insensitive prostate cancers still remains unclear. Here, we used a small hairpin RNA approach to directly assess AR activity in prostate cancer cells. Reduction of AR expression in the two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC4, significantly decreased AR-mediated transcription and cell growth. Intriguingly, in two androgen-insensitive...

  4. Human androgen deficiency: insights gained from androgen receptor knockout mouse models

    OpenAIRE

    Kesha Rana; Davey, Rachel A; Zajac, Jeffrey D

    2014-01-01

    The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immu...

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

    OpenAIRE

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

    2013-01-01

    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 sup...

  6. Genotype versus phenotype in families with androgen insensitivity syndrome

    NARCIS (Netherlands)

    Boehmer, ALM; Bruggenwirth, H; Van Assendelft, C; Otten, BJ; Verleun-Mooijman, MCT; Niermeijer, MF; Brunner, HG; Rouwe, CW; Waelkens, JJ; Oostdijk, W; Kleijer, WJ; Van der Kwast, TH; De Vroede, MA; Drop, SLS

    2001-01-01

    Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivit

  7. Reptides and Proteins Interacting with the Androgen Receptor

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis)

    2009-01-01

    textabstractAndrogens are important sex steroid hormones. The androgens testosterone and dihydrotestosterone (DHT) are essential for normal male sexual differentiation and for the development and maintenance of male reproductive tissues, including the prostate. Androgens mediate their effects by bin

  8. Uses of depleted uranium

    International Nuclear Information System (INIS)

    The depleted uranium is that in which percentage of uranium-235 fission executable is less than 0.2% or 0.3%. It is usually caused by the process of reprocessing the nuclear fuel burning, and also mixed with some other radioactive elements such as uranium 236, 238 and plutonium 239. The good features of the depleted uranium are its high density, low price and easily mined. So, the specifications for depleted uranium make it one of the best materials in case you need to have objects small in size, but quite heavy regarding its size. Uses of deplet ed uranium were relatively increased in domestic industrial uses as well as some uses in nuclear industry in the last few years. So it has increased uses in many areas of military and peaceful means such as: in balancing the giant air crafts, ships and missiles and in the manufacture of some types of concrete with severe hardness. (author)

  9. ACTINOMYCIN D ANALOGUES

    DEFF Research Database (Denmark)

    1997-01-01

    The present invention relates to new compounds being structurally and functionally similar to Actinomycin D and to combinatorial libraries of such compounds. The Actinomycin D analogues according to the present invention comprise two linear or cyclic peptide moieties constituted by $g...

  10. Cobalamin analogues in humans

    DEFF Research Database (Denmark)

    Hardlei, Tore Forsingdal; Obeid, Rima; Herrmann, Wolfgang;

    2013-01-01

    BACKGROUND: Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin of ...

  11. Synthetic Androgens as Designer Supplements

    OpenAIRE

    Joseph, Jan Felix; Parr, Maria Kristina

    2015-01-01

    Anabolic androgenic steroids (AAS) are some of the most common performance enhancing drugs (PED) among society. Despite the broad spectrum of adverse effects and legal consequences, AAS are illicitly marketed and distributed in many countries. To circumvent existing laws, the chemical structure of AAS is modified and these designer steroids are sold as nutritional supplements mainly over the Internet. Several side effects are linked with AAS abuse. Only little is known about the pharmacologic...

  12. ABUSE OF ANABOLIC ANDROGENIC STEROIDS

    OpenAIRE

    Abbas Yavari

    2009-01-01

    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 and widespread 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, ...

  13. NATURAL ANALOGUE SYNTHESIS REPORT

    International Nuclear Information System (INIS)

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the Yucca Mountain Site Description (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature along with results of quantitative studies conducted specifically for the Yucca Mountain Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement-drift degradation, waste-form degradation, waste-package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated-zone (SZ) transport, impact of radionuclide release on the biosphere

  14. Androgens and erythropoiesis: past and present.

    Science.gov (United States)

    Shahani, S; Braga-Basaria, M; Maggio, M; Basaria, S

    2009-09-01

    Association between androgens and erythropoiesis has been known for more than seven decades. Androgens stimulate hematopoietic system by various mechanisms. These include stimulation of erythropoietin release, increasing bone marrow activity and iron incorporation into the red cells. Before the discovery of recombinant erythropoietin (rhEpo), androgens were used in the treatment of anemia associated with renal disease, bone marrow suppression, and hypopituitarism. Anabolism is an additional advantage of androgen therapy. Furthermore, in light of recent reports regarding adverse effects of rhEpo, the role of androgen therapy in various types of anemias should be readdressed. Polycythemia remains a known side effect of androgen therapy. In this review, we will briefly discuss the initial animal and human studies which demonstrated the role of androgens in the treatment of anemia, their mechanism of action, a detailed account of the efficacy of androgens in the treatment of various anemias, the erythropoietic side effects of androgens and finally, the relationship between hematocrit levels and cardiovascular disease. PMID:19494706

  15. CEC natural analogue working group

    International Nuclear Information System (INIS)

    The second meeting of the CEC Natural Analogue Working Group took place on June 17-19, 1986, hosted by the Swiss NAGRA in Interlaken (CH). A review of recent progress in natural analogue programmes was carried out, and complemented by detailed discussions about geomicrobiology, archaeological analogues, natural colloids, and use of analogues to increase confidence in safety assessments for radioactive waste disposal. A statement drafted by the Group, and the presentations made, are put together in this report

  16. CEC Natural Analogue Working Group

    International Nuclear Information System (INIS)

    The central theme for the third meeting of the CEC analogue working group was ''How can analogue data be used for performance assessments, both in support of the results and for presentation to the public''. This report puts together the most recent achievements in this field, together with a review of on-going natural analogue programmes

  17. Prolonged androgen deprivation leads to downregulation of androgen receptor and prostate-specific membrane antigen in prostate cancer cells

    OpenAIRE

    Liu, Tiancheng; Wu, Lisa Y.; Fulton, Melody D.; JOHNSON, JACQUELINE M.; Berkman, Clifford E.

    2012-01-01

    Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate c...

  18. Progestagenic Aquatic Contaminants Act as Potent Androgens in Fish : Experimental Studies in Three-spined Stickleback and Zebrafish

    OpenAIRE

    Svensson, Johan

    2016-01-01

    The extensive use of pharmaceuticals and their poor removal by wastewater treatment plants has led to the emergence of pharmaceutical compounds as global aquatic contaminants. Progestins, the synthetic analogues to progesterone (P4), 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 have androgenic properties and are several orders of magnitude more potent in terms of reproducti...

  19. Changes in gene expression following androgen receptor blockade is not equivalent to androgen ablation by castration in the rat ventral prostate

    Indian Academy of Sciences (India)

    Anil M Limaye; Irfan Asangani; Thyagarajan Kalyani; Paturu Kondaiah

    2008-06-01

    Involution of the rat ventral prostate and concomitant modulation of gene expression post-castration is a well-documented phenomenon. While the rat castration model has been extensively used to study androgen regulation of gene expression in the ventral prostate, it is not clear whether all the gene expression changes post-castration are due to androgen depletion alone. To obtain insights into this, we performed differential display reverse transcriptase polymerase chain reaction (DD-RT-PCR) which resulted in the identification of castration and/or flutamide-regulated genes in the rat ventral prostate. These include clusterin, methionine adenosyl transferase II, and prostate-specific transcripts such as PBPC1BS, S100RVP and A7. While clusterin, PBPC1BS and methionine adenosyl transferase II are regulated by both castration and flutamide, S100 RVP and A7 are regulated by castration alone. Interestingly, we show that flutamide, unlike castration, does not induce apoptosis in the rat ventral prostate epithelium, which could be an underlying cause for the differential effects of castration and flutamide treatment. We propose that castration leads to enrichment and depletion of stromal and epithelial cell types, respectively, resulting in erroneous conclusions on some of the cell type-specific transcripts as being androgen regulated.

  20. The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer

    International Nuclear Information System (INIS)

    Testosterone binds to the androgen receptor in target tissue to mediate its effects. Variations in testosterone levels and androgen receptor activity may play a role in the etiology of breast cancer. Here, we review the epidemiologic evidence linking endogenous testosterone to breast cancer risk. Paradoxically, results from observational studies that have examined polymorphisms in the androgen receptor suggest that the low-activity androgen receptor increases breast cancer risk. We review the quality of this evidence and conclude with a discussion of how the androgen receptor and testosterone results coincide

  1. Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade

    OpenAIRE

    MOMOZONO, HIROYUKI; Miyake, Hideaki; TEI, HIROMOTO; Harada, Ken-ichi; Fujisawa, Masato

    2016-01-01

    The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With...

  2. PP005. Vitamin D depletion aggravates hypertension in transgenic rats

    DEFF Research Database (Denmark)

    Bjørkholt Andersen, Louise; Herse, Florian; Christesen, Henrik Thybo;

    2013-01-01

    overexpressing the human renin and angiotensinogen genes, group 1 (n=18) received vitamin D depleted chow; group 2 (n=15) standard chow and intraperitoneal paricalcitol at 800ng/kg thrice weekly; and group 3 (n=15) standard chow and vehicle injections. Blood pressure (tail cuff) and 24-h albuminuria were...... found between groups in mortality or proteinuria. CONCLUSION: Short-term vitamin D depletion aggravated hypertension and end-organ damage in a rat model of angiotensin II-induced hypertension. Short-term interventions with high-dose vitamin D analogues had no protective effect....

  3. Gastric inhibitory polypeptide analogues

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2002-01-01

    of GIP and GLP-1 receptors, the incretin effect is essential for normal glucose tolerance. In patients with type 2 diabetes mellitus it turns out that the incretin effect is severely impaired or abolished. The explanation seems to be that both the secretion of GLP-1 and the effect of GIP are impaired...... (whereas both the secretion of GIP and the effect of GLP-1 are near normal). The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances. The known genetic variations in the GIP receptor sequence are not associated with type 2 diabetes mellitus, but a defective insulinotropic...... and its analogues are attractive as therapeutic agents for type 2 diabetes mellitus, analogues of GIP are unlikely to be effective. On the other hand, GIP seems to play an important role in lipid metabolism, promoting the disposal of ingested lipids, and mice with a targeted deletion of the GIP receptor...

  4. Natural analogue working group

    International Nuclear Information System (INIS)

    A Natural Analogue Working Group was established by the Commission of the European Communities in 1985. The purpose of this group is to bring together modellers with earth scientists and others, so that maximum benefit can be obtained from natural analogue studies with a view to safe geological disposal of radioactive waste. The first meeting of this group was held in Brussels from November 5 to 7, 1985. The discussions mainly concerned the identification of the modellers' needs and of the earth scientists' capacity to provide for them. Following the debates, a written statement was produced by the Group; this document forms the core of the present Report. Notes and outlines of many of the presentations made are grouped in four appendixes. The valuable contribution of all those involved in the meeting is gratefully acknowledged

  5. Molecular mechanisms of androgen and antiandrogen action

    NARCIS (Netherlands)

    C.W. Kuil (Cor)

    1997-01-01

    textabstractThe steroid hormones testosterone and 5a-dihydrotestosterone (androgens) control the development, differentiation and function of male reproductive and accessory sex tissues, such as seminal vesicle, epididymis and prostate. Changes in cell properties induced by androgens require the pre

  6. The rat androgen receptor gene promoter

    NARCIS (Netherlands)

    W.M. Baarends (Willy); A.P.N. Themmen (Axel); L.J. Blok (Leen); P. Mackenbach (Petra); A.O. Brinkmann (Albert); D.N. Meijer (Dies); P.W. Faber; J. Trapman (Jan); J.A. Grootegoed (Anton)

    1990-01-01

    markdownabstractAbstract The androgen receptor (AR) is activated upon binding of testosterone or dihydrotestosterone and exerts regulatory effects on gene expression in androgen target cells. To study transcriptional regulation of the rat AR gene itself, the 5' genomic region of this gene was clon

  7. 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

  8. The Palmottu analogue project

    International Nuclear Information System (INIS)

    The report gives a summary of the results of investigations carried out in 1992 at the Palmottu natural analogue study site, which is a small U-Th mineralization in Nummi-Pusula, southwestern Finland. Additionally, the report includes several separate articles dealing with various aspects of the Palmottu Analogue Project: (1) deep groundwater flow, (2) interpretation of hydraulic connections, (3) characterization of groundwater colloids, (4) uranium mineral-groundwater equilibrium, (5) water-rock interaction and (6) modelling of in situ matrix diffusion. The Palmottu Analogue Project aims at a more profound understanding of radionuclide transport processes in fractured crystalline bedrock. The essential factors controlling transport are groundwater flow and interaction between water and rock. Accordingly, the study includes (1) structural interpretations partly based on geophysical measurements, (2) hydrological studies including hydraulic drill-hole measurements, (3) flow modelling, (4) hydrogeochemical characterization of groundwater, uranium chemistry and colloid chemistry, (5) mineralogical studies, (6) geochemical interpretation and modelling, (7) studies of radionuclide mobilization and retardation including matrix diffusion, and (8) modelling of uranium series data. Palaeohydrogeological aspects, due to the anticipated future glaciation of the Fennoscandian Shield, are of special interest. Quaternary sediments are studied to gain information on post-glacial migration in the overburden. (orig.)

  9. Quantum analogue computing.

    Science.gov (United States)

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  10. Intrinsic Depletion or Not

    DEFF Research Database (Denmark)

    Klösgen, Beate; Bruun, Sara; Hansen, Søren;

    with an AFM (2).    The intuitive explanation for the depletion based on "hydrophobic mismatch" between the obviously hydrophilic bulk phase of water next to the hydrophobic polymer. It would thus be an intrinsic property of all interfaces between non-matching materials. The detailed physical interaction path......  The presence of a depletion layer of water along extended hydrophobic interfaces, and a possibly related formation of nanobubbles, is an ongoing discussion. The phenomenon was initially reported when we, years ago, chose thick films (~300-400Å) of polystyrene as cushions between a crystalline...

  11. Intrinsic Depletion or Not

    DEFF Research Database (Denmark)

    Klösgen, Beate; Bruun, Sara; Hansen, Søren;

    with an AFM (2). The intuitive explanation for the depletion based on "hydrophobic mismatch" between the obviously hydrophilic bulk phase of water next to the hydrophobic polymer. It would thus be an intrinsic property of all interfaces between non-matching materials. The detailed physical interaction path......  The presence of a depletion layer of water along extended hydrophobic interfaces, and a possibly related formation of nanobubbles, is an ongoing discussion. The phenomenon was initially reported when we, years ago, chose thick films (~300-400Å) of polystyrene as cushions between a crystalline...

  12. Androgen receptor gene mutation, rearrangement, polymorphism.

    Science.gov (United States)

    Eisermann, Kurtis; Wang, Dan; Jing, Yifeng; Pascal, Laura E; Wang, Zhou

    2013-09-01

    Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.

  13. Shear-affected depletion interaction

    NARCIS (Netherlands)

    July, C.; Kleshchanok, D.; Lang, P.R.

    2012-01-01

    We investigate the influence of flow fields on the strength of the depletion interaction caused by disc-shaped depletants. At low mass concentration of discs, it is possible to continuously decrease the depth of the depletion potential by increasing the applied shear rate until the depletion force i

  14. Yolk androgens reduce offspring survival.

    OpenAIRE

    Sockman, K W; Schwabl, H

    2000-01-01

    Females may favour some offspring over others by differential deposition of yolk hormones. In American kestrels (Falco sparverius), we found that yolks of eggs laid late in the sequence of a clutch had more testosterone (T) and androstenedione (A4) than yolks of first-laid eggs. To investigate the effects of these yolk androgens on nestling 'fitness', we injected both T and A4 into the yolks of first-laid eggs and compared their hatching time, nestling growth and nestling survival with those ...

  15. 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.

  16. 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 transsex

  17. The androgen receptor in health and disease.

    Science.gov (United States)

    Matsumoto, Takahiro; Sakari, Matomo; Okada, Maiko; Yokoyama, Atsushi; Takahashi, Sayuri; Kouzmenko, Alexander; Kato, Shigeaki

    2013-01-01

    Androgens play pivotal roles in the regulation of male development and physiological processes, particularly in the male reproductive system. Most biological effects of androgens are mediated by the action of nuclear androgen receptor (AR). AR acts as a master regulator of downstream androgen-dependent signaling pathway networks. This ligand-dependent transcriptional factor modulates gene expression through the recruitment of various coregulator complexes, the induction of chromatin reorganization, and epigenetic histone modifications at target genomic loci. Dysregulation of androgen/AR signaling perturbs normal reproductive development and accounts for a wide range of pathological conditions such as androgen-insensitive syndrome, prostate cancer, and spinal bulbar muscular atrophy. In this review we summarize recent advances in understanding of the epigenetic mechanisms of AR action as well as newly recognized aspects of AR-mediated androgen signaling in both men and women. In addition, we offer a perspective on the use of animal genetic model systems aimed at eventually developing novel therapeutic AR ligands. PMID:23157556

  18. Methoxychalcone Inhibitors of Androgen Receptor Translocation and Function

    OpenAIRE

    Kim, Yeong Sang; Kumar, Vineet; Lee, Sunmin; Iwai, Aki; Neckers, Len; Malhotra, Sanjay V.; Trepel, Jane B

    2012-01-01

    Androgen receptor activity drives incurable castrate-resistant prostate cancer. All approved antiandrogens inhibit androgen receptor-driven transcription, and in addition the second-generation antiandrogen MDV3100 inhibits ligand-activated androgen receptor nuclear translocation, via an unknown mechanism. Here, we report methoxychalcones that lock the heat shock protein 90-androgen receptor complex in the cytoplasm in an androgen-non-responsive state, thus demonstrating a novel chemical scaff...

  19. Comparison of animal models for the evaluation of radiolabeled androgens

    International Nuclear Information System (INIS)

    Biodistribution of two 18F-labeled androgens and an 124I/125I-labeled androgen were studied in five androgen receptor (prostate) animal models with or lacking sex hormone binding globulin (SHBG). As models for androgen-receptor positive ovarian cancer, xenografts of three human ovarian cancer cell lines were tested in SCID mice. SHBG in the prostate model systems significantly affects the metabolism, clearance, and distribution of the radiolabeled androgens in several tissues, but ovarian cancer animal models were disappointing

  20. Androgen receptor: structure, role in prostate cancer and drug discovery

    OpenAIRE

    Tan, MH Eileen; Li, Jun; Xu, H. Eric; Melcher, Karsten; Yong, Eu-Leong

    2014-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer ...

  1. 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.

  2. Androgen and bone mass in men

    Institute of Scientific and Technical Information of China (English)

    AnnieW.C.Kung

    2003-01-01

    Androgens have multiple actions on the skeleton throughout life. Androgens promote skeletal growth and accumulation of minerals during puberty and adolescence and stimulate osteoblast but suppress osteoclast function,activity and lifespan through complex mechanisms. Also androgens increase periosteal bone apposition, resulting in larger bone size and thicker cortical bone in men. There is convincing evidence to show that aromatization to estrogens was an important pathway for mediating the action of testosterone on bone physiology. Estrogen is probably the dominant sex steroid regulating bone resorption in men, but both testosterone and estrogen are important in maintaining bone formation. ( Asian J Androl 2003 Jun; 5: 148-154)

  3. Androgen-responsive gene database: integrated knowledge on androgen-responsive genes.

    Science.gov (United States)

    Jiang, Mei; Ma, Yunsheng; Chen, Congcong; Fu, Xuping; Yang, Shu; Li, Xia; Yu, Guohua; Mao, Yumin; Xie, Yi; Li, Yao

    2009-11-01

    Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes. PMID:19762544

  4. Androgen-responsive gene database: integrated knowledge on androgen-responsive genes.

    Science.gov (United States)

    Jiang, Mei; Ma, Yunsheng; Chen, Congcong; Fu, Xuping; Yang, Shu; Li, Xia; Yu, Guohua; Mao, Yumin; Xie, Yi; Li, Yao

    2009-11-01

    Androgen signaling plays an important role in many biological processes. Androgen Responsive Gene Database (ARGDB) is devoted to providing integrated knowledge on androgen-controlled genes. Gene records were collected on the basis of PubMed literature collections. More than 6000 abstracts and 950 original publications were manually screened, leading to 1785 human genes, 993 mouse genes, and 583 rat genes finally included in the database. All the collected genes were experimentally proved to be regulated by androgen at the expression level or to contain androgen-responsive regions. For each gene important details of the androgen regulation experiments were collected from references, such as expression change, androgen-responsive sequence, response time, tissue/cell type, experimental method, ligand identity, and androgen amount, which will facilitate further evaluation by researchers. Furthermore, the database was integrated with multiple annotation resources, including National Center for Biotechnology Information, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway, to reveal the biological characteristics and significance of androgen-regulated genes. The ARGDB web site is mainly composed of the Browse, Search, Element Scan, and Submission modules. It is user friendly and freely accessible at http://argdb.fudan.edu.cn. Preliminary analysis of the collected data was performed. Many disease pathways, such as prostate carcinogenesis, were found to be enriched in androgen-regulated genes. The discovered androgen-response motifs were similar to those in previous reports. The analysis results are displayed in the web site. In conclusion, ARGDB provides a unified gateway to storage, retrieval, and update of information on androgen-regulated genes.

  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. PMID:18469090

  6. Radiolabeled somatostatin analogues

    International Nuclear Information System (INIS)

    Somatostatin is a naturally occurring tetradecapeptide that inhibits the secretion of many hormones. Large numbers of binding sites with high affinity for somatostatin have been reported in a variety of tumors. An octapeptide analogue of somatostatin, octreotide (Sandostatin), is currently used in the treatment of patients with somatostatin receptor-positive tumors to limit hormonal hyper secretion. In an effort to utilize the high specificity of octreotide for scintigraphic imaging of somatostatin receptor-positive tumors, a tyrosine derivative of octreotide was prepared and labeled with the radioactive isotope, I-123. While the early clinical results obtained with this radiopharmaceutical were encouraging, the I-123 labeling procedure proved cumbersome and variable. To circumvent these difficulties, researchers at University Hospital Rotterdam (Holland) and Sandoz Research Institute (Switzerland) developed an In-111 labeled analogue of octreotide. This radiopharmaceutical is easy to prepare and has proven to be even more effective than the I-123 derivative in the scintigraphic imaging of tumors. These radiopharmaceutical developments and clinical observations are discussed in light of their relevance to the generation of new radiolabeled peptides for the diagnosis and potential radiotherapy of cancer. (authors). 30 refs., 5 figs

  7. Depletion of intense fields

    CERN Document Server

    Seipt, D; Marklund, M; Bulanov, S S

    2016-01-01

    The interaction of charged particles and photons with intense electromagnetic fields gives rise to multi-photon Compton and Breit-Wheeler processes. These are usually described in the framework of the external field approximation, where the electromagnetic field is assumed to have infinite energy. However, the multi-photon nature of these processes implies the absorption of a significant number of photons, which scales as the external field amplitude cubed. As a result, the interaction of a highly charged electron bunch with an intense laser pulse can lead to significant depletion of the laser pulse energy, thus rendering the external field approximation invalid. We provide relevant estimates for this depletion and find it to become important in the interaction between fields of amplitude $a_0 \\sim 10^3$ and electron bunches with charges of the order of nC.

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

    OpenAIRE

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

    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-ba...

  9. Capital expenditure and depletion

    Energy Technology Data Exchange (ETDEWEB)

    Rech, O.; Saniere, A

    2003-07-01

    In the future, the increase in oil demand will be covered for the most part by non conventional oils, but conventional sources will continue to represent a preponderant share of the world oil supply. Their depletion represents a complex challenge involving technological, economic and political factors. At the same time, there is reason for concern about the decrease in exploration budgets at the major oil companies. (author)

  10. Capital expenditure and depletion

    International Nuclear Information System (INIS)

    In the future, the increase in oil demand will be covered for the most part by non conventional oils, but conventional sources will continue to represent a preponderant share of the world oil supply. Their depletion represents a complex challenge involving technological, economic and political factors. At the same time, there is reason for concern about the decrease in exploration budgets at the major oil companies. (author)

  11. Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs).

    Science.gov (United States)

    Gao, Wenqing; Dalton, James T

    2007-03-01

    Selective androgen receptor modulators (SARMs) are a novel class of androgen receptor (AR) ligands that might change the future of androgen therapy dramatically. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens to osteoporosis, muscle wasting, male contraception and diseases of the prostate. Mechanistic studies with currently available SARMs will help to define the contributions of differential tissue distribution, tissue-specific expression of 5alpha-reductase, ligand-specific regulation of gene expression and AR interactions with tissue-specific coactivators to their observed tissue selectivity, and lead to even greater expansion of selective anabolic therapies.

  12. ANABOLIC ANDROGENIC STEROIDS AND DEPENDENCE

    Directory of Open Access Journals (Sweden)

    IHSAN SARI

    2010-12-01

    Full Text Available Anabolic androgenic steroids are used for sportive, cosmetic, therapeutic and occupational reasons and there are many side effects reported (George, 2005; Nieminen et al., 1996; O'Sullivan et al., 2000. Prevalence of anabolic steroids’ use also indicates the importance of this topic. Moreover, it is now known that use of anabolic steroids could lead to dependence which could be psychological or/and physiological (Copeland et al., 2000. It isimportant to know about all aspects of anabolic steroids including dependence. Therefore, this study has attempted to give an insight into use of anabolic steroids and dependence. The discussion will focus on prevalence, reasons, and side effects of use and physiological and psychological dependence

  13. 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.

  14. Genetics Home Reference: androgen insensitivity syndrome

    Science.gov (United States)

    ... Patient Support and Advocacy Resources (3 links) National Organization for Rare Disorders Resolve: The ... Sources for This Page Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol. 2001 Jun 20;179(1-2):105- ...

  15. Ozone-depleting Substances (ODS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — This site includes all of the ozone-depleting substances (ODS) recognized by the Montreal Protocol. The data include ozone depletion potentials (ODP), global...

  16. A Short Term Analogue Memory

    DEFF Research Database (Denmark)

    Shah, Peter Jivan

    1992-01-01

    A short term analogue memory is described. It is based on a well-known sample-hold topology in which leakage currents have been minimized partly by circuit design and partly by layout techniques. Measurements on a test chip implemented in a standard 2.4 micron analogue CMOS process show a droop...

  17. Vorticity in analogue gravity

    CERN Document Server

    Cropp, Bethan; Turcati, Rodrigo

    2015-01-01

    In the analogue gravity framework, the acoustic disturbances in a moving fluid can be described by an equation of motion identical to a relativistic scalar massless field propagating in a curved spacetime. This description is possible only when the fluid under consideration is barotropic, inviscid and irrotational. In this case, the propagation of the perturbations is governed by an acoustic metric which depends algebrically on the local speed of sound, density and the background flow velocity, the latter assumed to be vorticity free. In this work we provide an straightforward extension in order to go beyond the irrotational constraint. Using a charged --- relativistic and non-relativistic --- Bose--Einstein condensate as a physical system, we show that in the low momentum limit and performing the eikonal approximation we can derive a d'Alembertian equation of motion for the charged phonons where the emergent acoustic metric depends on a flow velocity in the presence of vorticity.

  18. Alligator Rivers analogue project

    International Nuclear Information System (INIS)

    Australian Nuclear Science and Technology Organization has extensively evaluated uranium ore bodies in the Alligator Rivers Uranium Province in Australia as analogues of radioactive waste repositories. The work was extended for a three-year program as an international project based on the Koongarra uranium deposit and sponsored by the OECD Nuclear Energy Agency. The technical program comprises six major sub-projects involving modelling and experimental work: modelling of radionuclide migration; hydrogeology of the Koongarra uranium deposit; uranium/thorium series disequilibria studies; groundwater and colloid studies; fission product studies; transuranic nuclide studies; an outline of the technical programs and a summary of progress in the technical sub-projects is given. This is followed by a series of technical reports which briefly describe current research tasks, and which have been separately indexed

  19. Androgen receptor expression in gastrointestinal stromal tumor.

    Science.gov (United States)

    Lopes, Lisandro F; Bacchi, Carlos E

    2009-03-01

    The aim of this study was to evaluate the expression of estrogen, progesterone, and androgen receptors in a large series of gastrointestinal stromal tumors. Clinical and pathologic data were reviewed in 427 cases of gastrointestinal stromal tumor and the expression of such hormone receptors was investigated by immunohistochemistry using tissue microarray technique. All tumors were negative for estrogen receptor expression. Progesterone and androgen receptors expression was observed in 5.4% and 17.6% of tumors, respectively. We found the higher average age at diagnosis, the lower frequency of tumors located in the small intestine, and the higher frequency of extragastrointestinal tumors to be statistically significant in the group of tumors with androgen receptor expression in contrast to the group showing no androgen receptor expression. There was no statistic difference between such groups regarding sex, tumor size, mitotic count, cell morphology, and risk of aggressive behavior. Considering that the expression of androgen receptors in gastrointestinal stromal tumors is not negligible, further studies are encouraged to establish the role of androgen deprivation therapy for gastrointestinal stromal tumors.

  20. Stratospheric ozone depletion

    International Nuclear Information System (INIS)

    The amount of stratospheric ozone and the reduction of the ozone layer vary according to seasons and latitudes. At present total and vertical ozone is monitored over all Austria. The mean monthly ozone levels between 1994 and 2000 are presented. Data on stratospheric ozone and UV-B radiation are published daily on the home page http: www.lebesministerium.at. The use of ozone depleting substances such as chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) is provided. Besides, the national measures taken to reduce their use. Figs. 2, Tables 2. (nevyjel)

  1. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  2. Cardiovascular physiology of androgens and androgen testosterone therapy in postmenopausal women.

    Science.gov (United States)

    Ling, Shanhong; Komesaroff, Paul A; Sudhir, Krishnankutty

    2009-03-01

    Women before menopause are at relatively lower risk of cardiovascular disease (CVD) compared with age-matched men and after menopause this gender advantage disappears. Androgen has been known to be an independent factor contributing to the higher male susceptibility to CVD, through adverse effects on lipids, blood pressure, and glucose metabolism. High androgen levels also contribute to CVD development in women with polycystic ovary syndrome as well as androgen abusing athletes and body builders. On the other hand, decline in androgen levels, as a result of ageing in men, is associated with hypertension, diabetes and atherosclerosis. Postmenopausal women, particularly those with oophorectomy are generally in low levels of sex hormones and androgen insufficiency is independently associated with the higher incidence of atherosclerosis in postmenopausal women. Androgen testosterone therapy (ATT) has been commonly used to improve well-being and libido in aging men with low androgen levels. The therapy has been demonstrated also to effectively reduce atherogenesis in these people. The use of ATT in postmenopausal women has increased in recent years and to date, however, the cardiovascular benefits of such therapy in these women remain uncertain. This review focuses on research regarding the impact of endogenous androgens and ATT on the cardiovascular physiology and CVD development in postmenopausal women.

  3. Social modulation of androgens in male birds.

    Science.gov (United States)

    Goymann, Wolfgang

    2009-09-01

    Most seasonally reproducing vertebrates show pronounced changes in testosterone levels throughout the year. The Challenge Hypothesis [Wingfield, J.C., Hegner, R.E., Dufty, A.M., Ball, G. F., 1990. The "challenge hypothesis": theoretical implications for patterns of testosterone secretion, mating systems, and breeding strategies. Am. Nat. 136, 829-846] predicts that seasonal patterns in circulating androgen concentrations vary as a function of mating system, male-male aggression and paternal care. In most comparative studies, the predictions of the Challenge Hypothesis have been tested primarily by calculating the ratio between breeding peak and breeding baseline testosterone concentrations, using this ratio as a proxy for the effect that social interactions have on testosterone levels (androgen responsiveness R). Recently, we suggested that it is preferable to separate the seasonal testosterone response (R(season)) from the androgen responsiveness to male-male interactions (R(male-male)), as these two measures do not correlate and can differ both in magnitude and direction [Goymann, W., Landys, M.M., Wingfield, J.C., 2007. Distinguishing seasonal androgen responses from male-male androgen responsiveness-revisiting the Challenge Hypothesis. Horm. Behav. 51, 463-476]. Here, I discuss several methodological and ecological factors that may explain why R(season) and R(male-male) differ. Furthermore, I describe three other kinds of androgen responsiveness, namely the androgen responsiveness of males to receptive females (R(male-female)), to non-social environmental cues (R(environment)), and the potential androgen responsiveness (R(potential)). The latter is measured before and after an injection of gonadotropin releasing hormone (GnRH), which typically leads to a maximal release of testosterone from the testes. I argue that separation of different kinds of androgen responsiveness and putting them into context with the natural history and ecology of a study species may

  4. Natural Analogues of CO2 Geological Storage

    International Nuclear Information System (INIS)

    Geological storage of carbon dioxide is nowadays, internationally considered as the most effective method for greenhouse gas emission mitigation, in order to minimize the global climate change universally accepted. Nevertheless, the possible risks derived of this long-term storage have a direct influence on its public acceptance. Among the favourable geological formations to store CO2, depleted oil and gas fields, deep saline reservoirs, and unamiable coal seams are highlighted. One of the most important objectives of the R and D projects related to the CO2 geological storage is the evaluation of the CO2 leakage rate through the above mentioned geological formations. Therefore, it is absolutely necessary to increase our knowledge on the interaction among CO2, storage and sealing formations, as well as on the flow paths and the physical resistance of the sealing formation. The quantification of the CO2 leakage rate is essential to evaluate the effects on the human and animal health, as well as for the ecosystem and water quality. To achieve these objectives, the study of the natural analogues is very useful in order to know the natural leakage rate to the atmosphere, its flow paths, the physical, chemical and mineralogical modifications due to the long term interaction processes among the CO2 and the storage and sealing formations, as well as the effects on the groundwaters and ecosystems. In this report, we have tried to summarise the main characteristics of the natural reservoirs and surficial sources of CO2, which are both natural analogues of the geological storage and CO2 leakage, studied in EEUU, Europe and Australia. The main objective of this summary is to find the possible applications for long-term risk prediction and for the performance assessment by means of conceptual and numerical modelling, which will allow to validate the predictive models of the CO2 storage behaviour, to design and develop suitable monitoring techniques to control the CO2 behaviour

  5. Selective androgen receptor modulators as improved androgen therapy for advanced breast cancer.

    Science.gov (United States)

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2014-11-01

    Androgens were at one time a therapeutic mainstay in the treatment of advanced breast cancer. Despite comparable efficacy, SERMs and aromatase inhibitors eventually became the therapies of choice due to in part to preferred side-effect profiles. Molecular characterization of breast tumors has revealed an abundance of androgen receptor expression but the choice of an appropriate androgen receptor ligand (agonist or antagonist) has been confounded by multiple conflicting reports concerning the role of the receptor in the disease. Modern clinical efforts have almost exclusively utilized antagonists. However, the recent clinical development of selective androgen receptor modulators with greatly improved side-effect profiles has renewed interest in androgen agonist therapy for advanced breast cancer.

  6. Androgen-induced cell migration: role of androgen receptor/filamin A association.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Androgen receptor (AR controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK, paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. CONCLUSIONS/SIGNIFICANCE: The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development

  7. Riddle of depleted uranium

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is the waste product of uranium enrichment from the manufacturing of fuel rods for nuclear reactors in nuclear power plants and nuclear power ships. DU may also results from the reprocessing of spent nuclear reactor fuel. Potentially DU has both chemical and radiological toxicity with two important targets organs being the kidney and the lungs. DU is made into a metal and, due to its availability, low price, high specific weight, density and melting point as well as its pyrophoricity; it has a wide range of civilian and military applications. Due to the use of DU over the recent years, there appeared in some press on health hazards that are alleged to be due to DU. In these paper properties, applications, potential environmental and health effects of DU are briefly reviewed

  8. Depleted uranium: Metabolic disruptor?

    International Nuclear Information System (INIS)

    The presence of uranium in the environment can lead to long-term contamination of the food chain and of water intended for human consumption and thus raises many questions about the scientific and societal consequences of this exposure on population health. Although the biological effects of chronic low-level exposure are poorly understood, results of various recent studies show that contamination by depleted uranium (DU) induces subtle but significant biological effects at the molecular level in organs including the brain, liver, kidneys and testicles. For the first time, it has been demonstrated that DU induces effects on several metabolic pathways, including those metabolizing vitamin D, cholesterol, steroid hormones, acetylcholine and xenobiotics. This evidence strongly suggests that DU might well interfere with many metabolic pathways. It might thus contribute, together with other man-made substances in the environment, to increased health risks in some regions. (authors)

  9. 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.

  10. Androgen Control in Prostate Cancer.

    Science.gov (United States)

    Pelekanou, Vasiliki; Castanas, Elias

    2016-10-01

    Research on prostate cancer has extensively advanced in the past decade, through an improved understanding for its genetic basis and risk-stratification. Molecular classification of prostate cancer into distinct subtypes and the recognition of new histologic entities promise the development of tailored-made management strategies of patients. Nowadays, various alternatives are available for clinical management of localized disease ranging from observation alone through radical prostatectomy. In patients with castration-resistant prostate cancer, the approval of new drugs for the management of metastatic disease has offered promising results improving the survival of these patients. In this context, androgen receptors (AR) remain at the epicenter of prostate cancer research holding a prominent role in the biology and therapeutic regimens of prostate cancer. As many of castration-resistant tumors retain hormone-responsiveness, AR is a clinical relevant, druggable target. However, AR paradoxically remains neglected as a prostate cancer biomarker. The great advancements in prostate cancer preclinical and clinical research, imply further improvement in clinical and translational data, for patient selection and treatment optimization. For a precision medicine-guided clinical management of prostate cancer, AR evaluation has to be implemented in companion and complementary diagnostics, as discussed here. J. Cell. Biochem. 117: 2224-2234, 2016. © 2016 Wiley Periodicals, Inc. PMID:27104784

  11. Androgen actions on the human hair follicle: perspectives.

    Science.gov (United States)

    Inui, Shigeki; Itami, Satoshi

    2013-03-01

    Androgens stimulate beard growth but suppress hair growth in androgenetic alopecia (AGA). This condition is known as 'androgen paradox'. Human pilosebaceous units possess enough enzymes to form the active androgens testosterone and dihydrotestosterone. In hair follicles, 5α-reductase type 1 and 2, androgen receptors (AR) and AR coactivators can regulate androgen sensitivity of dermal papillae (DP). To regulate hair growth, androgens stimulate production of IGF-1 as positive mediators from beard DP cells and of TGF-β1, TGF-β2, dickkopf1 and IL-6 as negative mediators from balding DP cells. In addition, androgens enhance inducible nitric oxide synthase from occipital DP cells and stem cell factor for positive regulation of hair growth in beard and negative regulation of balding DP cells. Moreover, AGA involves crosstalk between androgen and Wnt/β-catenin signalling. Finally, recent data on susceptibility genes have provided us with the impetus to investigate the molecular pathogenesis of AGA. PMID:23016593

  12. 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....

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

    International Nuclear Information System (INIS)

    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

  14. Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

    Science.gov (United States)

    Ye, Fan; McCoy, Sean C; Ross, Heather H; Bernardo, Joseph A; Beharry, Adam W; Senf, Sarah M; Judge, Andrew R; Beck, Darren T; Conover, Christine F; Cannady, Darryl F; Smith, Barbara K; Yarrow, Joshua F; Borst, Stephen E

    2014-09-01

    Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth. PMID:24928725

  15. Androgen therapy and atherosclerotic cardiovascular disease

    Directory of Open Access Journals (Sweden)

    K-CY McGrath

    2008-02-01

    Full Text Available K-CY McGrath1, LS McRobb1,2, AK Heather1,21Heart Research Institute, Camperdown, NSW, Australia; 2Discipline of Medicine, University of Sydney, Sydney, NSW, AustraliaAbstract: Cardiovascular disease (CVD remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie.

  16. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines

    OpenAIRE

    Higuchi, M; Kudo, T; Suzuki, S.; Evans, TT; Sasaki, R.; Wada, Y; Shirakawa, T.; Sawyer, JR; Gotoh, A

    2006-01-01

    Prostate cancer progresses from an androgen-dependent to androgen-independent stage after androgen ablation therapy. Mitochondrial DNA plays a role in cell death and metastatic competence. Further, heteroplasmic large-deletion mitochondrial DNA is verycommon in prostate cancer. To investigate the role of mitochondrial DNA in androgen dependence of prostate cancers, we tested the changes of normal and deleted mitochondrial DNA in accordance with the progression of prostate cancer. We demonstra...

  17. 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.

  18. The Toxicity of Depleted Uranium

    OpenAIRE

    Wayne Briner

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a c...

  19. Computational Investigation on the Allosteric Modulation of Androgen Receptor

    Institute of Scientific and Technical Information of China (English)

    OU Min-Rui; LI Jun-Qian

    2012-01-01

    Androgens have similar structures with different biological activities. To identify molecular determinants responsible for the activity difference, we have docked six steroidal androgens to the binding site or the surface of androgen receptor by using molecular docking with computational investigation. The energy was calculated respectively based on the QM (quantum mechanics) and MM (molecular mechanics) methods. The result shows that the allosteric modulation of androgen receptor plays an important role in the binding process between androgens and receptor. The open state receptor is less stable than the close state one, but the latter is more favorable for binding with androgens. It is worthy of note that when the androgen receptors binding or without binding with androgen are in close state, they are difficult to return to their open state. This phenomenon is an exception of the well known two-state model theory in which the two states are reversible. Whether the internal of close state androgen receptor has a combination of androgen or not, the androgen receptor surface can be combined with another androgen, and their surface binding energies could be very close. The result is consistent with the experimental observations, but this phenomenon of continuous combination from open state is also an exception of the two-state model theory.

  20. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  1. Depleted zinc: Properties, application, production

    International Nuclear Information System (INIS)

    The addition of ZnO, depleted in the Zn-64 isotope, to the water of boiling water nuclear reactors lessens the accumulation of Co-60 on the reactor interior surfaces, reduces radioactive wastes and increases the reactor service-life because of the inhibitory action of zinc on inter-granular stress corrosion cracking. To the same effect depleted zinc in the form of acetate dihydrate is used in pressurized water reactors. Gas centrifuge isotope separation method is applied for production of depleted zinc on the industrial scale. More than 20 years of depleted zinc application history demonstrates its benefits for reduction of NPP personnel radiation exposure and combating construction materials corrosion.

  2. Depleted zinc: Properties, application, production.

    Science.gov (United States)

    Borisevich, V D; Pavlov, A V; Okhotina, I A

    2009-01-01

    The addition of ZnO, depleted in the Zn-64 isotope, to the water of boiling water nuclear reactors lessens the accumulation of Co-60 on the reactor interior surfaces, reduces radioactive wastes and increases the reactor service-life because of the inhibitory action of zinc on inter-granular stress corrosion cracking. To the same effect depleted zinc in the form of acetate dihydrate is used in pressurized water reactors. Gas centrifuge isotope separation method is applied for production of depleted zinc on the industrial scale. More than 20 years of depleted zinc application history demonstrates its benefits for reduction of NPP personnel radiation exposure and combating construction materials corrosion.

  3. SIRT1 IS REQUIRED FOR ANTAGONIST-INDUCED TRANSCRIPTIONAL REPRESSION OF ANDROGEN-RESPONSIVE GENES BY THE ANDROGEN RECEPTOR

    OpenAIRE

    Dai, Yan; Ngo, Duyen; Forman, Lora W.; Qin, David C.; Jacob, Johanna; Faller, Douglas V

    2007-01-01

    Androgen antagonists or androgen deprivation is a primary therapeutic modality for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which the androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this report, we demonstrate that SIRT1, a nicotinamide adenosine dinucleotide-dependent histone deacetylase linked to the regulation of ...

  4. Distinguishing seasonal androgen responses from male-male androgen responsiveness-revisiting the Challenge Hypothesis.

    Science.gov (United States)

    Goymann, Wolfgang; Landys, Meta M; Wingfield, John C

    2007-04-01

    Androgen levels show strong patterns throughout the year in male vertebrates and play an important role in the seasonal modulation of the frequency, intensity and persistence of aggression. The Challenge Hypothesis (Wingfield, J.C., Hegner, R.E., Dufty, A.M., Ball, G.F., 1990. The "Challenge Hypothesis": Theoretical implications for patterns of testosterone secretion, mating systems, and breeding strategies. Am. Nat. 136, 829-846) predicts that seasonal patterns in androgen levels vary as a function of mating system, male-male aggression and paternal care. Although many studies have addressed these predictions, investigators have often assumed that the ratio of the breeding season maximum and breeding baseline concentrations (termed "androgen responsiveness") reflects hormonal responses due to social stimulation. However, increasing evidence suggests that seasonal androgen elevations are not necessarily caused by social interactions between males. Here, we separate the seasonal androgen response (R(seasonal)) and the androgen responsiveness to male-male competition (R(male-male)) to begin to distinguish between different kinds of hormonal responses. We demonstrate that R(seasonal) and R(male-male) are fundamentally different and should be treated as separate variables. Differences are particularly evident in single-brooded male birds that show no increase in plasma androgen levels during simulated territorial intrusions (STIs), even though R(seasonal) is elevated. In multiple-brooded species, STIs typically elicit a rise in androgens. We relate these findings to the natural history of single- and multiple-brooded species and suggest a research approach that could be utilized to increase our understanding of the factors that determine different types of androgen responses. This approach does not only include R(seasonal) and R(male-male), but also the androgen responsiveness to receptive females (R(male-female)) and to non-social environmental cues (R

  5. Mutation of androgen receptor N-terminal phosphorylation site Tyr-267 leads to inhibition of nuclear translocation and DNA binding.

    Directory of Open Access Journals (Sweden)

    Mehmet Karaca

    Full Text Available Reactivation of androgen receptor (AR may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain. Y267F and Y363F mutants showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The Y363F mutant was less severely affected than the Y267F mutant. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. These results support the concept that phosphorylation of Tyr-267, and to a lesser extent Tyr-363, is required for AR nuclear translocation and recruitment and DNA binding and provide a rationale for development of novel approaches to inhibit AR activity.

  6. Mutation of androgen receptor N-terminal phosphorylation site Tyr-267 leads to inhibition of nuclear translocation and DNA binding.

    Science.gov (United States)

    Karaca, Mehmet; Liu, Yuanbo; Zhang, Zhentao; De Silva, Dinuka; Parker, Joel S; Earp, H Shelton; Whang, Young E

    2015-01-01

    Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain. Y267F and Y363F mutants showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The Y363F mutant was less severely affected than the Y267F mutant. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. These results support the concept that phosphorylation of Tyr-267, and to a lesser extent Tyr-363, is required for AR nuclear translocation and recruitment and DNA binding and provide a rationale for development of novel approaches to inhibit AR activity.

  7. Using Anabolic Androgenic Steroids in Sport

    Directory of Open Access Journals (Sweden)

    Sefa Lök

    2010-12-01

    Full Text Available It is known that sportsmen especially youngers who engaged in athletism, weight lifting and body building sport have beenusing ‘‘Anabolic Androgenic Steroid’’ (AAS intensively for purpose of doping during world sport history. Used dopingsubstances to increase sport performance differ from sport branches. In some sport branches, it is used to diminish neuralstress while in other sport branches it is used to increase force, endurance and resistance against exhaustion. Today amongsportsmen using ergogenic substances to increase rivalry and physical performance for purpose of doping are increased. Inthis study using anabolic androgenic steroids in sports will be assessed.

  8. The Toxicity of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Wayne Briner

    2010-01-01

    Full Text Available Depleted uranium (DU is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed.

  9. Depletable resources and the economy.

    NARCIS (Netherlands)

    Heijman, W.J.M.

    1991-01-01

    The subject of this thesis is the depletion of scarce resources. The main question to be answered is how to avoid future resource crises. After dealing with the complex relation between nature and economics, three important concepts in relation with resource depletion are discussed: steady state, ti

  10. Stratospheric ozone depletion.

    Science.gov (United States)

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  11. A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance.

    OpenAIRE

    M. Marcelli; Zoppi, S; Grino, P B; Griffin, J E; Wilson, J. D.; McPhaul, M J

    1991-01-01

    Androgen resistance is associated with a wide range of quantitative and qualitative defects in the androgen receptor. However, fibroblast cultures from approximately 10% of patients with the clinical, endocrine, and genetic features characteristic of androgen resistance express normal quantities of apparently normal androgen receptor in cultured genital skin fibroblasts (receptor-positive androgen resistance). We have analyzed the androgen receptor gene of one patient (P321) with receptor-pos...

  12. A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

    Science.gov (United States)

    Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

    2008-12-01

    For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

  13. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer

    OpenAIRE

    Fumio Ishizaki; Tsutomu Nishiyama; Takashi Kawasaki; Yoshimichi Miyashiro; Noboru Hara; Itsuhiro Takizawa; Makoto Naito; Kota Takahashi

    2013-01-01

    Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD1...

  14. Different types of androgen receptor mutations in patients with complete androgen insensitivity syndrome

    OpenAIRE

    Shao, Jialiang; Hou, Jiangang; Li, Bingkun; Li, Dongyang; Zhang, Ning; Wang, Xiang

    2015-01-01

    Mutations of androgen receptor (AR) are the most frequent cause of 46, XY disorders of sex development and associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome (CAIS)) to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). From 2009 to 2012, two young Chinese female individuals with CAIS from two families were referred to our hospital due to primary amenorrhea. Defects in testo...

  15. Evidence for an androgen receptor in porcine Leydig cells

    International Nuclear Information System (INIS)

    Cytosol and nuclear androgen receptor concentrations were measured in freshly prepared and cultured Leydig cells of immature pig testis with exchange assays using (3H)methyltrienolone as labelled ligand. Androgen receptors in Leydig cells had high affinity for (3H)methyltrienolone and sterios binding specificity typical of an androgen receptor. The mean receptor concentrations were 76 fmol/mg protein and 210 fmol/mg DNA for cytosol and nuclei, respectively. In sucrose gradients, cytosol androgen receptors sedimented in the 4 S region. The cells maintained androgen receptors under culture conditions. Exposure of cultured cells to (3H)methyltrienolone (10 nmol/l) resulted in accumulation of androgen receptors in the nuclei with maximal uptake by 1 h. We conclude that methyltrienolone binding sites with characteristics of androgen receptors were idenfified in both cytosol and nuclei of porcine Leydig cells. (author)

  16. Androgen receptor modulators: a marriage of chemistry and biology.

    Science.gov (United States)

    McEwan, Iain J

    2013-06-01

    Androgenic steroids are important for male development in utero and secondary sexual characteristics at puberty. In addition, androgens play a role in non-reproductive tissues, such as bone and muscle in both sexes. The actions of the androgens testosterone and dihydrotestosterone are mediated by a single receptor protein, the androgen receptor. Over the last 60-70 years there has been considerable research interest in the development of inhibitors of androgen receptor for the management of diseases such as prostate cancer. However, more recently, there is also a growing appreciation of the need for selective androgen modulators that would demonstrate tissue-selective agonist or antagonist activity. The chemistry and biology of selective agonists, antagonists and selective androgen receptor modulators will be discussed in this review.

  17. LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth and invasion

    OpenAIRE

    Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J.; Ferrari, Anna; Lee, Peng

    2009-01-01

    A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LE...

  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. PMID:26206424

  19. 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.

  20. Dihydrotestosterone Administration Does Not Increase Intraprostatic Androgen Concentrations or Alter Prostate Androgen Action in Healthy Men: A Randomized-Controlled Trial

    OpenAIRE

    Page, Stephanie T; Lin, Daniel W.; Mostaghel, Elahe A.; Marck, Brett T.; Wright, Jonathan L; Wu, Jennifer; Amory, John K.; Peter S Nelson; Matsumoto, Alvin M.

    2010-01-01

    Exogenous dihydrotestosterone (DHT), which substantially raises serum DHT and lowers serum T, does not significantly alter intraprostatic androgen levels or androgen-responsive gene expression in healthy men.

  1. Interactions of methoxyacetic acid with androgen receptor

    International Nuclear Information System (INIS)

    Endocrine disruptive compounds (EDC) alter hormone-stimulated, nuclear receptor-dependent physiological and developmental processes by a variety of mechanisms. One recently identified mode of endocrine disruption is through hormone sensitization, where the EDC modulates intracellular signaling pathways that control nuclear receptor function, thereby regulating receptor transcriptional activity indirectly. Methoxyacetic acid (MAA), the primary, active metabolite of the industrial solvent ethylene glycol monomethyl ether and a testicular toxicant, belongs to this EDC class. Modulation of nuclear receptor activity by MAA could contribute to the testicular toxicity associated with MAA exposure. In the present study, we evaluated the impact of MAA on the transcriptional activity of several nuclear receptors including the androgen receptor (AR), which plays a pivotal role in the development and maturation of spermatocytes. AR transcriptional activity is shown to be increased by MAA through a tyrosine kinase signaling pathway that involves PI3-kinase. In a combinatorial setting with AR antagonists, MAA potentiated the AR response without significantly altering the EC50 for androgen responsiveness, partially alleviating the antagonistic effect of the anti-androgens. Finally, MAA treatment of TM3 mouse testicular Leydig cells markedly increased the expression of Cyp17a1 and Shbg while suppressing Igfbp3 expression by ∼ 90%. Deregulation of these genes may alter androgen synthesis and action in a manner that contributes to MAA-induced testicular toxicity.

  2. Leverpatologi associeret med anaboliske-androgene steroider

    DEFF Research Database (Denmark)

    Søe, Katrine; Søe, Martin Jensen; Gluud, C N

    1994-01-01

    This review regards the liver damaging side-effects of anabolic-androgenic steroids (AAS). It seems that AAS can cause development of peliosis hepatis, subcellular changes of hepatocytes, hepatocellular hyperplasia and hepatocellular adenomas. On the other hand, it has not been convincingly proved...

  3. 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 ...

  4. Testing fully depleted CCD

    Science.gov (United States)

    Casas, Ricard; Cardiel-Sas, Laia; Castander, Francisco J.; Jiménez, Jorge; de Vicente, Juan

    2014-08-01

    The focal plane of the PAU camera is composed of eighteen 2K x 4K CCDs. These devices, plus four spares, were provided by the Japanese company Hamamatsu Photonics K.K. with type no. S10892-04(X). These detectors are 200 μm thick fully depleted and back illuminated with an n-type silicon base. They have been built with a specific coating to be sensitive in the range from 300 to 1,100 nm. Their square pixel size is 15 μm. The read-out system consists of a Monsoon controller (NOAO) and the panVIEW software package. The deafualt CCD read-out speed is 133 kpixel/s. This is the value used in the calibration process. Before installing these devices in the camera focal plane, they were characterized using the facilities of the ICE (CSIC- IEEC) and IFAE in the UAB Campus in Bellaterra (Barcelona, Catalonia, Spain). The basic tests performed for all CCDs were to obtain the photon transfer curve (PTC), the charge transfer efficiency (CTE) using X-rays and the EPER method, linearity, read-out noise, dark current, persistence, cosmetics and quantum efficiency. The X-rays images were also used for the analysis of the charge diffusion for different substrate voltages (VSUB). Regarding the cosmetics, and in addition to white and dark pixels, some patterns were also found. The first one, which appears in all devices, is the presence of half circles in the external edges. The origin of this pattern can be related to the assembly process. A second one appears in the dark images, and shows bright arcs connecting corners along the vertical axis of the CCD. This feature appears in all CCDs exactly in the same position so our guess is that the pattern is due to electrical fields. Finally, and just in two devices, there is a spot with wavelength dependence whose origin could be the result of a defectous coating process.

  5. Age dependence of myosin heavy chain transitions induced by creatine depletion in rat skeletal muscle

    Science.gov (United States)

    Adams, Gregory R.; Baldwin, Kenneth M.

    1995-01-01

    This study was designed to test the hypothesis that myosin heavy chain (MHC) plasticity resulting from creatine depletion is an age-dependent process. At weaning (age 28 days), rat pups were placed on either standard rat chow (normal diet juvenile group) or the same chow supplemented with 1% wt/wt of the creatine analogue beta-guanidinopropionic acid (creatine depletion juvenile (CDJ) group). Two groups of adult rats (age approximately 8 wk) were placed on the same diet regimens (normal diet adult and creatine depletion adult (CDA) groups). After 40 days (CDJ and normal diet juvenile groups) and 60 days (CDA and normal diet adult groups), animals were killed and several skeletal muscles were removed for analysis of creatine content or MHC ditribution. In the CDJ group, creatine depletion (78%) was accompanied by significant shifts toward expression of slower MHC isoforms in two slow and three fast skeletal muscles. In contrast, creatine depletion in adult animals did not result in similar shifts toward slow MHC isoform expression in either muscle type. The results of this study indicate that there is a differential effect of creatine depletion on MHC tranitions that appears to be age dependent. These results strongly suggest that investigators contemplating experimental designs involving the use of the creatine analogue beta-guanidinopropionic acid should consider the age of the animals to be used.

  6. Introduction to electronic analogue computers

    CERN Document Server

    Wass, C A A

    1965-01-01

    Introduction to Electronic Analogue Computers, Second Revised Edition is based on the ideas and experience of a group of workers at the Royal Aircraft Establishment, Farnborough, Hants. This edition is almost entirely the work of Mr. K. C. Garner, of the College of Aeronautics, Cranfield. As various advances have been made in the technology involving electronic analogue computers, this book presents discussions on the said progress, including some acquaintance with the capabilities of electronic circuits and equipment. This text also provides a mathematical background including simple differen

  7. Opioid-induced androgen deficiency (OPIAD).

    Science.gov (United States)

    Smith, Howard S; Elliott, Jennifer A

    2012-07-01

    Opioid therapy is one of the most effective forms of analgesia currently in use. In the past few decades, the use of opioids as a long-term treatment for chronic pain has increased dramatically. Accompanying this upsurge in the use of long-term opioid therapy has been an increase in the occurrence of opioid associated endocrinopathy, most commonly manifested as an androgen deficiency and therefore referred to as opioid associated androgen deficiency (OPIAD). This syndrome is characterized by the presence of inappropriately low levels of gonadotropins (follicle stimulating hormone and luteinizing hormone) leading to inadequate production of sex hormones, particularly testosterone. Symptoms that may manifest in patients with OPIAD include reduced libido, erectile dysfunction, fatigue, hot flashes, and depression. Physical findings may include reduced facial and body hair, anemia, decreased muscle mass, weight gain, and osteopenia or osteoporosis. Additionally, both men and women with OPIAD may suffer from infertility. While the literature regarding OPIAD remains limited, it is apparent that OPIAD is becoming increasingly prevalent among chronic opioid consumers but often goes unrecognized. OPIAD can have a significant negative impact on the the quality of life of opioid users, and clinicians should anticipate the potential for its occurrence whenever long-term opioid prescribing is undertaken. Once diagnosed, treatment for OPIAD may be offered utilizing a number of androgen replacement therapy options including a variety of testosterone preparations and, for female patients with OPIAD, dehydroepiandrosterone (DHEA) supplementation. Follow-up evaluation of patients receiving androgen replacement therapy should include a review of any unresolved symptoms of hypogonadism, laboratory evaluation, and surveillance for potential adverse effects of androgen replacement therapy including prostate disease in males.: PMID:22786453

  8. Social modulation of androgen levels in male teleost fish.

    Science.gov (United States)

    Oliveira, Rui F; Hirschenhauser, Katharina; Carneiro, Luis A; Canario, Adelino V M

    2002-05-01

    Androgens are classically thought of as the sex steroids controlling male reproduction. However, in recent years evidence has accumulated showing that androgens can also be affected by the interactions between conspecifics, suggesting reciprocal interactions between androgens and behaviour. These results have been interpreted as an adaptation for individuals to adjust their agonistic motivation and to cope with changes in their social environment. Thus, male-male interactions would stimulate the production of androgens, and the levels of androgens would be a function of the stability of its social environment ['challenge hypothesis', Gen. Comp. Endocrinol. 56 (1984) 417]. Here the available data on social modulation of androgen levels in male teleosts are reviewed and some predictions of the challenge hypothesis are addressed using teleosts as a study model. We investigate the causal link between social status, territoriality and elevated androgen levels and the available evidence suggests that the social environment indeed modulates the endocrine axis of teleosts. The association between higher androgen levels and social rank emerges mainly in periods of social instability. As reported in the avian literature, in teleosts the trade-off between androgens and parental care is indicated by the fact that during the parental phase breeding males decreased their androgen levels. A comparison of androgen responsiveness between teleost species with different mating and parenting systems also reveals that parenting explains the variation observed in androgen responsiveness to a higher degree than the mating strategy. Finally, the adaptive value of social modulation of androgens and some of its evolutionary consequences are discussed. PMID:11997222

  9. Novel acetylcholine and carbamoylcholine analogues

    DEFF Research Database (Denmark)

    Hansen, Camilla Petrycer; Jensen, Anders Asbjørn; Christensen, Jeppe K.;

    2008-01-01

    A series of carbamoylcholine and acetylcholine analogues were synthesized and characterized pharmacologically at neuronal nicotinic acetylcholine receptors (nAChRs). Several of the compounds displayed low nanomolar binding affinities to the alpha 4beta 2 nAChR and pronounced selectivity...

  10. Depletable resources and the economy.

    OpenAIRE

    Heijman, W. J. M.

    1991-01-01

    The subject of this thesis is the depletion of scarce resources. The main question to be answered is how to avoid future resource crises. After dealing with the complex relation between nature and economics, three important concepts in relation with resource depletion are discussed: steady state, time preference and efficiency.For the steady state, three variants are distinguished; the stationary state, the physical steady state and the state of steady growth. It is concluded that the so-call...

  11. Androgen insensitivity syndrome: do trinucleotide repeats in androgen receptor gene have any role?

    Institute of Scientific and Technical Information of China (English)

    Singh Rajender; Nalini J. Gupta; Baidyanath Chakravarty; Lalji Singh; Kumarasamy Thangaraj

    2008-01-01

    Aim: To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syn- drome (AIS) phenotype. Methods: We analyzed lengths of androgen receptor (AR)-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction (PCR) amplification followed by allelic genotyping to determine allele length. Results: Our study revealed significantly shorter mean lengths of CAG repeats in patients (mean 18.25 repeats, range 14-26 repeats) in comparison to the controls (mean 22.57 repeats, range 12-39 repeats) (two-tailed P < 0.0001). GGN repeats, however, did not differ significantly between patients (mean 21.48 repeats) and controls (mean 21.21 repeats) (two- tailed P = 0.474). Among patients' groups, the mean number of CAG repeats in partial androgen insensitivity cases (mean 15.83 repeats) was significantly less than in complete androgen insensitivity cases (mean 19.46 repeats) (two- tailed P < 0.0001). Conclusion: The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity. (Asian J Androl 2008 Jul; 10: 616-624)

  12. Study of Androgen and Androgen Receptor in Relation to Insulin Resistance in Polycystic Ovary Syndrome

    Institute of Scientific and Technical Information of China (English)

    初永丽; 孙永玉; 邱红玉

    2003-01-01

    In order to investigate the relationship between serum testosterone level and expression of androgen receptors in ovary in relation to insulin resistance in polycystic ovary syndrome (PCOS). Serum testosterone levels were determined by radioimmunoassay in 17 patients with PCOS and 20 cases as control group. The expression of androgen receptor in ovary was detected by immunohistochemistry method. The results showed that serum testosterone level [ (3. 1± 1.5) nmol/L] and insulin resistance index (0. 85±0. 49) in patients with PCOS were significantly higher than in control group (P<0. 05), and showed a positive relation (r=0. 65, P<0. 01). The expression levels of androgen receptor in ovary of patients with PCOS were significantly higher than that in control group (P<0.05). The optical density value was positively related with insulin resistance index (r=0.59,P<0. 01). It was concluded that androgen and androgen receptor could accelerate insulin resistance and the interaction of them might aggravate the pathophysiological change in PCOS.

  13. Androgens and Androgen Derivatives: Science, Myths, and Theories: Explored From a Special Operations Perspective.

    Science.gov (United States)

    Givens, Melissa L; Deuster, Patricia

    2015-01-01

    Androgen use outside of legitimate medical therapy is a perceived concern that is drawing attention across military and specifically Special Operations Forces (SOF) communities. For leadership and the medical community to properly address the issue and relate to those individuals who are using or considering use, it will be crucial to understand the scope of the problem. Limited data suggest that the prevalence of androgen use may be increasing, and inferences made from the scientific literature suggest that SOF may be a population of concern. While risks of androgen use are well known, there are little data specific to military performance that can be applied to a rigorous risk:benefit analysis, allowing myths and poorly supported theories to perpetuate within the community. Further efforts to define the potential benefits balanced against the short- and long-term risks should be undertaken. Providers within the SOF community should arm themselves with information to engage androgen users and leadership in meaningful discussion regarding androgen use. PMID:26360363

  14. Is there a correlation between androgens and sexual desire in women?

    DEFF Research Database (Denmark)

    Wåhlin-Jacobsen, Sarah; Pedersen, Anette Tønnes; Kristensen, Ellids;

    2015-01-01

    INTRODUCTION: For women, the correlation between circulating androgens and sexual desire is inconclusive. Substitution with androgens at physiological levels improves sexual function in women who experience decreased sexual desire and androgen deficiency from surgical menopause, pituitary disease...

  15. 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 associat

  16. Bone mineral density in Jamaican men on androgen deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Mayhew Richard G

    2011-09-01

    Full Text Available Abstract Background Androgen deprivation therapy (ADT has been reported to reduce the bone mineral density (BMD in men with prostate cancer (CaP. However, Afro-Caribbeans are under-represented in most studies. The aim was to determine the effect of androgen deprivation therapy (ADT on the bone mineral density (BMD of men with prostate cancer in Jamaica. Methods The study consisted of 346 Jamaican men, over 40 years of age: 133 ADT treated CaP cases (group 1, 43 hormone-naïve CaP controls (group 2 and 170 hormone naïve controls without CaP (group 3. Exclusion criteria included metastatic disease, bisphosphonate therapy or metabolic disease affecting BMD. BMD was measured with a calcaneal ultrasound and expressed in S.D. units relative to young adult men (T score, according to the World Health Organization definition. Patient weight, height and BMI were assessed. Results Mean ± sd, age of patients in group 1 (75± 7.4 yrs was significantly greater than groups 2 and 3 (67 ± 8.1 yrs; 65±12.0 yrs. There was no significant difference in weight and BMI between the 3 groups. . The types of ADT (% of cases, median duration in months with IQR included LHRH (Luteinizing hormone releasing hormone analogues (28.6%, 17.9, IQR 20.4, oestrogens (9.8%, 60.5, IQR 45.6 anti-androgens (11.3%, 3.3, IQR 15.2 and orchiectomy (15.7%, 43.4, IQR 63.9. Unadjusted t score of group 1, mean ± sd, (-1.6± 1.5 was significantly less than group 2 (-0.9±1.1 and group 3 (-0.7±1.4, p Conclusions ADT is associated with lower BMD in Jamaican men on hormonal therapy for prostate cancer.

  17. Androgen Receptor Is Expressed in Genital Warts

    Institute of Scientific and Technical Information of China (English)

    Jiang Haiyang; Zhang Li; Fan Min; Yang Dexiu

    2003-01-01

    Objective:To study the expression of androgen receptor(AR) in genital warts. Methods:The expressions of AR weredetected in 40 samples of genital warts from 28 males and 12 females and 9 normal foreskins by immunohistochemical stain S-Pmethod. The status of AR expression in wart and normal foreskin were compared. Results:The AR expression was revealed in all 40samples of genital wart and 9 samples of normal foreskin.There weren's any differences in AR expression between the genital wartsand normal foreskins. Conclusions:It' s supposed that androgens may play an important role in regulating the metabolism of GW andthe HPV might be one of viruses which addicts to the tissues expressing AR properly.

  18. Androgen receptor gene polymorphism in zebra species

    Directory of Open Access Journals (Sweden)

    Hideyuki Ito

    2015-09-01

    Full Text Available Androgen receptor genes (AR have been found to have associations with reproductive development, behavioral traits, and disorders in humans. However, the influence of similar genetic effects on the behavior of other animals is scarce. We examined the loci AR glutamine repeat (ARQ in 44 Grevy's zebras, 23 plains zebras, and three mountain zebras, and compared them with those of domesticated horses. We observed polymorphism among zebra species and between zebra and horse. As androgens such as testosterone influence aggressiveness, AR polymorphism among equid species may be associated with differences in levels of aggression and tameness. Our findings indicate that it would be useful to conduct further studies focusing on the potential association between AR and personality traits, and to understand domestication of equid species.

  19. 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).

  20. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens

    NARCIS (Netherlands)

    J. Veldscholte (Jos); C. Ris-Stalpers (Carolyn); G.G.J.M. Kuiper (George); G.W. Jenster (Guido); C.A. Berrevoets (Cor); H.J.H.M. Claassen (Eric); H.C.J. van Rooij (Henri); J. Trapman (Jan); A.O. Brinkmann (Albert); E. Mulder (Eppo)

    1990-01-01

    markdownabstractAbstract INCaP prostate tumor cells contain an abnormal androgen receptor system. Progestagens, estradiol and anti-androgens can compete with androgens for binding to the androgen receptor and can stimulate both cell growth and excretion of prostate specific acid phosphatase. We ha

  1. Social modulation of androgen levels in male teleost fish

    OpenAIRE

    Oliveira, R. F.; Hirschenhauser, K.; Carneiro, L. A.; Canario, Adelino V. M.

    2002-01-01

    Androgens are classically thought of as the sex steroids controlling male reproduction. However, in recent years evidence has accumulated showing that androgens can also be affected by the interactions between conspecifics, suggesting reciprocal interactions between androgens and behaviour. These results have been interpreted as an adaptation for individuals to adjust their agonistic motivation and to cope with changes in their social environment. Thus, male–male interactions would stimulate ...

  2. Indirect androgen doping by oestrogen blockade in sports

    OpenAIRE

    Handelsman, D J

    2008-01-01

    Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drug...

  3. Androgen receptor signaling and mutations in prostate cancer

    OpenAIRE

    Koochekpour, Shahriar

    2010-01-01

    Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-indep...

  4. Spongian diterpenoids inhibit androgen receptor activity

    OpenAIRE

    Yang, Yu Chi; Labros G Meimetis; Tien, Amy H; Mawji, Nasrin R.; Carr, Gavin; Wang, Jun; Andersen, Raymond J.; Sadar, Marianne D.

    2013-01-01

    Androgen receptor (AR) is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiological ligands for AR ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit AR transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semi-synthetic...

  5. Stress and Androgen Activity During Fetal Development

    OpenAIRE

    Barrett, Emily S.; Swan, Shanna H.

    2015-01-01

    Prenatal stress is known to alter hypothalamic-pituitary-adrenal axis activity, and more recent evidence suggests that it may also affect androgen activity. In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, associations differ by species. In humans, studies show that (1) associations between prenatal stress and child outcomes are often sex-dependent, (2) prenatal stress predicts several disorders with notable sex difference...

  6. Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.

    OpenAIRE

    Ris-Stalpers, C.; Kuiper, G G; Faber, P.W.; SCHWEIKERT, H. U.; van Rooij, H C; Zegers, N.D.; Hodgins, M B; Degenhart, H J; Trapman, J; Brinkmann, A.O.

    1990-01-01

    Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symptoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. We report a G----T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46,XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely a...

  7. Hematological changes during androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Mathis Grossmann; Jeffrey D Zajac

    2012-01-01

    Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects,consistent with the androgen dependency of multiple reproductive and somatic tissues.One such tissue is the hemopoietic system,and one of the most predictable consequences of ADT is the development of anemia.Although anemia caused by ADT is rarely severe,ADT is often given to frail,elderly men with increased susceptibility to anemia due to multiple other causes.ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men,although this requires further study.While anemia is an independent risk factor of mortality in men with prostate cancer,it is not known whether treatment of ADT-associated anemia alters clinically important outcomes,or whether treatment affects mortality.Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia.However,assessment and treatment of more severe anemia may be required.This should be determined on an individual basis.In contrast to the well-described actions of ADT on erythrepoiesis,its effect on other hemopoietic lineages has been less well elucidated.While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils,lymphocytes and platelets,the implications of these findings for men with prostate cancer receiving ADT require further studies.

  8. Androgen receptor gene mutations in 46, XY females

    Directory of Open Access Journals (Sweden)

    Mir Davood Omrani

    2006-12-01

    Full Text Available The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilization. A point mutation of the androgen receptor gene affecting two siblings with complete androgen insensitivity syndrome is described. On examination they both had normal external female genitalia. Genomic DNA was extracted from EDTA-preserved blood samples and isolated according to standard procedures. The androgen receptor gene was screened for mutations using an automated sequence analyzer (ABI Prism 310. Both girls possess one substitutions (G>A at position 2086 in exon 4, leading to D695N mutation. Mother was found to be a heterozygous carrier for this mutation. GTG banded karyotype of the girls showed they both have male karyotype (46, XY. In addition, the SRY gene screening showed they both have intact SRY gene. The labioscrotal folds contained palpable gonads measuring 1.5 cm in largest diameter. Ultrasound examination of the pelvis revealed absence of the uterus. Serum follicle stimulating hormone (FSH, luteinizing hormone (LH, and testosterone values were higher than normal range. To our knowledge this is the first confirmed instance of AIS due to an AR mutation occurring in familial cases in this country. Furthermore, the phenotype has complete association with this mutation. KEY WORDS: Androgen insensitivity syndrome, androgen receptor

  9. Androgens exert sexually dimorphic effects on angiogenesis: novel insight into the relationship between androgens and cardiovascular disease

    Institute of Scientific and Technical Information of China (English)

    Katya B Rubinow; John K Amory; Stephanie T Page

    2011-01-01

    @@ The effects of androgen exposure on cardiovascular disease (CVD) risk in men remain poorly understood.Given the earlier incidence of CVD among men relative to women, androgens historically have been assumed to potentiate CVD in men.However,mounting clinical data challenge this assumption and increasingly implicate low levels of circulating testosterone as a risk factor for CVD and mortality.1,2 In their recenfly published report 'A sex-specific role for androgens in angiogenesis',3 Sieveking and colleagues make striking observations regarding the impact of androgens on angiogenesis and recovery from ischemic injury, important components of vascular repair which might provide a mechanism whereby androgens could exert protective cardiovascular effects.Moreover, these findings were sex-specific in both in vitro and in vivo model systems, suggesting a sexually dimorphic effect of androgens in modulating CVD.

  10. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome.

    Science.gov (United States)

    Hara, Takahito; Miyazaki, Jun-ichi; Araki, Hideo; Yamaoka, Masuo; Kanzaki, Naoyuki; Kusaka, Masami; Miyamoto, Masaomi

    2003-01-01

    Most prostate cancers (PCs) become resistant to combined androgen blockade therapy with surgical or medical castration and antiandrogens after several years. Some of these refractory PCs regress after discontinuation of antiandrogen administration [antiandrogen withdrawal syndrome (AWS)]. Although the molecular mechanisms of the AWS are not fully understood because of the lack of suitable experimental models, one hypothesis of the mechanism is mutation of androgen receptor (AR). However, bicalutamide, which has become the most prevalent pure antiandrogen, does not work as an agonist for any mutant AR detected thus far in PC. To elucidate the mechanisms of the AWS, we established and characterized novel LNCaP cell sublines, LNCaP-cxDs, which were generated in vitro by culturing androgen-dependent LNCaP-FGC human PC cells in androgen-depleted medium with bicalutamide to mimic the combined androgen blockade therapy. LNCaP-FGC cells did not grow at first, but they started to grow after 6-13 weeks of culture. Bicalutamide stimulated LNCaP-cxD cell growth and increased prostate-specific antigen secretion from LNCaP-cxD cells both in vitro and in vivo. Sequencing of AR transcripts revealed that the AR in LNCaP-cxD cells harbors a novel mutation in codon 741, TGG (tryptophan) to TGT (cysteine; W741C), or in codon 741, TGG to TTG (leucine; W741L), in the ligand-binding domain. Transactivation assays showed that bicalutamide worked as an agonist for both W741C and W741L mutant ARs. Importantly, another antiandrogen, hydroxyflutamide, worked as an antagonist for these mutant ARs. In summary, we demonstrate for the first time that within only 6-13 weeks of in vitro exposure to bicalutamide, LNCaP-FGC cells, whose growth had initially been suppressed, came to use bicalutamide as an AR agonist via W741 AR mutation to survive. Our data strongly support the hypothesis that AR mutation is one possible mechanism of the AWS and suggest that flutamide might be effective as a second

  11. Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development

    OpenAIRE

    Keil, Kimberly P.; Mehta, Vatsal; Branam, Amanda M.; Abler, Lisa L.; Buresh-Stiemke, Rita A.; Joshi, Pinak S.; Schmitz, Christopher T.; Marker, Paul C.; Vezina, Chad M.

    2012-01-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-respons...

  12. Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions

    OpenAIRE

    Decker, Keith F.; Zheng, Dali; He, Yuhong; Bowman, Tamara; Edwards, John R.; Jia, Li

    2012-01-01

    The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signaling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant ...

  13. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells

    OpenAIRE

    David J. DeGraff; Aguiar, Adam A.; Chen, Qian; Adams, Lisa K.; Williams, B. Jill; Sikes, Robert A.

    2010-01-01

    The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment...

  14. The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner

    OpenAIRE

    Jiwen Cheng; Keqin Yang; Qingyun Zhang; Yang Yu; Qinggui Meng; Ning Mo; Yang Zhou; Xianlin Yi; Chengzhong Ma; Aming Lei; Yan Liu

    2016-01-01

    Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa ce...

  15. Nonlinear lower hybrid wave depletion

    International Nuclear Information System (INIS)

    Two numerical ray tracing codes with focusing are used to compute lower hybrid daughter wave amplification by quasi-mode parametric decay. The first code, LHPUMP provides a numerical pump model on a grid. This model is used by a second code, LHFQM which computes daughter wave amplification inside the pump extent and follows the rays until their energy is absorbed by the plasma. An analytic model is then used to estimate pump depletion based on the numerical results. Results for PLT indicate strong pump depletion at the plasma edge at high density operation for the 800 Mhz wave frequency, but weak depletion for the 2.45 Ghz experiment. This is proposed to be the mechanism responsible for the high density limit for current drive as well as for the difficulty to heat ions

  16. Policy issues in space analogues

    Science.gov (United States)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  17. Androgen regulation of the TMPRSS2 gene and the effect of a SNP in an androgen response element.

    Science.gov (United States)

    Clinckemalie, Liesbeth; Spans, Lien; Dubois, Vanessa; Laurent, Michaël; Helsen, Christine; Joniau, Steven; Claessens, Frank

    2013-12-01

    More than 50% of prostate cancers have undergone a genomic reorganization that juxtaposes the androgen-regulated promoter of TMPRSS2 and the protein coding parts of several ETS oncogenes. These gene fusions lead to prostate-specific and androgen-induced ETS expression and are associated with aggressive lesions, poor prognosis, and early-onset prostate cancer. In this study, we showed that an enhancer at 13 kb upstream of the TMPRSS2 transcription start site is crucial for the androgen regulation of the TMPRSS2 gene when tested in bacterial artificial chromosomal vectors. Within this enhancer, we identified the exact androgen receptor binding sequence. This newly identified androgen response element is situated next to two binding sites for the pioneer factor GATA2, which were identified by DNase I footprinting. Both the androgen response element and the GATA-2 binding sites are involved in the enhancer activity. Importantly, a single nucleotide polymorphism (rs8134378) within this androgen response element reduces binding and transactivation by the androgen receptor. The presence of this SNP might have implications on the expression and/or formation levels of TMPRSS2 fusions, because both have been shown to be influenced by androgens.

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

    International Nuclear Information System (INIS)

    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.

  19. A physiological role for androgen actions in the absence of androgen receptor DNA binding activity.

    Science.gov (United States)

    Pang, Tammy P S; Clarke, Michele V; Ghasem-Zadeh, Ali; Lee, Nicole K L; Davey, Rachel A; MacLean, Helen E

    2012-01-01

    We tested the hypothesis that androgens have physiological actions via non-DNA binding-dependent androgen receptor (AR) signaling pathways in males, using our genetically modified mice that express a mutant AR with deletion of the 2nd zinc finger of the DNA binding domain (AR(ΔZF2)) that cannot bind DNA. In cultured genital skin fibroblasts, the mutant AR(ΔZF2) has normal ligand binding ability, phosphorylates ERK-1/2 in response to 1 min DHT treatment (blocked by the AR antagonist bicalutamide), but has reduced androgen-dependent nuclear localization compared to wildtype (WT). AR(ΔZF2) males have normal baseline ERK-1/2 phosphorylation, with a 1.5-fold increase in Akt phosphorylation in AR(ΔZF2) muscle vs WT. To identify physiological actions of non-DNA binding-dependent AR signaling, AR(ΔZF2) males were treated for 6 weeks with dihydrotestosterone (DHT). Cortical bone growth was suppressed by DHT in AR(ΔZF2) mice (6% decrease in periosteal and 7% decrease in medullary circumference vs untreated AR(ΔZF2) males). In conclusion, these data suggest that non-DNA binding dependent AR actions suppress cortical bone growth, which may provide a mechanism to fine-tune the response to androgens in bone.

  20. A competitive inhibitor that reduces recruitment of androgen receptor to androgen-responsive genes.

    Science.gov (United States)

    Cherian, Milu T; Wilson, Elizabeth M; Shapiro, David J

    2012-07-01

    The androgen receptor (AR) has a critical role in the growth and progression of androgen-dependent and castration-resistant prostate cancers. To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells, a luciferase-based high-throughput screen of ~160,000 small molecules was performed in cells stably expressing AR and a prostate-specific antigen (PSA)-luciferase reporter. CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors. CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines, with minimal toxicity in AR-negative cell lines. CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells. CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A. CPIC treatment did not reduce AR levels or alter its nuclear localization. We used chromatin immunoprecipitation to identify the site of action of CPIC. CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide. CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer.

  1. 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 ...

  2. 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....

  3. In the mood for sex : The value of androgens

    NARCIS (Netherlands)

    Apperloo, MJA; Van der Stege, JG; Hoek, A; Schultz, WCMW

    2003-01-01

    Androgen substitution is increasingly being employed to enhance sexual desire in women based on the assumption that low androgen levels cause low sexual desire, Sexual functioning in women is complex; therefore, decreased sexual interest can have various causes. An adequate female sexual biopsycboso

  4. Development of selective androgen receptor modulators and their therapeutic applications.

    Science.gov (United States)

    Chen, Fang; Rodan, Gideon A; Schmidt, Azi

    2002-01-01

    Androgens control a broad range of physiological functions. The androgen receptor (AR), a steroid receptor that mediates the diverse biological actions of androgens, is a ligand inducible transcription factor. Abnormalities in the androgen signaling system result in many disturbances ranging from changes in gender determination and sexual development to psychiatric and emotional disorders. Androgen replacement therapy can improve many clinical conditions including hypogonadism and osteoporosis, but is limited by the lack of efficacious and safe therapeutic agents with easy delivery options. Recent progress in the area of gene regulation by steroid receptors and by selective receptor modulators provides an opportunity to examine if selective androgen receptor modulators (SARMs) could address some of the problems associated with current androgen therapy. Since the composition of the transcriptional initiation complex recruited by liganded AR determines the specificity of gene regulation, synthetic ligands aimed at initiating transcription of tissue and promoter specific genes offers hope for developing better androgen therapy. Establishment of assays that predict synthetic ligand activity is critical for SARM development. Advancement in high throughput compound screening and gene fingerprinting technologies, such as microarrays and proteomics, will facilitate and accelerate identification of effective SARMs.

  5. The Werkendam natural CO2 accumulation: An analogue for CO2 storage in depleted oil reservoirs

    Science.gov (United States)

    Bertier, Pieter; Busch, Andreas; Hangx, Suzanne; Kampman, Niko; Nover, Georg; Stanjek, Helge; Weniger, Philipp

    2015-04-01

    The Werkendam natural CO2 accumulation is hosted in the Röt (Early Triassic) sandstone of the West Netherlands Basin, at a depth of 2.8 km, about 20 km south-east of Rotterdam (NL). This reservoir, in a fault-bound structure, was oil-filled prior to charging with magmatic CO2 in the early Cretaceous. It therefore offers a unique opportunity to study long-term CO2-water-rock interactions in the presence of oil. This contribution will present the results of a detailed mineralogical and geochemical characterisation of core sections from the Werkendam CO2 reservoir and an adjacent, stratigraphically equivalent aquifer. X-ray diffraction combined with X-ray fluorescence spectrometry revealed that the reservoir samples contain substantially more feldspar and more barite and siderite than those from the aquifer, while the latter have higher hematite contents. These differences are attributed to the effects hydrocarbons and related fluids on diagenesis in the closed system of the CO2 reservoir versus the open-system of the aquifer. Petrophysical analyses yielded overall higher and more anisotropic permeability for the reservoir samples, while the porosity is overall not significantly different from that of their aquifer equivalents. The differences are most pronounced in coarse-grained sandstones. These have low anhydrite contents and contain traces of calcite, while all other analyzed samples contain abundant anhydrite, dolomite/ankerite and siderite, but no calcite. Detailed petrography revealed mm-sized zones of excessive primary porosity. These are attributed to CO2-induced dissolution of precompactional, grain-replacive anhydrite cement. Diagenetic dolomite/ankerite crystals are covered by anhedral, epitaxial ankerite, separated from the crystals by bitumen coats. Since these carbonates were oil-wet before CO2-charging, the overgrowths are interpreted to have grown after CO2-charging. Their anhedral habit suggests growth in a 2-phase water-CO2 system. Isotopic analysis yielded an internal source for all carbon, oxygen and sulphur, which implies that mineral trapping of CO2 was insignificant.

  6. [Recent aspects of therapy with androgenic and anabolic steroids].

    Science.gov (United States)

    Schambach, H; Nitschke, U; Kröhne, H J

    1983-11-15

    From the pharmacology of the therapeutically available androgen preparations and the clinical experience results that a highly dosed androgen long-term therapy is effectively possible only by testosterone esters which are to be injected intramuscularly (e.g. testosterone oenanthate). It is indicated in all forms of endocrine hypogonadism, certain aplastic anaemias and if necessary in extreme male high growth. In partial androgen deficiency (pubertas tarda, Klinefelter's syndrome, climacterium virile and others) orally applicable androgens such as testosterone-undecanoate (Andriol) and mesterolone (Vistimon) can be used. The latter is to be preferred when a hyperoestrogenism is present, e.g. in liver cirrhosis. When 17-alpha-alkylated oral androgens are used, their often not sufficiently confirmed anabolic effect and their potential liver toxicity should more be taken into consideration. PMID:6666179

  7. Androgens regulate Hedgehog signalling and proliferation in androgen-dependent prostate cells.

    Science.gov (United States)

    Sirab, Nanor; Terry, Stéphane; Giton, Frank; Caradec, Josselin; Chimingqi, Mihelaiti; Moutereau, Stéphane; Vacherot, Francis; de la Taille, Alexandre; Kouyoumdjian, Jean-Claude; Loric, Sylvain

    2012-09-15

    Prostate cancer (PCa) is androgen sensitive in its development and progression to metastatic disease. Hedgehog (Hh) pathway activation is important in the initiation and growth of various carcinomas including PCa. We and others have observed aberrations of Hh pathway during the progression of PCa to the castration-resistant state. The involvement of androgen signalling in Hh pathway activation, however, remains largely elusive. Here we investigate the direct role of androgen signalling on Hh pathway. We examined the effect of Dihydrosterone (DHT), antiandrogen, bicalutamide, and Hh pathway inhibitor, KAAD-cyclopamine in four human prostate cell lines (two cancerous: LNCaP, VCaP, and two normal: PNT2 and PNT2-ARm which harbours a mutant version of androgen receptor (AR) that is commonly found in LNCaP). Cell proliferation as well as Hh pathway members (SHH, IHH, DHH, GLI, PTCH) mRNA expression levels were assessed. We showed that KAAD-cyclopamine decreased cell proliferation of DHT-stimulated LNCaP, VCaP and PNT2-ARm cells. SHH expression was found to be downregulated by DHT in all AR posititve cells. The negative effect of DHT on SHH expression was counteracted when cells were treated by bicalutamide. Importantly, KAAD-cyclopamine treatment seemed to inhibit AR activity. Moreover, bicalutamide as well as KAAD-cyclopamine treatments induced GLI and PTCH expression in VCaP and PNT2-ARm. Our results suggest that Hh pathway activity can be regulated by androgen signalling. Specifically, we show that the DHT-induced inhibition of Hh pathway is AR dependent. The mutual interaction between these two pathways might be important in the regulation of cell proliferation in PCa.

  8. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    Science.gov (United States)

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  9. Androgen therapy and atherosclerotic cardiovascular disease

    OpenAIRE

    K-CY McGrath; LS McRobb; AK Heather

    2008-01-01

    K-CY McGrath1, LS McRobb1,2, AK Heather1,21Heart Research Institute, Camperdown, NSW, Australia; 2Discipline of Medicine, University of Sydney, Sydney, NSW, AustraliaAbstract: Cardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen ...

  10. Deoxyribonucleic acid-binding ability of androgen receptors in whole cells: implications for the actions of androgens and antiandrogens

    NARCIS (Netherlands)

    C.W. Kuil (Cor); E. Mulder (Eppo)

    1996-01-01

    textabstractIn whole cells, the effects of several androgens and antiandrogens on the in the induction of DNA binding for the human wild-type androgen receptor (AR) and a mutant receptor ARL (LNCaP mutation; codon 868, Thr to Ala) were examined and related to the transc

  11. Functional analysis of a novel androgen receptor mutation, Q902K, in an individual with partial androgen insensitivity.

    NARCIS (Netherlands)

    A. Umar (Arzu); C.A. Berrevoets (Cor); N.M. Van (Mai); M. van Leeuwen (Marije); M.M.P.J. Verbiest (Michael); W.J. Kleijer (Wim); D. Dooijes (Dennis); J.A. Grootegoed (Anton); S.L.S. Drop (Stenvert); A.O. Brinkmann (Albert)

    2005-01-01

    textabstractAndrogen insensitivity syndrome (AIS) is caused by defects in the androgen receptor (AR) that render the AR partially or completely inactive. As a result, embryonic sex differentiation is impaired. Here, we describe a novel mutation in the AR found in a patient with par

  12. RAINBOW TROUT ANDROGEN RECEPTOR ALPHA AND THE HUMAN ANDROGEN RECEPTOR: COMPARISONS IN THE COS WHOLE CELL BINDING ASSAY

    Science.gov (United States)

    Rainbow Trout Androgen Receptor Alpha And Human Androgen Receptor: Comparisons in the COS Whole Cell Binding Assay Mary C. Cardon, L. Earl Gray, Jr. and Vickie S. WilsonU.S. Environmental Protection Agency, ORD, NHEERL, Reproductive Toxicology Division, Research Triangle...

  13. Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells.

    Science.gov (United States)

    Khurana, Namrata; Talwar, Sudha; Chandra, Partha K; Sharma, Pankaj; Abdel-Mageed, Asim B; Mondal, Debasis; Sikka, Suresh C

    2016-10-01

    Prostate cancer (PCa) cells utilize androgen for their growth. Hence, androgen deprivation therapy (ADT) using anti-androgens, e.g. bicalutamide (BIC) and enzalutamide (ENZ), is a mainstay of treatment. However, the outgrowth of castration resistant PCa (CRPC) cells remains a significant problem. These CRPC cells express androgen receptor (AR) and utilize the intratumoral androgen towards their continued growth and invasion. Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, can decrease AR protein levels. In the present study, we tested the combined efficacy of anti-androgens and SFN in suppressing PCa cell growth, motility and clonogenic ability. Both androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells were used to monitor the effects of BIC and ENZ, alone and in combination with SFN. Co-exposure to SFN significantly (pcell migration. In addition, long-term exposures (14 days) to much lower concentrations of these agents, SFN (0.2 µM), BIC (1 µM) and/or ENZ (0.4 µM) significantly (pcells. PMID:27499349

  14. Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.

    Science.gov (United States)

    Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise; Malewska, Alicia; Wei, Xing; Zhang, Li; Brinkley, William; Zhang, Yiqun; Castro, Patricia D; Titus, Mark; Chen, Rui; Sayeeduddin, Mohammad; Raj, Ganesh V; Mauck, Ryan; Roehrborn, Claus; Creighton, Chad J; Strand, Douglas W; Ittmann, Michael M; Xin, Li

    2016-09-15

    Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases. PMID:27594448

  15. GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis.

    Science.gov (United States)

    Agarwal, Neeraj; Dancik, Garrett M; Goodspeed, Andrew; Costello, James C; Owens, Charles; Duex, Jason E; Theodorescu, Dan

    2016-09-01

    In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well-validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells and blocked cell proliferation in vitro and tumor xenograft growth in vivo Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1, and CD24 was elevated compared with normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate, and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities. Cancer Res; 76(17); 5175-85. ©2016 AACR.

  16. What Can We Learn From Analogue Experiments?

    CERN Document Server

    Thebault, Karim P Y

    2016-01-01

    In 1981 Unruh proposed that fluid mechanical experiments could be used to probe key aspects of the quantum phenomenology of black holes. In particular, he claimed that an analogue to Hawking radiation could be created within a fluid mechanical `dumb hole', with the event horizon replaced by a sonic horizon. Since then an entire sub-field of `analogue gravity' has been created. In 2016 Steinhauer reported the experimental observation of quantum Hawking radiation and its entanglement in a Bose-Einstein condensate analogue black hole. What can we learn from such analogue experiments? In particular, in what sense can they provide evidence of novel phenomena such as black hole Hawking radiation?

  17. 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.

  18. Androgen receptor accelerates premature senescence of human dermal papilla cells in association with DNA damage.

    Directory of Open Access Journals (Sweden)

    Yi-Chien Yang

    Full Text Available The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16(INK4a, and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature senescence of dermal papilla cells, we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients. Exposure of androgen induced premature senescence in dermal papilla cells from non-balding frontal and transitional zone of balding scalp follicles but not in beard follicles. Overexpression of the AR promoted androgen-induced premature senescence in association with p16(INK4a upregulation, whereas knockdown of the androgen receptor diminished the effects of androgen. An analysis of γ-H2AX expression in response to androgen/androgen receptor signaling suggested that DNA damage contributes to androgen/androgen receptor-accelerated premature senescence. These results define androgen/androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen/androgen receptor-mediated DNA damage-p16(INK4a axis is a potential therapeutic target in the treatment of androgenetic alopecia.

  19. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  20. The androgen receptor: Functional structure and expression in transplanted human prostate tumors and prostate tumor cell lines

    OpenAIRE

    Trapman, Jan; Ris-Stalpers, Carolyn; Korput, J. A G M; Kuiper, George; Faber, P.W.; Romijn, Johannes; Mulder, Eppo; Brinkmann, Albert

    1990-01-01

    markdownabstractAbstract The growth of the majority of prostate tumors is androgen-dependent, for which the presence of a functional androgen receptor is a prerequisite. Tumor growth can be inhibited by blockade of androgen receptor action. However, this inhibition is transient. To study the role of the androgen receptor in androgen-dependent and androgen-independent prostate tumor cell growth, androgen receptor mRNA expression was monitored in six different human prostate tumor cell lines an...

  1. Opioid-Induced Androgen Deficiency (OPIAD): Diagnosis, Management, and Literature Review.

    Science.gov (United States)

    O'Rourke, Timothy K; Wosnitzer, Matthew S

    2016-10-01

    Opioid-induced androgen deficiency (OPIAD) was initially recognized as a possible consequence of opioid use roughly four decades ago. Long-acting opioid use carries risks of addiction, tolerance, and systemic side effects including hypogonadotropic hypogonadism with consequent testosterone depletion leading to multiple central and peripheral effects. Hypogonadism is induced through direct inhibitory action of opioids on receptors within the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes as well as testosterone production within the testes. Few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD. Clomiphene citrate, a selective estrogen receptor modulator (SERM), is a testosterone enhancement treatment which upregulates endogenous hypothalamic function. This review will focus on the pathophysiology, diagnosis, and management of OPIAD, including summary of literature evaluating OPIAD treatment with TRT, and areas of future investigation. PMID:27586511

  2. CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Choi, Hanbyeul; Lee, Sang Hyup; Um, Soo-Jong; Kim, Eun-Joo

    2016-07-01

    The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding. Depletion of CACUL1 enhances the LSD1 occupancy of the AR-target promoter, accompanied by decreased accumulation of H3K9me2, a repressive transcriptional marker. CACUL1 and LSD1 oppositely regulate CDX-induced cell death in AR-positive LNCaP and metastatic castrate-resistant LNCaP-LN3 cells. These data suggest that CACUL1 impairs LSD1-mediated activation of AR, thereby implicating it as a potential antitumor target in PCa. PMID:27085459

  3. The Valles natural analogue project

    Energy Technology Data Exchange (ETDEWEB)

    Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  4. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin.

    Science.gov (United States)

    Sharma, Vikas; Kumar, Lokesh; Mohanty, Sujit K; Maikhuri, Jagdamba P; Rajender, Singh; Gupta, Gopal

    2016-08-15

    Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer. PMID:27132804

  5. L712V mutation in the androgen receptor gene causes complete androgen insensitivity syndrome due to severe loss of androgen function.

    Science.gov (United States)

    Rajender, Singh; Gupta, Nalini J; Chakrabarty, Baidyanath; Singh, Lalji; Thangaraj, Kumarasamy

    2013-12-11

    Inability to respond to the circulating androgens is named as androgen insensitivity syndrome (AIS). Mutations in the androgen receptor (AR) gene are the most common cause of AIS. A cause and effect relationship between some of these mutations and the AIS phenotype has been proven by in vitro studies. Several other mutations have been identified, but need to be functionally validated for pathogenicity. Screening of the AR mutations upon presumptive diagnosis of AIS is recommended. We analyzed a case of complete androgen insensitivity syndrome (CAIS) for mutations in the AR gene. Sequencing of the entire coding region revealed C>G mutation (CTT-GTT) at codon 712 (position according to the NCBI database) in exon 4 of the gene, resulting in replacement of leucine with valine in the ligand-binding domain of the AR protein. No incidence of this mutation was observed in 230 normal male individuals analyzed for comparison. In vitro androgen binding and transactivation assays using mutant clone showed approximately 71% loss of ligand binding and about 76% loss of transactivation function. We conclude that CAIS in this individual was due to L712V substitution in the androgen receptor protein.

  6. Ozone Depletion from Nearby Supernovae

    CERN Document Server

    Gehrels, N; Jackman, C H; Cannizzo, J K; Mattson, B J; Chen, W; Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan

    2003-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time, improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made in theoretical modeling of supernovae and of the resultant gamma-ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma-rays and cosmic rays. We find that for the combined ozone depletion roughly to double the ``biologically active'' UV flux received at the surface of the Earth, the supernova mu...

  7. Ozone Depletion from Nearby Supernovae

    Science.gov (United States)

    Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan; Bhartia, P. K. (Technical Monitor)

    2002-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made also in theoretical modeling of supernovae and of the resultant gamma ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma rays and cosmic rays. We find that for the combined ozone depletion from these effects roughly to double the 'biologically active' UV flux received at the surface of the Earth, the supernova must occur at approximately or less than 8 parsecs.

  8. HD depletion in starless cores

    CERN Document Server

    Sipilä, O; Harju, J

    2013-01-01

    Aims: We aim to investigate the abundances of light deuterium-bearing species such as HD, H2D+ and D2H+ in a gas-grain chemical model including an extensive description of deuterium and spin state chemistry, in physical conditions appropriate to the very centers of starless cores. Methods: We combine a gas-grain chemical model with radiative transfer calculations to simulate density and temperature structure in starless cores. The chemical model includes deuterated forms of species with up to 4 atoms and the spin states of the light species H2, H2+ and H3+ and their deuterated forms. Results: We find that HD eventually depletes from the gas phase because deuterium is efficiently incorporated to grain-surface HDO, resulting in inefficient HD production on grains. HD depletion has consequences not only on the abundances of e.g. H2D+ and D2H+, whose production depends on the abundance of HD, but also on the spin state abundance ratios of the various light species, when compared with the complete depletion model ...

  9. 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 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.

  10. 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.

  11. Stress and Androgen Activity During Fetal Development.

    Science.gov (United States)

    Barrett, Emily S; Swan, Shanna H

    2015-10-01

    Prenatal stress is known to alter hypothalamic-pituitary-adrenal axis activity, and more recent evidence suggests that it may also affect androgen activity. In animal models, prenatal stress disrupts the normal surge of testosterone in the developing male, whereas in females, associations differ by species. In humans, studies show that (1) associations between prenatal stress and child outcomes are often sex-dependent, (2) prenatal stress predicts several disorders with notable sex differences in prevalence, and (3) prenatal exposure to stressful life events may be associated with masculinized reproductive tract development and play behavior in girls. In this minireview, we examine the existing literature on prenatal stress and androgenic activity and present new, preliminary data indicating that prenatal stress may also modify associations between prenatal exposure to diethylhexyl phthalate, (a synthetic, antiandrogenic chemical) and reproductive development in infant boys. Taken together, these data support the hypothesis that prenatal exposure to both chemical and nonchemical stressors may alter sex steroid pathways in the maternal-placental-fetal unit and ultimately alter hormone-dependent developmental endpoints. PMID:26241065

  12. Beyond androgen deprivation: ancillary integrative strategies for targeting the androgen receptor addiction of prostate cancer.

    Science.gov (United States)

    McCarty, Mark F; Hejazi, Jalal; Rastmanesh, Reza

    2014-09-01

    The large majority of clinical prostate cancers remain dependent on androgen receptor (AR) activity for proliferation even as they lose their responsiveness to androgen deprivation or antagonism. AR activity can be maintained in these circumstances by increased AR synthesis--often reflecting increased NF-κB activation; upregulation of signaling pathways that promote AR activity in the absence of androgens; and by emergence of AR mutations or splice variants lacking the ligand-binding domain, which render the AR constitutively active. Drugs targeting the N-terminal transactivating domain of the AR, some of which are now in preclinical development, can be expected to inhibit the activity not only of unmutated ARs but also of the mutant forms and splice variants selected for by androgen deprivation. Concurrent measures that suppress AR synthesis or boost AR turnover could be expected to complement the efficacy of such drugs. A number of nutraceuticals that show efficacy in prostate cancer xenograft models--including polyphenols from pomegranate, grape seed, and green tea, the crucifera metabolite diindolylmethane, and the hormone melatonin--have the potential to suppress AR synthesis via downregulation of NF-κB activity; clinical doses of salicylate may have analogous efficacy. The proteasomal turnover of the AR is abetted by diets with a high ratio of long-chain omega-3 to omega-6 fatty acids, which are beneficial in prostate cancer xenograft models; berberine and sulforaphane, by inhibiting AR's interaction with its chaperone Hsp90, likewise promote AR proteasomal degradation and retard growth of human prostate cancer in nude mice. Hinge region acetylation of the AR is required for optimal transactivational activity, and low micromolar concentrations of the catechin epigallocatechin-3-gallate (EGCG) can inhibit such acetylation--possibly explaining the ability of EGCG administration to suppress androgenic activity and cell proliferation in prostate cancer

  13. New method for labeling and autoradiographic localization of androgen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Peters, C.A.; Barrack, E.R.

    1987-07-01

    We have used a novel receptor labeling and autoradiographic technique to localize androgen receptors in the intact rat ventral prostate at the morphological level. Frozen slide-mounted prostate tissue sections (10 micron thick) were incubated with increasing concentrations of (/sup 3/H)-R1881 in the absence and presence of excess unlabeled R1881. Tissue sections labeled in this way were subjected to concurrent biochemical and autoradiographic analysis. After incubation and washing to remove free (/sup 3/H)-steroid, some of the sections were wiped from the slides for scintillation counting in order to characterize and quantitate (/sup 3/H)-R1881 binding. Androgen receptors could indeed be labeled in slide-mounted tissue sections, and specific (/sup 3/H)-R1881 binding to these receptors was high-affinity (Kd = 1 nM), saturable, and androgen-specific. All cellular androgen receptors appear to be retained, because receptor content in sections was comparable to the sum of receptors in subcellular fractions of homogenized tissue. Replicate labeled slide-mounted tissue sections were dried rapidly, apposed to dry emulsion-coated coverslips, and exposed in the dark for autoradiography. Silver grains were counted over nuclei or cytoplasm of epithelium or stroma to evaluate specific androgen receptor location. Autoradiographic analysis demonstrated androgen receptor localization almost exclusively in the epithelial nuclei, with little or none in the stroma. We discuss here the unique features and advantages of labeling androgen receptors in slide-mounted frozen tissue sections for autoradiographic localization.

  14. New method for labeling and autoradiographic localization of androgen receptors

    International Nuclear Information System (INIS)

    We have used a novel receptor labeling and autoradiographic technique to localize androgen receptors in the intact rat ventral prostate at the morphological level. Frozen slide-mounted prostate tissue sections (10 micron thick) were incubated with increasing concentrations of [3H]-R1881 in the absence and presence of excess unlabeled R1881. Tissue sections labeled in this way were subjected to concurrent biochemical and autoradiographic analysis. After incubation and washing to remove free [3H]-steroid, some of the sections were wiped from the slides for scintillation counting in order to characterize and quantitate [3H]-R1881 binding. Androgen receptors could indeed be labeled in slide-mounted tissue sections, and specific [3H]-R1881 binding to these receptors was high-affinity (Kd = 1 nM), saturable, and androgen-specific. All cellular androgen receptors appear to be retained, because receptor content in sections was comparable to the sum of receptors in subcellular fractions of homogenized tissue. Replicate labeled slide-mounted tissue sections were dried rapidly, apposed to dry emulsion-coated coverslips, and exposed in the dark for autoradiography. Silver grains were counted over nuclei or cytoplasm of epithelium or stroma to evaluate specific androgen receptor location. Autoradiographic analysis demonstrated androgen receptor localization almost exclusively in the epithelial nuclei, with little or none in the stroma. We discuss here the unique features and advantages of labeling androgen receptors in slide-mounted frozen tissue sections for autoradiographic localization

  15. Androgen insensitivity syndrome, a case report and literature review

    Directory of Open Access Journals (Sweden)

    Venkatreddy Malipatil

    2016-06-01

    Full Text Available A case of androgen insensitivity syndrome who presented with left labial mass and inguinal hernia was managed by surgery and counselling. The aim of this report is to present a rare case of androgen insensitivity syndrome, its cause, diagnosis and treatment along with review of literature and its management. Androgen insensitivity syndrome is a X linked disorder of male sexual differentiation caused by mutation affecting the androgen receptor gene Xq 11-12 resulting in decreased peripheral responsiveness to circulating androgens, with variable phenotypic expression. Over 300 mutations have been identical worldwide. A 8 year old girl presented to surgical outpatient department with pain in the left labial mass. She was investigated and operated. She was confirmed of having androgen insensitivity syndrome after testing for abdominal ultrasound, estimation of antimullerian hormone (AMH levels, karyotyping and histopathological examination of labial mass. A literature search and update was made on the causes, clinical issues and management of androgen insensitivity syndrome (AIS. [Int J Res Med Sci 2016; 4(6.000: 1830-1833

  16. Selective androgen receptor modulators for frailty and osteoporosis.

    Science.gov (United States)

    Kilbourne, Edward J; Moore, William J; Freedman, Leonard P; Nagpal, Sunil

    2007-10-01

    Androgens play an important role not only in male sexual differentiation, puberty, sexual behavior and spermatogenesis, but also in the maintenance of bone architecture and muscle mass and strength. For decades, steroidal androgens have been used by hypogonadal and aging men as hormone replacement therapy, and abused by prominent athletes as anabolic agents for enhancing physical performance. The use of steroidal androgens is associated with hepatotoxicity, potential for prostate stimulation, virilizing actions and other side effects resulting from their cross-reactivity to related steroid receptors. Therefore, to utilize the therapeutic potential of the androgen receptor for the treatment of indications such as osteoporosis and frailty, several pharmaceutical and biotechnology companies are developing non-steroidal tissue-selective androgen receptor modulators (SARMs) that retain the beneficial properties of natural androgens and exhibit better therapeutic indices. This article reviews the mechanism of androgen action, novel non-steroidal ligands under development and future directions of SARM research for the discovery of novel modulators for frailty and osteoporosis.

  17. Aberrant splicing of androgenic receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Ris-Stalpers, C.; Kuiper, G.G.J.M.; Faber, P.W.; van Rooij, H.C.J.; Degenhart, H.J.; Trapman, J.; Brinkmann, A.O. (Erasmus Univ., Rotterdam (Netherlands)); Schweikert, H.U. (Univ. of Bonn (Germany)); Zegers, N.D. (Medical Biological Laboratory-Organization for Applied Scientific Research, Rijswijk (Netherlands)); Hodgins, M.B. (Glasgow Univ. (United Kingdom))

    1990-10-01

    Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symtpoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. The authors report a G {r arrow} T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46, XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein {approx}5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.

  18. Aberrant splicing of androgenic receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity

    International Nuclear Information System (INIS)

    Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symtpoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. The authors report a G → T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46, XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein ∼5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo

  19. Androgen via p21 Inhibits Tumor Necrosis Factor α-induced JNK Activation and Apoptosis*

    OpenAIRE

    Tang, Fangming; Kokontis, John; Lin, Yuting; Liao, Shutsung; Lin, Anning; Xiang, Jialing

    2009-01-01

    The male hormone androgen is a growth/survival factor for its target tissues or organs. Yet, the underlying mechanism is incompletely understood. Here, we report that androgen via p21 inhibits tumor necrosis factor α-induced JNK activation and apoptosis. Inhibition by androgen requires the transcription activity of androgen receptor (AR) and de novo protein synthesis. Androgen·AR induces expression of p21 that in turn inhibits tumor necrosis factor α-induced JNK and apoptosis. Furthermore, ge...

  20. Regulation of androgen action during establishment of pregnancy.

    Science.gov (United States)

    Gibson, Douglas A; Simitsidellis, Ioannis; Saunders, Philippa T K

    2016-07-01

    During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women.

  1. CO2 Capture with Enzyme Synthetic Analogue

    Energy Technology Data Exchange (ETDEWEB)

    Cordatos, Harry

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  2. Genes regulated by androgen in the rat ventral prostate

    OpenAIRE

    Wang, Zhou; Tufts, Rachel; Haleem, Riffat; Cai, Xiaoyan

    1997-01-01

    Genes that are regulated by androgen in the prostate were studied in the rat. Four of the less than 10 genes that are down-regulated by androgen in the ventral prostate of a 7-day castrated rat were identified; their mRNAs decayed with identical kinetics. Twenty-five of the estimated 56 genes that are up-regulated by androgen in the castrated prostate have been isolated. The up-regulated genes fall into two kinetic types. Early genes are significantly up-regulated by 6.5 hr whereas the delaye...

  3. Androgens and breast cancer in men and women.

    Science.gov (United States)

    Dimitrakakis, Constantine

    2011-09-01

    Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Clinical and nonhuman primate studies support the notion that androgens inhibit mammary proliferation and, thus, may protect from breast cancer. On the other hand, administration of conventional estrogen treatment suppresses endogenous androgens and may, thus, enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk, but the impact of this combined use on mammary gland homeostasis still needs evaluation.

  4. [Bone and Men's Health. Bone selective androgen receptor modulators].

    Science.gov (United States)

    Furuya, Kazuyuki

    2010-02-01

    Androgen, one of the sex steroid hormones shows various biological activities on the corresponding various tissues. Many efforts to produce novel drug materials maintaining a desired biological activity with an adequate tissue selectivity, which is so-called selective androgen receptor modulators (SARMs) , are being performed. As one of such efforts, studies on SARMs against bone tissues which possess a significant potential to stimulate a bone formation with reducing undesirable androgenic virilizing activities are in progress all over the world. This review focuses on the research and development activities of such SARMs and discuses their usefulness for the treatment of osteoporosis.

  5. Strategy and methodology of dynamical analogue prediction

    Institute of Scientific and Technical Information of China (English)

    REN; HongLi; CHOU; JiFan

    2007-01-01

    In order to effectively improve numerical prediction level by using current models and data, the strategy and methodology of dynamical analogue prediction (DAP) is deeply studied in the present paper. A new idea to predict the prediction errors of dynamical model on the basis of historical analogue information is put forward so as to transform the dynamical prediction problem into the estimation problem of prediction errors. In terms of such an idea, a new prediction method of final analogue correction of errors (FACE) is developed. Furthermore, the FACE is applied to extra-seasonal prediction experiments on an operational atmosphere-ocean coupled general circulation model. Prediction results of summer mean circulation and total precipitation show that the FACE can to some extent reduce prediction errors, recover prediction variances, and improve prediction skills. Besides, sensitive experiments also show that predictions based on the FACE are evidently influenced by the number of analogues, analogue-selected variables and analogy metric.

  6. Fully analogue photonic reservoir computer.

    Science.gov (United States)

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  7. S578N mutation of the androgen receptor in an adolescent with complete androgen insensitivity syndrome

    Institute of Scientific and Technical Information of China (English)

    XIAO Yuan; WANG De-fen; LI Xiao-ying; YANG Jun; WANG Wei

    2010-01-01

    @@ Androgen insensitivity syndrome (AIS) was first described by the American gynecologist Morris in 1953 and was initially described in 82 patients.1 The syndrome was designated "testicular feminization syndrome" , because the testes produce hormones with estrogen-like actions.1 Clinical AIS manifestations include the appearance of normal female external genitalia without internal female genital organs. Other clinical manifestations include undescended testes, normal female breast development, and scant axillary and pubic hair. AIS is the most common condition that cancause male undermasculinisation.

  8. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

    Science.gov (United States)

    Dubois, Vanessa; Laurent, Michaël R; Sinnesael, Mieke; Cielen, Nele; Helsen, Christine; Clinckemalie, Liesbeth; Spans, Lien; Gayan-Ramirez, Ghislaine; Deldicque, Louise; Hespel, Peter; Carmeliet, Geert; Vanderschueren, Dirk; Claessens, Frank

    2014-07-01

    Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ∼10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.-Dubois, V., Laurent, M. R., Sinnesael, M., Cielen, N., Helsen, C., Clinckemalie, L., Spans, L., Gayan-Ramirez, G., Deldicque, L., Hespel, P., Carmeliet, G., Vanderschueren, D., and Claessens, F. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

  9. 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.

  10. The Case of Ozone Depletion

    Science.gov (United States)

    Lambright, W. Henry

    2005-01-01

    While the National Aeronautics and Space Administration (NASA) is widely perceived as a space agency, since its inception NASA has had a mission dedicated to the home planet. Initially, this mission involved using space to better observe and predict weather and to enable worldwide communication. Meteorological and communication satellites showed the value of space for earthly endeavors in the 1960s. In 1972, NASA launched Landsat, and the era of earth-resource monitoring began. At the same time, in the late 1960s and early 1970s, the environmental movement swept throughout the United States and most industrialized countries. The first Earth Day event took place in 1970, and the government generally began to pay much more attention to issues of environmental quality. Mitigating pollution became an overriding objective for many agencies. NASA's existing mission to observe planet Earth was augmented in these years and directed more toward environmental quality. In the 1980s, NASA sought to plan and establish a new environmental effort that eventuated in the 1990s with the Earth Observing System (EOS). The Agency was able to make its initial mark via atmospheric monitoring, specifically ozone depletion. An important policy stimulus in many respects, ozone depletion spawned the Montreal Protocol of 1987 (the most significant international environmental treaty then in existence). It also was an issue critical to NASA's history that served as a bridge linking NASA's weather and land-resource satellites to NASA s concern for the global changes affecting the home planet. Significantly, as a global environmental problem, ozone depletion underscored the importance of NASA's ability to observe Earth from space. Moreover, the NASA management team's ability to apply large-scale research efforts and mobilize the talents of other agencies and the private sector illuminated its role as a lead agency capable of crossing organizational boundaries as well as the science-policy divide.

  11. 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.

  12. Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen-dependent prostate development.

    Science.gov (United States)

    Keil, Kimberly P; Mehta, Vatsal; Branam, Amanda M; Abler, Lisa L; Buresh-Stiemke, Rita A; Joshi, Pinak S; Schmitz, Christopher T; Marker, Paul C; Vezina, Chad M

    2012-12-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5α-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/β-catenin-responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation.

  13. Identification and characterization of the minimal androgen-regulated kidney-specific kidney androgen-regulated protein gene promoter

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The kidney androgen-regulated protein (Kap) gene is tissue specific and regulated by androgen in mouse kidney proximal tubule cells (PTCs). In the present study, we aimed to identify the minimal PTC-specific androgen-regulated Kap promoter and analyze its androgen response elements (AREs).Adeletion series of the Kap1542 promoter/luciferase constructs were assayed in opossum kidney (OK) PTCs in the presence or absence of 15 nM dihydrotestosterone (DHT). Kap 1542 and Kap637 had low activity and no androgen induction; Kap224 had a basal activity that was 4- to 5-fold higher than that of Kap 1542, but was only sfightly induced by DHT. Kap 147 had a basal activity that was 2- to 3-fold higher than that of Kap 1542 and was induced by DHT 4- to 6-fold. Kap77 abol-ished basal promoter activity but was still induced by DHT. Results showed that, in vitro, Kap147 was a minimal androgen-regulated promoter. Transient transfection in different cells demonstrated that Kap147 specifically initi-ated reporter gene expression in PTCs. Sequence analysis revealed two potential AREs located at positions -124 and -39 of Kap147. Mutational assays showed that only the ARE at -124 was involved in androgen response in OK cells. Electrophoretic mobility shift assay also verified -124 ARE bound specifically to androgen receptor. In conclusion, we defined the minimal Kap 147 promoter that may be a good model for the study of kidney PTC-specific expression and molecular mechanisms that lead to an androgen-specific responsiveness in vivo.

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

    Directory of Open Access Journals (Sweden)

    Kathy Bailey

    Full Text Available 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.

  15. 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

  16. A single nucleotide substitution introduces a premature termination codon into the androgen receptor gene of a patient with receptor-negative androgen resistance.

    OpenAIRE

    M. Marcelli; Tilley, W. D.; Wilson, C.M.; Wilson, J. D.; Griffin, J E; McPhaul, M J

    1990-01-01

    Mutations of the androgen receptor that impair the action of 5 alpha-dihydrotestosterone and testosterone result in abnormal male sexual development. The definition of the organization of the androgen receptor gene has permitted us to examine its structure in nine patients with androgen resistance that exhibit absent 5 alpha-dihydrotestosterone binding in cultured fibroblasts (receptor-negative androgen resistance). Using labeled probes specific for each individual coding exon, we find no gro...

  17. Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone.

    Science.gov (United States)

    Culig, Z; Stober, J; Gast, A; Peterziel, H; Hobisch, A; Radmayr, C; Hittmair, A; Bartsch, G; Cato, A C; Klocker, H

    1996-01-01

    The androgen receptor (AR) plays a central regulatory role in prostatic carcinoma and is a target of androgen ablation therapy. Recent detection of mutant receptors in tumor specimens suggest a contribution of AR alterations to progression towards androgen independence. In a specimen derived from metastatic prostate cancer we have reported a point mutation in the AR gene that leads to a single amino acid exchange in the ligand binding domain of the receptor. Another amino acid exchange resulting from a point mutation was also identified 15 amino acids away from our mutation. This mutation was detected in the AR gene isolated from an organ-confined prostatic tumor. Here we report the functional characterization of the two mutant receptors in the presence of adrenal androgens and testosterone metabolites. These studies were performed by cotransfecting androgen-responsive reporter genes and either the wild-type or mutant AR expression vectors into receptor negative DU-145 and CV-1 cells. The indicator genes used consisted of the promoter of the androgen-inducible prostate-specific antigen gene or the C' Delta9 enhancer fragment from the promoter of the mouse sex-limited protein driving the expression of the bacterial chloramphenicol acetyl transferase gene. Cotransfection-transactivation assays revealed that the adrenal androgen androstenedione and two products of testosterone metabolism, androsterone and androstandiol, induced reporter gene activity more efficiently in the presence of the mutant receptors than in the presence of the wild-type receptor. No difference between wild-type and mutant receptors was observed in the presence of the metabolite androstandione. The interaction of receptor-hormone complexes with target DNA was studied in vitro by electrophoretic mobility shift assays (EMSA). Dihydrotestosterone and the synthetic androgen mibolerone induced a faster migrating complex with all receptors, whereas the androgen metabolite androstandione induced this

  18. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor. PMID:27372877

  19. A case of postmenopausal androgen excess.

    Science.gov (United States)

    Lambrinoudaki, Irene; Dafnios, Nikos; Kondi-Pafiti, Agathi; Triantafyllou, Nikos; Karopoulou, Evangelia; Papageorgiou, Anastasia; Augoulea, Areti; Armeni, Eleni; Creatsa, Maria; Vlahos, Nikolaos

    2015-10-01

    Ovarian steroid cell tumors are very rare but potentially life-threatening neoplasms. They represent less than 0.1% of all ovarian tumors, typically present in premenopausal women and frequently manifest with virilization. Signs of hyperandrogenism may appear in postmenopausal women due to tumorοus and non-tumorοus adrenal and ovarian causes as well due to the normal aging process. In any case, steroid cell tumor should be suspected in postmenopausal women who present with rapid progressive androgen excess symptoms. This report describes a case of a 67-year-old postmenopausal woman with signs of hyperandrogenism, where an ovarian steroid cell tumor was diagnosed and treated by laparoscopic bilateral salpingo-oophorectomy and synchronous hysterectomy. PMID:26287476

  20. 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. PMID:24517037

  1. Anabolic androgenic steroid-induced hepatotoxicity.

    Science.gov (United States)

    Bond, Peter; Llewellyn, William; Van Mol, Peter

    2016-08-01

    Anabolic androgenic steroids (AAS) have been abused for decades by both professional and amateur athletes in order to improve physical performance or muscle mass. AAS abuse can cause adverse effects, among which are hepatotoxic effects. These effects include cholestatic icterus and possibly peliosis hepatis and hepatocellular carcinoma or adenoma. In particular, 17α-alkylated AAS appear to be hepatotoxic, whereas nonalkylated AAS appear not to be. The 17α-alkyl substitution retards hepatic metabolism of the AAS rendering it orally bioavailable. The mechanism responsible for the hepatotoxicity induced by 17α-alkylated AAS remains poorly understood. However, oxidative stress has been repeatedly shown to be associated with it. In this manuscript we present a hypothesis which describes a potential mechanism responsible for AAS-induced hepatotoxicity, based on several observations from the literature which suggest oxidative stress being a causal factor.

  2. Androgen deprivation therapy-associated vasomotor symptoms

    Institute of Scientific and Technical Information of China (English)

    Jason M Jones; Manish Kohli; Charles L Loprinzi

    2012-01-01

    Androgen deprivation therapy (ADT) is widely used as standard therapy in the treatment of locally advanced and metastatic prostate cancer.While efficacious,ADT is associated with multiple side effects,including decreased libido,erectile dysfunction,diabetes,loss of muscle tone and altered body composition,osteoporosis,lipid changes,memory loss,gynecomastia and hot flashes.The breadth of literature for the treatment of hot flashes is much smaller in men than that in women.While hormonal therapy of hot flashes has been shown to be effective,multiple non-hormonal medications and treatment methods have also been developed.This article reviews current options for the treatment of hot flashes in patients taking ADT.

  3. "When the going gets tough, who keeps going?" : Depletion sensitivity moderates the ego-depletion effect

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; De Vet, Emely; Fennis, Bob M.; De Ridder, Denise T. D.

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In thre

  4. 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

    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 th

  5. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage

    Institute of Scientific and Technical Information of China (English)

    Yuting Lin; Junichi Fukuchi; Richard A Hiipakka; John M Kokontis; Jialing Xiang

    2007-01-01

    Bcl-2 is an anti-apoptotic oncoprotein and its protein levels are inversely correlated with prognosis in many cancers.However, the role of Bcl-2 in the progression of prostate cancer is not clear. Here we report that Bcl-2 is required for the progression of LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. The mRNA and protein levels of Bcl-2 are significantly increased in androgen-independent prostate cancer cells, shRNA-mediated gene silencing of Bcl-2 in androgen-independent prostate cancer cells promotes UV-induced apoptosis and suppresses the growth of prostate tumors in vivo. Growing androgen-dependent cells under androgen-deprivation conditions results in formation of androgen-independent colonies; and the transition from androgen-dependent to androgen-independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA. Thus, our results demonstrate that Bcl-2 is not only critical for the survival of androgen-independent prostate cancer cells, but is also required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage.

  6. Genetic analysis of a family with complete androgen insensitivity syndrome

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Kota

    2013-01-01

    Full Text Available Androgen insensitivity causes impaired embryonic sex differentiation leading to developmental failure of normal male external genitalia in 46 XY genetic men. It results from diminished or absent biological actions of androgens, which is mediated by the androgen receptor (AR in both the embryo and secondary sexual development. Mutations in the AR located on the X chromosome are responsible for the disease. Almost 70% of affected individuals inherit the mutation from their carrier mother. We hereby report a 10-year-old girl with all the characteristics of complete androgen insensitivity syndrome (CAIS. Similar scenario was observed in 3 maternal aunts, Sequencing of the AR gene in all the family members revealed C 2754 to T transition in exon 6. It was concluded that the C 2754 to T transition rendered the AR incapable of both ligand-binding and activating the transcription and was the cause of CAIS in the patient.

  7. Male osteoporosis and androgenic therapy: from testosterone to SARMs.

    Science.gov (United States)

    Cilotti, Antonio; Falchetti, Alberto

    2009-09-01

    As in the women, male osteoporosis represents an important social problem, amplified by the increasing life expectance.Differently from women, 50% of male osteoporosis is secondary to treatments and/or diseases that make mandatory their search through an accurate clinical investigations in every newly diagnosed osteoporotic men. Male osteoporosis is frequently underdiagnosed and consequently undertreated, and too often it is revealed only after the occurrence of a fragility fracture. Androgens may prevent the loss of cancellous bone and stimulate periosteal cortical bone apposition. The anabolic effect of testosterone on both bone and muscle, is limited by the high incidence of androgenic side effects. Hypogonadism is the only situation where the benefits of the use of testosterone formulations exceed the side effects. Selective androgen receptor modulators can dissociate androgenic and anabolic effect on different tissues with various strategies. Many compounds have been studied with positive results in vivo and in clinical trials.

  8. 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.

  9. The 1988 Antarctic ozone depletion - Comparison with previous year depletions

    Science.gov (United States)

    Schoeberl, Mark R.; Stolarski, Richard S.; Krueger, Arlin J.

    1989-01-01

    The 1988 spring Antarctic ozone depletion was observed by TOMS to be substantially smaller than in recent years. The minimum polar total ozone values declined only 15 percent during September 1988, compared to nearly 50 percent during September 1987. At southern midlatitudes, exceptionally high total ozone values were recorded beginning in July 1988. The total integrated southern hemispheric ozone increased rapidly during the Austral spring, approaching 1980 levels during October. The high midlatitude total ozone values were associated with a substantial increase in eddy activity as indicated by the standard deviation in total ozone in the zonal band 30-60 deg S. Mechanisms through which the increased midlatitude eddy activity could disrupt the formation of the Antarctic ozone hole are briefly discussed.

  10. No effects of ingesting or rinsing sucrose on depleted self-control performance.

    Science.gov (United States)

    Boyle, N B; Lawton, C L; Allen, R; Croden, F; Smith, K; Dye, L

    2016-02-01

    Self-control tasks appear to deplete a limited resource resulting in reduced subsequent self-control performance; a state of ego depletion. Evidence of reduced peripheral glucose by exertion of self-control, and attenuation of ego depletion by carbohydrate metabolism underpins the proposition that this macronutrient provides the energetic source of self-control. However, the demonstration of positive, non-metabolic effects on ego depletion when merely sensing carbohydrates orally contradicts this hypothesis. Recent studies have also failed to support both metabolic and non-metabolic accounts. The effects of ingesting or rinsing a carbohydrate (sucrose) and an artificially sweetened (sucralose) solution on capillary blood and interstitial glucose, and depleted self-control performance were examined in older adults. Forty, healthy, adults (50-65years) ingested and rinsed sucrose and sucralose solutions in a 2 (method)×2 (source), fully counterbalanced, repeated measures, crossover design. Capillary blood and interstitial glucose responses were assayed. Depleted self-control performance (induced by the Bakan visual processing task) on an attention switch task was assessed under each study condition. Ego depletion had no consistent effects on peripheral glucose levels and no significant effects of ingesting or rinsing sucrose on self-control were observed. The act of rinsing the solutions, independent of energetic content, resulted in a small, non-significant enhancement of performance on the attention switch task relative to ingesting the same solutions (RT: p=.05; accuracy: p=.09). In conclusion, a metabolic account of self-control was not supported. Whilst a positive effect of rinsing on depleted self-control performance was demonstrated, this was independent of energetic content. Findings suggest glucose is an unlikely physiological analogue for self-control resources.

  11. Dermoscopy in Female Androgenic Alopecia: Method Standardization and Diagnostic Criteria

    OpenAIRE

    Rakowska, Adriana; Slowinska, Monika; Kowalska-Oledzka, Elzbieta; Olszewska, Malgorzata; Rudnicka, Lidia

    2009-01-01

    Objective: Establishing the trichoscopy criteria of female androgenic alopecia (FAGA). Design: Trichoscopy images were retrospectively evaluated. Setting: Dermatologic hospital-based clinic and private practice offices. Patients and methods: One hundred and thirty-one females (59 with androgenic alopecia, 33 with chronic telogen effluvium (CTE), 39 healthy controls). The diagnosis was based on clinical examination and confirmed by histopatology. Main Outcome Measure: Trichoscopy results obtai...

  12. Training volume, androgen use and serum creatine kinase activity.

    OpenAIRE

    Häkkinen, K; Alén, M

    1989-01-01

    Serum creatine kinase (CK) activities were investigated in elite male strength athletes (n = 20) during normal weight training and bodybuilding training (one training session per day), during high volume strength training (two sessions per day) and during strength training (one session per day) with the use of high dose synthetic androgens (five athletes in each subgroup). The findings demonstrated that the increase in serum CK was highest in the subgroup using androgens. These results sugges...

  13. Cortical venous thrombosis following exogenous androgen use for bodybuilding

    OpenAIRE

    Sveinsson, Olafur; Herrman, Lars

    2013-01-01

    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 pat...

  14. 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.

  15. Impact of early postnatal androgen exposure on voice development.

    Directory of Open Access Journals (Sweden)

    Leila Grisa

    Full Text Available BACKGROUND: The impact of early postnatal androgen exposure on female laryngeal tissue may depend on certain characteristics of this exposure. We assessed the impact of the dose, duration, and timing of early androgen exposure on the vocal development of female subjects who had been treated for adrenocortical tumor (ACT in childhood. METHODS: The long-term effects of androgen exposure on the fundamental vocal frequency (F0, vocal pitch, and final height and the presence of virilizing signs were examined in 9 adult (age, 18.4 to 33.5 years and 10 adolescent (13.6 to 17.8 years female ACT patients. We also compared the current values with values obtained 0.9 years to 7.4 years after these subjects had undergone ACT surgery, a period during which they had shown normal androgen levels. RESULTS: Of the 19 subjects, 17 (89% had been diagnosed with ACT before 4 years of age, 1 (5% at 8.16 years, and 1 (5% at 10.75 years. Androgen exposure (2 to 30 months was sufficiently strong to cause pubic hair growth in all subjects and clitoromegaly in 74% (14/19 of the subjects, but did not reduce their height from the target value. Although androgen exposure induced a remarkable reduction in F0 (132 Hz and moderate pitch virilization in 1 subject and partial F0 virilization, resulting in F0 of 165 and 169 Hz, in 2 subjects, the majority had normal F0 ranging from 189 to 245 Hz. CONCLUSIONS: Female laryngeal tissue is less sensitive to androgen exposure between birth and adrenarche than during other periods. Differential larynx sensitivity to androgen exposure in childhood and F0 irreversibility in adulthood are age-, concentration-, duration-, and timing-dependent events that may also be affected by exposure to inhibitory or stimulatory hormones. Further studies are required to better characterize each of these factors.

  16. Minoxidil may suppress androgen receptor-related functions

    OpenAIRE

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

    2014-01-01

    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-positi...

  17. 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....

  18. Androgenic regulation of novel genes in the epididymis

    Institute of Scientific and Technical Information of China (English)

    Bernard Robaire; Shayesta Seenundun; Mahsa Hamzeh; Sophie-Anne Lamour

    2007-01-01

    The epididymis is critically dependent on the presence of the testis. Although several hormones, such as retinoids and progestins, and factors secreted directly into the epididymal lumen, such as androgen binding protein and fibroblast growth factor, might play regulatory roles in epididymal function, testosterone (T) and its metabolites,dihydrotestosterone (DHT) and estradiol (E2), are accepted as the primary regulators of epididymal structure and functions, with the former playing the greater role. To ascertain the molecular action of androgens on the epididymis,three complementary approaches were pursued to monitor changes in gene expression in response to different hormonal milieux. The first was to establish changes in gene expression along the epididymis as androgenic support is withdrawn. The second was to determine the sequence of responses that occur in an androgen deprived tissue upon re-administration of the two metabolites of T, DHT and E2. The third was to study the effects of androgen withdrawal and re-administration on gene expression in immortalized murine caput epididymidal principal cells. Specific responses were observed under each of these conditions, with an expected major difference in the panoply of genes expressed upon hormone withdrawal and re-administration; however, some key common features were the common roles of genes in insulin like growth factor/epidermal growth factor and the relatively minor and specific effects of E2 as compared to DHT. Together, these results provide novel insights into the mechanisms of androgen regulation in epididymal principal cells.

  19. 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.

  20. Androgen receptor: structure, role in prostate cancer and drug discovery.

    Science.gov (United States)

    Tan, M H Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

    2015-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

  1. Enhanced evaluation of selective androgen receptor modulators in vivo.

    Science.gov (United States)

    Otto-Duessel, M; He, M; Adamson, T W; Jones, J O

    2013-01-01

    Selective androgen receptor modulators (SARMs) are a class of drugs that control the activity of the androgen receptor (AR), which mediates the response to androgens, in a tissue-selective fashion. They are specifically designed to reduce the possible complications that result from the systemic inhibition or activation of AR in patients with diseases that involve androgen signalling. However, there are no ideal in vivo models for evaluating candidate SARMs. Therefore, we created a panel of androgen-responsive genes in clinically relevant AR expressing tissues including prostate, skin, bone, fat, muscle, brain and kidney. We used select genes from this panel to compare transcriptional changes in response to the full agonist dihydrotestosterone (DHT) and the SARM bolandiol at 16 h and 6 weeks. We identified several genes in each tissue whose expression at each of these time points correlates with the known tissue-specific effects of these compounds. For example, in the prostate we found four genes whose expression was much lower in animals treated with bolandiol compared with animals treated with DHT for 6 weeks, which correlated well with differences in prostate weight. We demonstrate that adding molecular measurements (androgen-regulated gene expression) to the traditional physiological measurements (tissue weights, etc.) makes the evaluation of potential SARMs more accurate, thorough and perhaps more rapid by allowing measurement of selectivity after only 16 h of drug treatment.

  2. Synthesis and biological evaluation of febrifugine analogues.

    Science.gov (United States)

    Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

    2014-12-01

    A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity. PMID:25632466

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

    International Nuclear Information System (INIS)

    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-59Fe-disappearance rate, RBC 59Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

  4. Pomegranate Polyphenols Downregulate Expression of Androgen Synthesizing Genes in Human Prostate Cancer Cells Overexpressing the Androgen Receptor

    OpenAIRE

    Hong, Mee Young; Seeram, Navindra P.; Heber, David

    2008-01-01

    Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state where they progress in the absence of circulating testosterone leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis which maintains cancer cell growth in the absence of significant amounts ...

  5. Space analogue studies in Antarctica

    Science.gov (United States)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  6. Condensed matter analogues of cosmology

    Science.gov (United States)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the

  7. Antimicrobial Activity of Resveratrol Analogues

    Directory of Open Access Journals (Sweden)

    Malik Chalal

    2014-06-01

    Full Text Available Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew. Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold. The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups and antimicrobial activity.

  8. Depleted uranium disposal options evaluation

    International Nuclear Information System (INIS)

    The Department of Energy (DOE), Office of Environmental Restoration and Waste Management, has chartered a study to evaluate alternative management strategies for depleted uranium (DU) currently stored throughout the DOE complex. Historically, DU has been maintained as a strategic resource because of uses for DU metal and potential uses for further enrichment or for uranium oxide as breeder reactor blanket fuel. This study has focused on evaluating the disposal options for DU if it were considered a waste. This report is in no way declaring these DU reserves a ''waste,'' but is intended to provide baseline data for comparison with other management options for use of DU. To PICS considered in this report include: Retrievable disposal; permanent disposal; health hazards; radiation toxicity and chemical toxicity

  9. Depleted Argon from Underground Sources

    International Nuclear Information System (INIS)

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however 39Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in 39Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO2 well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO2. We first concentrate the argon locally to 3% in an Ar, N2, and He mixture, from the CO2 through chromatographic gas separation, and then the N2 and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO2 facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  10. Depleted uranium. Nuclear related problems

    International Nuclear Information System (INIS)

    Depleted uranium (DU) has found a military application in Golf War, in Bosnia and in Yugoslavia (Kosovo). In military sense it was very efficient. But the fact that some parts of that ammunition are manufactured from depleted uranium, low level radioactive waste, implies other aspects of this application like radiological, ecological, jurist, ethical and psychological. The subject of this paper is just physical aspect. There are several problems concerning this aspect: production of DU, total amount of DU in the world, 235U/238U relation, radioactivity of DU, measurements, and presence of other radionuclides like plutonium. DU is by product of nuclear technology and represents low-level nuclear waste. Therefore it should be stored. Total amount of DU in the world is about one million tons with an annual increase of 30 000 t. The content of 235U in DU can vary in the range 0.16-0.3%. The total radioactivity of DU is a consequence of 7 radionuclides and amounts 39.42 Bq/mg. This include alpha, beta and gamma radioactivity. Because of characteristics of this radioactivity it is difficult to prospect the terrain except at the site of action. During the impact of DU rods four types of DU particles could be produced: whole penetrators, penetrator parts, big aerosols (>10 μm) and small aerosols (<10 μm). Most of these particles fall locally, although some of them could be find several tens of kilometers away. All these problems have been discussed in this paper. (author)

  11. Sulfur analogues of psychotomimetic agents. Monothio analogues of mescaline and isomescaline.

    Science.gov (United States)

    Jacob, P; Shulgin, A T

    1981-11-01

    Two monothio analogues of mescaline and three monothio analogues of 2,3,4-trimethoxyphenethylamine (isomescaline) have been synthesized and characterized. Only the two mescaline analogues (3-and 4-thiomescaline) were found to be psychotomimetics in man, being 6 and 12 times more potent than mescaline, respectively. All five compounds can serve as substrates for bovine plasma monoamine oxidase in vitro, but no positive correlation is apparent between the extent of enzymatic degradation and human psychotomimetic potency.

  12. Acoustojet: acoustic analogue of photonic jet phenomenon

    CERN Document Server

    Minin, Igor V

    2016-01-01

    It has been demonstrated for the first time that an existence of acoustic analogue of photonic jet phenomenon, called acoustojet, providing for subwavelength localization of acoustic field in the shadow area of arbitrary 3D penetrable mesoscale particle, is possible.

  13. Natural analogues and radionuclide transport model validation

    International Nuclear Information System (INIS)

    In this paper, some possible roles for natural analogues are discussed from the point of view of those involved with the development of mathematical models for radionuclide transport and with the use of these models in repository safety assessments. The characteristic features of a safety assessment are outlined in order to address the questions of where natural analogues can be used to improve our understanding of the processes involved and where they can assist in validating the models that are used. Natural analogues have the potential to provide useful information about some critical processes, especially long-term chemical processes and migration rates. There is likely to be considerable uncertainty and ambiguity associated with the interpretation of natural analogues, and thus it is their general features which should be emphasized, and models with appropriate levels of sophistication should be used. Experience gained in modelling the Koongarra uranium deposit in northern Australia is drawn upon. (author)

  14. Total Synthesis of the Analogue of Icogenin

    Institute of Scientific and Technical Information of China (English)

    Shu Jie HOU; Peng XU; Liang ZHOU; De Quan YU; Ping Sheng LEI; Chuan Chun ZOU

    2006-01-01

    One of the analogues of icogenin, a natural furostanol saponin showing strong cytotoxic effect on cancer cell, was first synthesized via convergent strategy by using diosgenin and available monosaccharides as starting materials,

  15. Second-Generation Fluorescent Quadracyclic Adenine Analogues

    DEFF Research Database (Denmark)

    Dumat, Blaise; Bood, Mattias; Wranne, Moa S.;

    2015-01-01

    Fluorescent base analogues comprise a group of increasingly important molecules for the investigation of nucleic acid structure, dynamics, and interactions with other molecules. Herein, we report on the quantum chemical calculation aided design, synthesis, and characterization of four new putativ...

  16. The structure activity relationship of discodermolide analogues.

    Science.gov (United States)

    Shaw, Simon J

    2008-03-01

    The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

  17. Newer insulin analogues and inhaled insulin

    OpenAIRE

    Girish C; Manikandan S; Jayanthi M

    2006-01-01

    Diabetes is a metabolic disease with high prevalence worldwide. Exogenous insulin is used in the management of this condition. The development of human insulin has provided tighter control of glycaemia in diabetic patients. Insulin analogues like insulin lispro and aspart were developed to closely match its profile with physiological secretion. The newer additions to this armamentarium are insulin glulisine, insulin detemir and albulin.Insulin glulisine is a short acting analogue with a rapid...

  18. Synthesis of caged Garcinia xanthone analogues

    OpenAIRE

    Cho, Woo Cheal

    2009-01-01

    A new synthetic strategy is developed toward the synthesis of the caged Garcinia xanthone analogues. The key to the strategy is a Pd-catalyzed reverse prenylation reaction. This new synthetic approach provides a rapid and efficient access to various caged analogues, including cluvenone which is known to induce apoptosis and exhibit significant cytotoxicity in various cancer cell lines. Evaluation of their growth inhibitory activities also leads to identification of the pharmacophoric motif of...

  19. Somatostatin analogue treatment of neuroendocrine tumours.

    OpenAIRE

    de Herder, W. W.; van der Lely, A.J.; Lamberts, S. W.

    1996-01-01

    The long-acting analogues of somatostatin have an established place in the medical treatment of patients with neuroendocrine tumours. They act through binding with specific, high-affinity membrane receptors. Somatostatin analogue therapy is an effective and safe treatment for most growth hormone and thyrothropin-secreting pituitary adenomas. The potential therapeutic consequences of the presence of somatostatin receptors on clinically 'nonfunctioning' pituitary tumours are still uncertain. So...

  20. Clodronate treatment significantly depletes macrophages in chickens

    OpenAIRE

    Kameka, Amber M.; Haddadi, Siamak; Jamaldeen, Fathima Jesreen; Moinul, Prima; He, Xiao T.; Nawazdeen, Fathima Hafsa P.; Bonfield, Stephan; Sharif, Shayan; van Rooijen, Nico; Abdul-Careem, Mohamed Faizal

    2014-01-01

    Macrophages function as phagocytes and antigen-presenting cells in the body. As has been demonstrated in mammals, administration of clodronate [dichloromethylene bisphosphonate (Cl2MBP)] encapsulated liposomes results in depletion of macrophages. Although this compound has been used in chickens, its effectiveness in depleting macrophages has yet to be fully determined. Here, we show that a single administration of clodronate liposomes to chickens results in a significant depletion of macropha...

  1. Repulsive depletion interactions in colloid polymer mixtures

    OpenAIRE

    Rudhardt, Daniel; Bechinger, Clemens; Leiderer, Paul

    1999-01-01

    Depletion forces in colloidal systems are known to be entirely attractive, as long as the background of macromolecules is small enough that an ideal gas approach is valid. At higher densities, however, structural correlation effects of the macromolecules which lead to additional repulsive parts in the depletion interaction, have to be taken into account. We have measured the depletion interaction between a single polystyrene sphere and a wall in the presence of non-ionic polymer coils. Althou...

  2. 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.

  3. 50 CFR 216.15 - Depleted species.

    Science.gov (United States)

    2010-10-01

    ... Assistant Administrator as depleted under the provisions of the MMPA. (a) Hawaiian monk seal (Monachus schauinslandi). (b) Bowhead whale (Balaena mysticetus). (c) North Pacific fur seal (Callorhinus...

  4. Ego depletion increases risk-taking.

    Science.gov (United States)

    Fischer, Peter; Kastenmüller, Andreas; Asal, Kathrin

    2012-01-01

    We investigated how the availability of self-control resources affects risk-taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk-taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings. PMID:22931000

  5. Illicit anabolic-androgenic steroid use.

    Science.gov (United States)

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

    2010-06-01

    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

  6. 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).

  7. Expression of Androgen Receptor in Meningiomas

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In order to investigate the expression of androgen receptor (AR) in meningiomas and its relation to tumor proliferative potential, we examined the expression of AR and proliferating cell nuclear antigen (PCNA) by avidine-biotin complex immunohistochemistry in 39 cases of meningiomas. Of the 39 cases of meningiomas, 20(51 %) showed positive AR immunoreactivity. The AR expression positivity rates were 31 % (6/19) in benign meningiomas, 58 % (7/12) in atypical meningiomas, 87.5 % (7/8) in malignant meningiomas, respectively. In addition to the tumor cells, cells of microvascular endothelial proliferation were frequently AR positive. Malignant meningiomas had a significantly higher percentage of AR positive cells compared with atypical and benign meningiomas (P<0.05). The mean proliferating cell nuclear antigen labeling index (PCNA LI) was significantly higher in the malignant meningiomas when compared with atypical meningiomas (P<0.05) and benign meningiomas (P<0.05). AR positive meningiomas had higher PCNA LI than AR negative meningiomas (P<0.05). The expression of AR in tumor tissues was significantly related with PCNA LI. These data indicated that AR in the meningiomas was correlated with histological grade and AR might participate in the growth of these tumors and tumor angiogenesis. The measurement of AR in these tumors may indirectly represent tumor growth potential.

  8. Effect of androgen deprivation on penile ultrastructure

    Institute of Scientific and Technical Information of China (English)

    Zhou-JunSHEN; Xie-LaiZHOU; Ying-LiLU; Zhao-DianCHEN

    2003-01-01

    Aim:To investigate the ultrastructural changes of penile corpus cavernosum and tunica albuginea in rats treated with castration or finasteride.Methods:Eighteen male Sprague-Dawley rats of nine weeks old were randomly divided into three groups with 6 rats each,Group A served as the control,Group B was castrated and Group C,treated with finasteride,Four weeks later,rats were anesthetized and blood samples obtained for the determination of serum testosterone(T)and dihydrotestosterone(DHT) levels;penile tissues were taken for scanning electron microscopy.Results:The T,free T and DHT levels in Group B and the DHT level in Group C were significantly lower than those in Group A(P0.05).Elastic fibers in the tunica albuginea of Group A were very rich and arranged regularly and undulatedly,but in Group B,most of the elastic fibers were replaced by collagenous fibers.In Group C,the tunica albuginea was mainly composed of thick and irregular-arranged collagenous fibers.In Group A,there were abundant smooth muscle fibers in the trabeculae of corpus cavernosum,but they were much less in Group C and scarce or even disappeared in Group B.In Groups B and C,the diminished/disappeared smooth muscle fibers were replaced by irregularly arranged collagenous fibers.Conclusion:In rats,androgen is essential for maintaining the normal structure of penile tunica albuginea and corpus carvenosum.

  9. 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.

  10. Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions.

    Science.gov (United States)

    Dubois, Vanessa; Laurent, Michaël; Boonen, Steven; Vanderschueren, Dirk; Claessens, Frank

    2012-05-01

    Androgens increase both the size and strength of skeletal muscle via diverse mechanisms. The aim of this review is to discuss the different cellular targets of androgens in skeletal muscle as well as the respective androgen actions in these cells leading to changes in proliferation, myogenic differentiation, and protein metabolism. Androgens bind and activate a specific nuclear receptor which will directly affect the transcription of target genes. These genes encode muscle-specific transcription factors, enzymes, structural proteins, as well as microRNAs. In addition, anabolic action of androgens is partly established through crosstalk with other signaling molecules such as Akt, myostatin, IGF-I, and Notch. Finally, androgens may also exert non-genomic effects in muscle by increasing Ca(2+) uptake and modulating kinase activities. In conclusion, the anabolic effect of androgens on skeletal muscle is not only explained by activation of the myocyte androgen receptor but is also the combined result of many genomic and non-genomic actions.

  11. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.

    Science.gov (United States)

    Zhu, Meng-Lei; Bakhru, Pearl; Conley, Bridget; Nelson, Jennifer S; Free, Meghan; Martin, Aaron; Starmer, Joshua; Wilson, Elizabeth M; Su, Maureen A

    2016-01-01

    Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity. PMID:27072778

  12. Postmenopausal serum androgens, oestrogens and breast cancer risk : the European prospective investigation into cancer and nutrition

    NARCIS (Netherlands)

    Kaaks, R; Rinaldi, S; Key, TJ; Berrino, F; Peeters, PHM; Biessy, C; Dossus, L; Lukanova, A; Binghan, S; Khaw, KTG; Allen, NE; Bueno-De-Mesquita, HB; van Gils, CH; Grobbee, D; Boeing, H; Lahmann, PH; Nagel, G; Chang-Claude, J; Clavel-Chapelon, F; Fournier, A; Thiebaut, A; Gonzalez, CA; Quiros, [No Value; Tormo, MJ; Ardanaz, E; Amiano, P; Krogh, [No Value; Palli, D; Panico, S; Tumino, R; Vineis, P; Trichopoulou, A; Kalapothaki, [No Value; Trichopoulos, D; Ferrari, P; Norat, T; Saracci, R; Riboli, E

    2005-01-01

    Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids - notably androgens and oestrogens - promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has

  13. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition

    NARCIS (Netherlands)

    Kaaks, R.; Rinaldi, S.; Key, T.J.; Berrino, F.; Peeters, P.H.M.; Biessy, C.; Dossus, L.; Lukanova, A.; Bingham, S.; Khaw, K-T.; Allen, N.E.; Bueno-de-Mesquita, H.B.; Gils, C.H. van; Grobbee, D.E.; Boeing, H.; Lahmann, P.H.; Nagel, G.; Chang-Claude, J.; Clavel-Chapelon, F.; Fournier, A.; Thiébaut, A.; Gonzalez, C.A.; Quirós, J.R.; Tormo, M-J.; Ardanaz, E.; Amiano, P.; Krogh, V.; Palli, D.; Panico, S.; Tumino, R.; Vineis, P.; Trichopoulou, A.; Kalapothaki, V.; Trichopoulos, D.; Ferrari, P.; Norat, T.; Saracci, R.; Riboli, E.

    2005-01-01

    Considerable experimental and epidemiological evidence suggests that elevated endogenous sex steroids — notably androgens and oestrogens — promote breast tumour development. In spite of this evidence, postmenopausal androgen replacement therapy with dehydroepiandrosterone (DHEA) or testosterone has

  14. Depleted argon from underground sources

    Energy Technology Data Exchange (ETDEWEB)

    Back, H.O.; /Princeton U.; Alton, A.; /Augustana U. Coll.; Calaprice, F.; Galbiati, C.; Goretti, A.; /Princeton U.; Kendziora, C.; /Fermilab; Loer, B.; /Princeton U.; Montanari, D.; /Fermilab; Mosteiro, P.; /Princeton U.; Pordes, S.; /Fermilab

    2011-09-01

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic {sup 39}Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in {sup 39}Ar. In Cortez Colorado a CO{sub 2} well has been discovered to contain approximately 500ppm of argon as a contamination in the CO{sub 2}. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation. The N{sub 2} and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  15. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-01-01

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors. PMID:27623747

  16. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V.

    2016-01-01

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors. PMID:27623747

  17. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-09-14

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.

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

    International Nuclear Information System (INIS)

    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 10-9M) and in a saturable manner. The number of binding sites was comparable to that for 5α-dihydrotestosterone (5α-DHT). [3H]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 [3H]-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 [3H]TSAA-291 was examined, specific binding of [3H]TSAA-291 was observed in fractions corresponding to 8-10 S. Binding of the [3H]TSAA-291-macromolecules comples to prostatic nuclei and DNA-cellulose was considerably less than binding by the [3H]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)

  19. Identification of Comamonas testosteroni as an androgen degrader in sewage

    Science.gov (United States)

    Chen, Yi-Lung; Wang, Chia-Hsiang; Yang, Fu-Chun; Ismail, Wael; Wang, Po-Hsiang; Shih, Chao-Jen; Wu, Yu-Ching; Chiang, Yin-Ru

    2016-01-01

    Numerous studies have reported the masculinization of freshwater wildlife exposed to androgens in polluted rivers. Microbial degradation is a crucial mechanism for eliminating steroid hormones from contaminated ecosystems. The aerobic degradation of testosterone was observed in various bacterial isolates. However, the ecophysiological relevance of androgen-degrading microorganisms in the environment is unclear. Here, we investigated the biochemical mechanisms and corresponding microorganisms of androgen degradation in aerobic sewage. Sewage samples collected from the Dihua Sewage Treatment Plant (Taipei, Taiwan) were aerobically incubated with testosterone (1 mM). Androgen metabolite analysis revealed that bacteria adopt the 9, 10-seco pathway to degrade testosterone. A metagenomic analysis indicated the apparent enrichment of Comamonas spp. (mainly C. testosteroni) and Pseudomonas spp. in sewage incubated with testosterone. We used the degenerate primers derived from the meta-cleavage dioxygenase gene (tesB) of various proteobacteria to track this essential catabolic gene in the sewage. The amplified sequences showed the highest similarity (87–96%) to tesB of C. testosteroni. Using quantitative PCR, we detected a remarkable increase of the 16S rRNA and catabolic genes of C. testosteroni in the testosterone-treated sewage. Together, our data suggest that C. testosteroni, the model microorganism for aerobic testosterone degradation, plays a role in androgen biodegradation in aerobic sewage. PMID:27734937

  20. Development of the VCaP Androgen Independent Model of Prostate Cancer

    OpenAIRE

    Loberg, Robert D; St. John, Lauren N; Day, LaShon L.; Neeley, Chris K; Kenneth J. Pienta

    2006-01-01

    Prostate epithelial cell growth is dependent on the presence of androgens and the transition of prostate cancer to an androgen independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male SCID mice. Androgen independence was confirmed by WST-1 (a tetraz...

  1. Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer.

    OpenAIRE

    Sehgal, I.; Powers, S.; B. Huntley; Powis, G; Pittelkow, M; Maihle, N J

    1994-01-01

    After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to ...

  2. Androgen Receptor Accelerates Premature Senescence of Human Dermal Papilla Cells in Association with DNA Damage

    OpenAIRE

    Yi-Chien Yang; Hung-Chun Fu; Ching-Yuan Wu; Kuo-Ting Wei; Ko-En Huang; Hong-Yo Kang

    2013-01-01

    The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16(INK4a), and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature...

  3. Hyperactive androgen receptor in prostate cancer, what does it mean for new therapy concepts?

    OpenAIRE

    Culig, Z.; Hobisch, A.; Hittmair, A; Radmayr, C.; Peterziel, H.; Bartsch, G; Cato, A. C. B.; Klocker, H

    1997-01-01

    Investigations on androgen signaling alterations in the late stages of prostate cancer revealed new molecular mechanisms that may be in part responsible for failure of endocrine therapy. Both primary and metastatic lesions from prostate cancer express androgen receptor protein. Amplification of androgen receptor gene occurs in a subset of prostate cancer patients. Several point mutations of androgen receptor gene have been described; they generate receptors whi...

  4. Androgen Receptor Accelerates Premature Senescence of Human Dermal Papilla Cells in Association with DNA Damage

    OpenAIRE

    Yang, Yi-Chien; Fu, Hung-Chun; Wu, Ching-Yuan; Wei, Kuo-Ting; Huang, Ko-En; Kang, Hong-Yo

    2013-01-01

    The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16 INK4a , and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature...

  5. A case of androgen-secreting adrenal carcinoma with non-classical congenital adrenal hyperplasia

    OpenAIRE

    Tarun Varma; Roopal Panchani; Ashutosh Goyal; Robin Maskey

    2013-01-01

    Androgen excess is one of the most common and disturbing endocrine disorder of reproductive-aged women, affecting approximately 7% of this population Androgen excess results in the development of androgenic features in the women affected, with the development of hirsutism, androgenic alopecia, ovulatory dysfunction, and, if extreme, even virilization and masculinization. Adrenocortical carcinoma (ACC) is a rare malignancy accounting for 0.02% of all annual cancers reported. About 60% are func...

  6. Sequence variation in the androgen receptor gene is not a common determinant of male sexual orientation.

    OpenAIRE

    Macke, J. P.; Hu, N; S. Hu; Bailey, M.; King, V L; Brown, T.; Hamer, D; Nathans, J

    1993-01-01

    To test the hypothesis that DNA sequence variation in the androgen receptor gene plays a causal role in the development of male sexual orientation, we have (1) measured the degree of concordance of androgen receptor alleles in 36 pairs of homosexual brothers, (2) compared the lengths of polyglutamine and polyglycine tracts in the amino-terminal domain of the androgen receptor in a sample of 197 homosexual males and 213 unselected subjects, and (3) screened the the entire androgen receptor cod...

  7. Androgen-dependent apoptosis in male germ cells is regulated through the proto-oncoprotein Cbl

    OpenAIRE

    El Chami, Nisrine; Ikhlef, Fouziha; Kaszas, Krisztian; Yakoub, Sadok; Tabone, Eric; Siddeek, Benazir; Cunha, Stéphanie; Beaudoin, Claude; Morel, Laurent; Benahmed, Mohamed; Régnier, Daniel C.

    2005-01-01

    The proto-oncoprotein Cbl is known to control several signaling processes. It is highly expressed in the testis, and because spermatogenesis is androgen dependent, we investigated the androgen dependency expression of Cbl through its testicular sublocalization and its expression levels in rats that were exposed to the antiandrogen flutamide or were hypophysectomized. We report the androgen dependency of Cbl as it localizes in pachytene spermatocytes during androgen-dependent stages, is down-r...

  8. Andrographolide Targets Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

    OpenAIRE

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2011-01-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The auth...

  9. Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate.

    Science.gov (United States)

    Purushottamachar, Puranik; Kwegyir-Afful, Andrew K; Martin, Marlena S; Ramamurthy, Vidya P; Ramalingam, Senthilmurugan; Njar, Vincent C O

    2016-07-14

    Degradation of all forms of androgen receptors (ARs) is emerging as an advantageous therapeutic paradigm for the effective treatment of prostate cancer. In continuation of our program to identify and develop improved efficacious novel small-molecule agents designed to disrupt AR signaling through enhanced AR degradation, we have designed, synthesized, and evaluated novel C-3 modified analogues of our phase 3 clinical agent, galeterone (5). Concerns of potential in vivo stability of our recently discovered more efficacious galeterone 3β-imidazole carbamate (6) led to the design and synthesis of new steroidal compounds. Two of the 11 compounds, 3β-pyridyl ether (8) and 3β-imidazole (17) with antiproliferative GI50 values of 3.24 and 2.54 μM against CWR22Rv1 prostate cancer cell, are 2.75- and 3.5-fold superior to 5. In addition, compounds 8 and 17 possess improved (∼4-fold) AR-V7 degrading activities. Importantly, these two compounds are expected to be metabolically stable, making them suitable for further development as new therapeutics against all forms of prostate cancer. PMID:27437082

  10. Oil depletion and terms of trade

    OpenAIRE

    Irimia-Vladu, Marina; Thompson, Henry

    2007-01-01

    A model of the international oil market model with optimal depletion and offer curves suggests importers face a backward bending offer curve. An oil tariff would then raise oil imports and lower the price of oil including the tariff. Simulations of price and extraction paths for the coming century provide insight into the future of oil depletion and terms of trade.

  11. Depletion sensitivity predicts unhealthy snack purchases

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; Fennis, Bob M.; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose we

  12. Depletion sensitivity predicts unhealthy snack purchases

    NARCIS (Netherlands)

    Salmon, Stefanie J.; Adriaanse, Marieke A.; Fennis, Bob M.; Vet, De Emely; Ridder, De Denise T.D.

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose

  13. The Chemistry and Toxicology of Depleted Uranium

    Directory of Open Access Journals (Sweden)

    Sidney A. Katz

    2014-03-01

    Full Text Available Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U down to reactor grade uranium (~5% 235U, and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles. Such weapons were used by the military in the Persian Gulf, the Balkans and elsewhere. The testing of depleted uranium weapons and their use in combat has resulted in environmental contamination and human exposure. Although the chemical and the toxicological behaviors of depleted uranium are essentially the same as those of natural uranium, the respective chemical forms and isotopic compositions in which they usually occur are different. The chemical and radiological toxicity of depleted uranium can injure biological systems. Normal functioning of the kidney, liver, lung, and heart can be adversely affected by depleted uranium intoxication. The focus of this review is on the chemical and toxicological properties of depleted and natural uranium and some of the possible consequences from long term, low dose exposure to depleted uranium in the environment.

  14. 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...

  15. Proteomic analysis of androgen-regulated protein expression in a mouse fetal vas deferens cell line

    NARCIS (Netherlands)

    A. Umar (Arzu); T.M. Luider (Theo); C.A. Berrevoets (Cor); J.A. Grootegoed (Anton); A.O. Brinkmann (Albert)

    2003-01-01

    textabstractDuring sex differentiation, androgens are essential for development of the male genital tract. The Wolffian duct is an androgen-sensitive target tissue that develops into the epididymis, vas deferens, and seminal vesicle. The present study aimed to identify androgen-reg

  16. Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor.

    Science.gov (United States)

    Li, Huifang; Ban, Fuqiang; Dalal, Kush; Leblanc, Eric; Frewin, Kate; Ma, Dennis; Adomat, Hans; Rennie, Paul S; Cherkasov, Artem

    2014-08-14

    The human androgen receptor (AR) is considered as a master regulator in the development and progression of prostate cancer (PCa). As resistance to clinically used anti-AR drugs remains a major challenge for the treatment of advanced PCa, there is a pressing need for new anti-AR therapeutic avenues. In this study, we identified a binding site on the DNA binding domain (DBD) of the receptor and utilized virtual screening to discover a set of micromolar hits for the target. Through further exploration of the most potent hit (1), a structural analogue (6) was identified demonstrating 10-fold improved anti-AR potency. Further optimization resulted in a more potent synthetic analogue (25) with anti-AR potency comparable to a newly FDA-approved drug Enzalutamide. Site-directed mutagenesis demonstrated that the developed inhibitors do interact with the intended target site. Importantly, the AR DBD inhibitors could effectively inhibit the growth of Enzalutamide-resistant cells as well as block the transcriptional activity of constitutively active AR splice variants, such as V7.

  17. Specification for the VERA Depletion Benchmark Suite

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kang Seog [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  18. Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues

    Directory of Open Access Journals (Sweden)

    Xu-Wen Li

    2013-07-01

    Full Text Available Aurachins are myxobacterial 3-farnesyl-4(1H-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

  19. 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.

  20. Intermittent versus continuous androgen deprivation therapy.

    Science.gov (United States)

    Higano, Celestia S

    2014-05-01

    Androgen deprivation therapy (ADT) has been the standard of care for metastatic prostate cancer for decades; however, the choice of continuous or intermittent administration is a matter of debate. Two large phase III trials have reported results comparing these 2 forms of ADT administration. The National Cancer Institute of Canada (NCIC) PR-7 trial studied men with an increasing prostate-specific antigen (PSA) level and no evidence of metastatic disease after definitive or salvage radiation therapy and radical prostatectomy. The Southwest Oncology Group 9346 trial studied men with newly diagnosed hormone-sensitive metastatic disease. The primary end point in both trials was overall survival with a noninferiority design. The NCIC trial showed that the overall survival in men treated with intermittent ADT was not inferior to that of men treated with continuous ADT, but the SWOG trial was inconclusive regarding noninferiority. Certain domains of quality of life were better in the intermittent arms of both trials. If using ADT in the setting of biochemical relapse, intermittent ADT should be strongly considered over continuous ADT, except perhaps in patients with Gleason score of 8 or higher. In men with metastatic disease, continuous ADT remains the standard of care, because the SWOG trial did not establish noninferiority of intermittent ADT with respect to survival. However, for those with significant side effects from ADT, establishing the risk group, as determined by PSA value after 7 months of ADT or the presence of pain at diagnosis, may help guide the choice of intermittent versus continuous ADT in men with metastatic disease. PMID:24812139

  1. Detection of androgen receptor in human prostatic adenoma by autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Demura, Takayoshi; Sakashita, Shigeo; Takamura, Takao; Kuroda, Kazuhide (Asahikawa Medical Coll., Hokkaido (Japan))

    1982-09-01

    We developed a new amplified method to detect the localization of androgen receptors within the human prostatic tissue specimens. The tissue sections were treated with 50 ..mu..l of 100 nM tritiated dihydrotestosterone (/sup 3/H-DHT). The binding of /sup 3/H-DHT to receptors was demonstrated as silver grains on the stained tissue sections. The binding of /sup 3/H-DHT to the prostatic tissue was inhibited by additional non-radioactive DHT remarkably and by testosterone partially, but not affected by additional progesterone and 17..beta..-estradiol. No binding of /sup 3/H-DHT to the bladder tissue was found. These results showed that the binding of /sup 3/H-DHT to the prostatic tissue was a specific reaction of /sup 3/H-DHT and androgen receptor. Androgen receptors were seen in the nuclei and the cytoplasmas of glandular epithelial cells of prostate. However, stromal cells contained less abundant androgen receptors. The method reported here has several advantages in detecting the androgen receptor of the prostatic tissue in comparison with the radioreceptor assay and other histochemical methods. 1) The needle biopsied specimens are big enough to examine. 2) Morphological observations are also possible on the same specimen because the specimens are stained with hematoxylin simultaneously. Therefore, we can know the relative ratio of androgen receptor positive cells and negative cells. 3) Binding of /sup 3/H-DHT to the receptor with this method may be more specific than other histochemical methods, since binding of /sup 3/H-DHT to the receptor was inhibited by 200-fold excess of non-radioactive DHT. 4) Treatment of scintillator, fluorographic technique shortens the exposure periods. The exposure periods are approximately six to twelve times shorter than that of the conventional autoradiography.

  2. Anti-androgen effects of the pyrethroid pesticide cypermethrin on interactions of androgen receptor with corepressors

    International Nuclear Information System (INIS)

    Graphical abstract: In the mammalian two-hybrid assay, cypermethrin enhanced the AR–SRMT interaction, as well as the AR–NCoR interaction, and the significant enhancement was detected at the concentration of 10−5 M. - Highlights: • We have developed the mammalian two-hybrid assays. • The AR N terminus interacts with RIDs of SMRT and NCoR in the mammalian cells. • Cypermethrin enhances the interaction of AR with SMRT. • Cypermethrin enhances the interaction of AR with NCoR. - Abstract: To clarify whether the mechanism of androgen receptor (AR) antagonism of the pyrethroid pesticide cypermethrin associates with the interactions between the AR and corepressors silencing mediator for thyroid hormone receptors (SMRT) and nuclear receptor corepressor (NCoR), we have developed the mammalian two-hybrid assays. The AR N-terminal domain 1–660 amino acid residues were subcloned into the plasmid pVP16 to construct VP16-ARNTD. The C-terminal receptor interaction domains (RIDs) of SMRT and NCoR were used to construct pM-SMRT and pM-NCoR. The constructed vectors pVP16-ARNTD, pM-SMRT or pM-NCoR, the reporter pG5CAT and the control pCMVβ were cotranfected into the CV-1 cells. The cells were treated with cypermethrin at the indicated concentrations. The AR N terminus interacted with RIDs of SMRT and NCoR. The interactions between the AR and corepressors SMRT and NCoR were enhanced by cypermethrin, and the significant enhancement was detected at the concentration of 10−5 M. The mammalian two-hybrid assays demonstrate the utility to detect the interactions of the AR with SMRT and NCoR. Cypermethrin functions as an anti-androgen by enhancing the associations of the AR with SMRT and NCoR. We provide a novel mechanism in anti-androgen action of cypermethrin associated with the recruitment of SMRT and NCoR to AR

  3. Geomagnetic properties of Proxima Centauri b analogues

    CERN Document Server

    Zuluaga, Jorge I

    2016-01-01

    The recent discovery of a planet around the closest star, Proxima Centauri, could represent a quantum leap on the testability of models in exoplanet sciences. Unlike any other discovered exoplanet, models of planetary processes in Proxima b could be contrasted against near future telescopic observations and far future in-situ measurements. In this paper we study the geomagnetic properties of Proxima b analogues, namely, solid planets with masses close but larger than Earth's mass, periods of rotation of several days and habitable surface conditions. Assuming different planetary masses, bulk compositions and periods of rotations, we calculate for each planetary analogue its radius, heat flux, time of inner core formation, dynamo lifetime and minimum dipole magnetic moment. We find that most ($\\gtrsim$70\\%) Proxima b analogues develop intrinsic dynamos that last at least 3 Gyr, although only half of them are older than the present age of the host star ($4-6$ Gyr). Relying in our planetary evolution models, we p...

  4. Synthesis and anticancer evaluation of spermatinamine analogues

    KAUST Repository

    Moosa, Basem A.

    2016-02-04

    Spermatinamine was isolated from an Australian marine sponge, Pseudoceratina sp. as an inhibitor of isoprenylcystiene carboxyl methyltransferase (Icmt), an attractive and novel anticancer target. Herein, we report the synthesis of spermatinamine analogues and their cytotoxic evaluation against three human cancer cell lines i.e. cervix adenocarcinoma (HeLa), breast adenocarcinoma (MCF-7), and prostate carcinoma (DU145). Analogues 12, 14 and 15 were found to be the most potent against one or more cell lines with the IC50 values in the range of 5 - 10 μM. The obtained results suggested that longer polyamine linker along with aromatic oxime substitution provided the most potent analogue compounds against cancer cell lines.

  5. Influence of obesity and androgen deficiency on prostatic blood circulation

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2012-01-01

    Full Text Available In Study at 120 Diabetes Mellitus II type men the high frequency Obesity (71,7% and Androgen Deficiency (52,8—64,5% of the patients depending on a degree of the indemnification and them pathogenic authentic communications were shown. The blood level of total testosterone was represented by the critical factor of Prostatic arterial Blood Circulation. Obesity and Androgen Deficiency are seem as independent risk factors to development of ischemic prostatopathy, such as Prostatic blood circulation Disorders can develop earlier than other variants of the diabetic microangiophaty.

  6. Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs).

    Science.gov (United States)

    Handlon, Anthony L; Schaller, Lee T; Leesnitzer, Lisa M; Merrihew, Raymond V; Poole, Chuck; Ulrich, John C; Wilson, Joseph W; Cadilla, Rodolfo; Turnbull, Philip

    2016-01-14

    A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 μM), and high oral bioavailability in rats (83%).

  7. Classical Simulated Annealing Using Quantum Analogues

    Science.gov (United States)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-06-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  8. Classical Simulated Annealing Using Quantum Analogues

    Science.gov (United States)

    La Cour, Brian R.; Troupe, James E.; Mark, Hans M.

    2016-08-01

    In this paper we consider the use of certain classical analogues to quantum tunneling behavior to improve the performance of simulated annealing on a discrete spin system of the general Ising form. Specifically, we consider the use of multiple simultaneous spin flips at each annealing step as an analogue to quantum spin coherence as well as modifications of the Boltzmann acceptance probability to mimic quantum tunneling. We find that the use of multiple spin flips can indeed be advantageous under certain annealing schedules, but only for long anneal times.

  9. PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.

    Science.gov (United States)

    Wang, Yin; Wu, Xiaohou; Ou, Liping; Yang, Xue; Wang, Xiaorong; Tang, Min; Chen, E; Luo, Chunli

    2015-06-28

    Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

  10. Angiogenin mediates androgen-stimulated growth of prostate cancer cells and correlates with castration resistance

    OpenAIRE

    Li, Shuping; Hu, Miaofen G.; Sun, Yeqing; YOSHIOKA, NORIE; IBARAGI, SOICHIRO; Sheng, Jinghao; Sun, Guangjie; Kishimoto, Koji; Hu, Guo-fu

    2013-01-01

    Androgen receptor (AR) is a critical effector of prostate cancer (PCa) development and progression. Androgen-dependent PCa rely on the function of AR for growth and progression. Many castration-resistant PCa continue to depend on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of PCa cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the...

  11. Dominant-negative androgen receptor inhibition of intracrine androgen-dependent growth of castration-recurrent prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mark A Titus

    Full Text Available BACKGROUND: Prostate cancer (CaP is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR and its ligands has been linked to castration-recurrent CaP growth. PRINCIPAL FINDING: In this report, the ligand-dependent dominant-negative ARΔ142-337 (ARΔTR was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands. CONCLUSION: The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.

  12. EXPRESSION OF ANDROGEN RECEPTOR IN THE DEVELOPING RAT EPIDIDYMIS AND ITS REGULATION BY ANDROGENS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective To study the distribution, developmental patterns, and hormonal control of androgen re- ceptors(AR) in the developing and ethane dimethane sulfonate(EDS) treated male SD rat epididymis. Methods The ABC technique of immunohistochemistry and image analysis were used to assess optodensity means (OPTDM) of AR, providing a measure of relative nuclear AR concentration. Results The specific AR immunostaining was observed in the nuclei of epididymal epithelium, peritubular smooth muscle cells and intertubular connective tissue cells. The rela- tive AR concentrations varied with the different segments of the epididymis in the adult rat(P<0. 05 or P<0.01). AR protein was highest in the caput (0. 763--0. 026),lowest in the corpus (0. 712±0. 025) and intermediate in the cauda (0. 736±0. 008). Levels of epididymal AR changed with development. In the cauda, AR level was highest on day 21 (0. 773±0. 028),intermediate on day 35(0. 762±0. 022),and lowest on day 90~120(0. 736±0. 008). The 90~120d group was significantly different from the 21d group (P<0. 01)and 35d group (P<0. 05). After the adult rats were treated with EDS to eradicate Leydig cells and endogenous testosterone, it was observed that the OPTDM of AR in the epididymal cauda epithelium was significantly reduced (P<0. 001), and was restored to the control level by using ex- ogenous testosterone replacement (P<0. 001). Conclusion These results suggest that the epididymal corpus depends least on androgens and the AR expression in the epididymis decreases with age and is dependent on circulating andro- gens.

  13. Different types of androgen receptor mutations in patients with complete androgen insensitivity syndrome.

    Science.gov (United States)

    Shao, Jialiang; Hou, Jiangang; Li, Bingkun; Li, Dongyang; Zhang, Ning; Wang, Xiang

    2015-02-01

    Mutations of androgen receptor (AR) are the most frequent cause of 46, XY disorders of sex development and associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome (CAIS)) to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS). From 2009 to 2012, two young Chinese female individuals with CAIS from two families were referred to our hospital due to primary amenorrhea. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Physical examination revealed that the patients have normal female external genitalia, normal breast development, vellus hair in the axilla and on the arms and legs, but absence of pubic hair, and a blind-ending vagina. Two different types of AR mutations have been detected by sequencing of genomic DNA: Family A showed deletion of exon 2 in AR gene; Family B showed a single nucleotide C-to-T transition in exon 8 of AR gene resulting in a proline 893-to-leucine substitution (Pro893Leu). Testicular histology showed developmental immaturity of seminiferous tubules with the absence of spermatogenic cells or spermatozoa. No AR immunoreactivity was observed in either case. Three adult patients recovered well from bilateral orchiectomy. The juvenile patient of family B was followed up. Our present study on these two families revealed two different types of AR mutation. The definitive diagnosis of AIS was based on clinical examination and genetic investigations. Our findings verified the mechanism of CAIS and also enriched AR Gene Mutation Database. PMID:25674389

  14. Promoter-dependent activity on androgen receptor N-terminal domain mutations in androgen insensitivity syndrome.

    Science.gov (United States)

    Tadokoro-Cuccaro, Rieko; Davies, John; Mongan, Nigel P; Bunch, Trevor; Brown, Rosalind S; Audi, Laura; Watt, Kate; McEwan, Iain J; Hughes, Ieuan A

    2014-01-01

    Androgen receptor (AR) mutations are associated with androgen insensitivity syndrome (AIS). Missense mutations identified in the AR-N-terminal domain (AR-NTD) are rare, and clinical phenotypes are typically mild. We investigated 7 missense mutations and 2 insertion/deletions located in the AR-NTD. This study aimed to elucidate the pathogenic role of AR-NTD mutants in AIS and to use this knowledge to further define AR-NTD function. AR-NTD mutations (Q120E, A159T, G216R, N235K, G248V, L272F, and P380R) were introduced into AR-expression plasmids. Stably expressing cell lines were established for del57L and ins58L. Transactivation was measured using luciferase reporter constructs under the control of GRE and Pem promoters. Intrinsic fluorescence spectroscopy and partial proteolysis studies were performed for mutations which showed reduced activities by using a purified AR-AF1 protein. Pem-luciferase reporter activation was reduced for A159T, N235K, and G248V but not the GRE-luciferase reporter. Protein structure analysis detected no significant change in the AR-AF1 region for these mutations. Reduced cellular expression and transactivation activity were observed for ins58L. The mutations Q120E, G216R, L272F, P380R, and del57L showed small or no detectable changes in function. Thus, clinical and experimental analyses have identified novel AR-signalling defects associated with mutations in the structurally disordered AR-NTD domain in patients with AIS.

  15. Complete androgen insensitivity syndrome due to a new frameshift deletion in exon 4 of the androgen receptor gene: Functional analysis of the mutant receptor

    OpenAIRE

    Lobaccaro, J M; Lumbroso, S.; Poujol, Nicolas; Georget, V.; Brinkmann, Albert; Malpuech, Georges; Sultan, C.

    1995-01-01

    textabstractWe studied the androgen receptor gene in a large kindred with complete androgen insensitivity syndrome and negative receptor-binding activity, single-strand conformation polymorphism (SSCP) analysis and sequencing identified a 13 base pair deletion within exon 4. This was responsible for a predictive frameshift in the open reading frame and introduction of a premature stop codon at position 783 instead of 919. The deletion was reproduced in androgen receptor wildtype cDNA and tran...

  16. Substitution of arginine-839 by cysteine or histidine in the androgen receptor causes different receptor phenotypes in cultured cells and coordinate degrees of clinical androgen resistance.

    OpenAIRE

    Beitel, L K; Kazemi-Esfarjani, P; Kaufman, M; Lumbroso, R; DiGeorge, A M; Killinger, D W; Trifiro, M A; Pinsky, L.

    1994-01-01

    We aim to correlate point mutations in the androgen receptor gene with receptor phenotypes and with clinical phenotypes of androgen resistance. In two families, the external genitalia were predominantly female at birth, and sex-of-rearing has been female. Their androgen receptor mutation changed arginine-839 to histidine. In a third family, the external genitalia were predominantly male at birth, and sex-of-rearing has been male: their codon 839 has mutated to cysteine. In genital skin fibrob...

  17. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

    OpenAIRE

    Lallous, Nada; Volik, Stanislav V.; Awrey, Shannon; LeBlanc, Eric; Tse, Ronnie; Murillo, Josef; Singh, Kriti; Azad, Arun A.; Wyatt, Alexander W.; LeBihan, Stephane; Chi, Kim N.; Gleave, Martin E.; Paul S. Rennie; Collins, Colin C; Cherkasov, Artem

    2016-01-01

    Background The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In orde...

  18. Analogue alternative the electronic analogue computer in Britain and the USA, 1930-1975

    CERN Document Server

    Small, James S

    2013-01-01

    We are in the midst of a digital revolution - until recently, the majority of appliances used in everyday life have been developed with analogue technology. Now, either at home or out and about, we are surrounded by digital technology such as digital 'film', audio systems, computers and telephones. From the late 1940s until the 1970s, analogue technology was a genuine alternative to digital, and the two competing technologies ran parallel with each other. During this period, a community of engineers, scientists, academics and businessmen continued to develop and promote the analogue computer.

  19. Scaling issues for analogue circuits using Double Gate SOI transistors

    Science.gov (United States)

    Lim, Tao Chuan; Armstrong, G. Alastair

    2007-02-01

    This work presents a systematic analysis on the impact of source-drain engineering using gate "non-overlapped" on the RF performance of nano-scaled fully depleted Double Gate SOI transistors, when used in the design of a typical two stage Operational Transconductance Amplifier (OTA). It is evident that for a gate length less than 40 nm, the incorporation of optimal source-drain engineering requiring a spacer length, which may exceed the length of the gate, is particularly beneficial in analogue applications. Lengthening the spacer reduces gate capacitance in the weak/moderate inversion region more than transconductance, improving cut-off frequency fT. This improvement is particularly significant in a circuit application where an optimal spacer of 1.5 times the gate length is proposed. This gate under-lapped concept with extended spacer can also significantly enhance DC gain of the OTA, by increasing the Early Voltage, while maximising the transconductance to current ratio in the weak to moderate inversion, close to threshold voltage. With optimally designed devices, the sensitivity of OTA circuit performance to doping profile is shown to be relatively low.

  20. Depletion of intrinsic expression of Interleukin-8 in prostate cancer cells causes cell cycle arrest, spontaneous apoptosis and increases the efficacy of chemotherapeutic drugs

    Directory of Open Access Journals (Sweden)

    Lokeshwar Bal L

    2009-07-01

    Full Text Available Abstract Background The progression of all cancers is characterized by increased-cell proliferation and decreased-apoptosis. The androgen-independent prostate cancer (AIPC is the terminal stage of the disease. Many chemokines and cytokines are suspects to cause this increased tumor cell survival that ultimately leads to resistance to therapy and demise of the host. The AIPC cells, but not androgen-responsive cells, constitutively express abundant amount of the pro-inflammatory chemokine, Interleukin-8 (IL-8. The mechanism of IL-8 mediated survival and therapeutic resistance in AIPC cells is unclear at present. The purpose of this report is to show the pervasive role of IL-8 in malignant progression of androgen-independent prostate cancer (AIPC and to provide a potential new therapeutic avenue, using RNA interference. Results The functional consequence of IL-8 depletion in AIPC cells was investigated by RNA interference in two IL-8 secreting AIPC cell lines, PC-3 and DU145. The non-IL-8 secreting LNCaP and LAPC-4 cells served as controls. Cells were transfected with RISC-free siRNA (control or validated-pool of IL-8 siRNA. Transfection with 50 nM IL-8 siRNA caused >95% depletion of IL-8 mRNA and >92% decrease in IL-8 protein. This reduction in IL-8 led to cell cycle arrest at G1/S boundary and decreases in cell cycle-regulated proteins: Cyclin D1 and Cyclin B1 (both decreased >50% and inhibition of ERK1/2 activity by >50%. Further, the spontaneous apoptosis was increased by >43% in IL-8 depleted cells, evidenced by increases in caspase-9 activation and cleaved-PARP. IL-8 depletion caused significant decreases in anti-apoptotic proteins, BCL-2, BCL-xL due to decrease in both mRNA and post-translational stability, and increased levels of pro-apoptotic BAX and BAD proteins. More significantly, depletion of intracellular IL-8 increased the cytotoxic activity of multiple chemotherapeutic drugs. Specifically, the cytotoxicity of Docetaxel

  1. Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

    OpenAIRE

    Kim, Desok; Gregory, Christopher W.; French, Frank S.; Smith, Gary J.; Mohler, James L.

    2002-01-01

    Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed

  2. A case of androgen-secreting adrenal carcinoma with non-classical congenital adrenal hyperplasia

    Directory of Open Access Journals (Sweden)

    Tarun Varma

    2013-01-01

    Full Text Available Androgen excess is one of the most common and disturbing endocrine disorder of reproductive-aged women, affecting approximately 7% of this population Androgen excess results in the development of androgenic features in the women affected, with the development of hirsutism, androgenic alopecia, ovulatory dysfunction, and, if extreme, even virilization and masculinization. Adrenocortical carcinoma (ACC is a rare malignancy accounting for 0.02% of all annual cancers reported. About 60% are functional tumors secreting hormones, with its consequent clinical manifestations, the Cushing′s syndrome due to cortisone, virilization due to androgens, feminization due to estrogens, or hypertension due to aldosterone. Adrenal tumors that secrete androgens exclusively are extremely rare. Here, we present a rare case of androgen-secreting adrenocortical carcinoma with non-classical congenital adrenal hyperplasia.

  3. A case of androgen-secreting adrenal carcinoma with non-classical congenital adrenal hyperplasia.

    Science.gov (United States)

    Varma, Tarun; Panchani, Roopal; Goyal, Ashutosh; Maskey, Robin

    2013-10-01

    Androgen excess is one of the most common and disturbing endocrine disorder of reproductive-aged women, affecting approximately 7% of this population Androgen excess results in the development of androgenic features in the women affected, with the development of hirsutism, androgenic alopecia, ovulatory dysfunction, and, if extreme, even virilization and masculinization. Adrenocortical carcinoma (ACC) is a rare malignancy accounting for 0.02% of all annual cancers reported. About 60% are functional tumors secreting hormones, with its consequent clinical manifestations, the Cushing's syndrome due to cortisone, virilization due to androgens, feminization due to estrogens, or hypertension due to aldosterone. Adrenal tumors that secrete androgens exclusively are extremely rare. Here, we present a rare case of androgen-secreting adrenocortical carcinoma with non-classical congenital adrenal hyperplasia. PMID:24251173

  4. Vocal area-related expression of the androgen receptor in the budgerigar (Melopsittacus undulatus) brain.

    Science.gov (United States)

    Matsunaga, Eiji; Okanoya, Kazuo

    2008-05-01

    The androgen receptor is a steroid hormone receptor widely expressed in the vocal control nuclei in songbirds. Here, we analysed androgen receptor expression in the brains of juvenile and adult budgerigars. With a species-specific probe for budgerigar androgen receptor mRNA, we found that the androgen receptor was expressed in the vocal areas, such as the central nucleus of the lateral nidopallium, the anterior arcopallium, the oval nucleus of the mesopallium, the oval nucleus of the anterior nidopallium and the tracheosyringeal hypoglossal nucleus. With the present data, together with previous reports, it turned out that the androgen receptor expression in telencephalic vocal control areas is similar amongst three groups of vocal learners--songbirds, hummingbirds and parrots, suggesting the possibility that the androgen receptor might play a role in vocal development and that the molecular mechanism regulating the androgen receptor expression in the vocal areas might be important in the evolution of vocal learning.

  5. From AR to c-Met: Androgen deprivation leads to a signaling pathway switch in prostate cancer cells

    OpenAIRE

    Liu, Tiancheng; Mendes, Desiree E.; Berkman, Clifford E.

    2013-01-01

    Elucidating the role of androgen deprivation in the transition from androgen-dependence to independence may enable the development of more specific therapeutic strategies against prostate cancer. Our previous in vitro model was employed to further assess the effects of continuous androgen-deprivation on prostate cancer cells (LNCaP) with respect to both androgen receptor (AR) and c-Met expression. The results indicated that long-term androgen deprivation resulted in a signaling pathway switch...

  6. In Vivo Depletion of T Lymphocytes.

    Science.gov (United States)

    Laky, Karen; Kruisbeek, Ada M

    2016-01-01

    In vivo depletion of T lymphocytes is a means of studying the role of specific T cell populations during defined phases of in vivo immune responses. In this unit, a protocol is provided for injecting monoclonal antibodies (mAbs) into wild-type adult mice. Depletion of the appropriate subset of cells is verified by flow cytometry analysis of lymph node and spleen cell suspensions in pilot experiments. Once conditions have been established, depleted mice can be used to study the impact of T cell subsets on a variety of in vivo immune responses. The depleted condition may be maintained by repeated injections of the monoclonal antibody, or reversed by normal thymopoiesis following discontinuation of antibody administration. PMID:27038463

  7. Polar stratospheric clouds and ozone depletion

    Science.gov (United States)

    Toon, Owen B.; Turco, Richard P.

    1991-01-01

    A review is presented of investigations into the correlation between the depletion of ozone and the formation of polar stratospheric clouds (PSCs). Satellite measurements from Nimbus 7 showed that over the years the depletion from austral spring to austral spring has generally worsened. Approximately 70 percent of the ozone above Antarctica, which equals about 3 percent of the earth's ozone, is lost during September and October. Various hypotheses for ozone depletion are discussed including the theory suggesting that chlorine compounds might be responsible for the ozone hole, whereby chlorine enters the atmosphere as a component of chlorofluorocarbons produced by humans. The three types of PSCs, nitric acid trihydrate, slowly cooling water-ice, and rapidly cooling water-ice clouds act as important components of the Antarctic ozone depletion. It is indicated that destruction of the ozone will be more severe each year for the next few decades, leading to a doubling in area of the Antarctic ozone hole.

  8. Depleted UF6 programmatic environmental impact statement

    International Nuclear Information System (INIS)

    The US Department of Energy has developed a program for long-term management and use of depleted uranium hexafluoride, a product of the uranium enrichment process. As part of this effort, DOE is preparing a Programmatic Environmental Impact Statement (PEIS) for the depleted UF6 management program. This report duplicates the information available at the web site (http://www.ead.anl.gov/web/newduf6) set up as a repository for the PEIS. Options for the web site include: reviewing recent additions or changes to the web site; learning more about depleted UF6 and the PEIS; browsing the PEIS and related documents, or submitting official comments on the PEIS; downloading all or part of the PEIS documents; and adding or deleting one's name from the depleted UF6 mailing list

  9. Ecological considerations of natural and depleted uranium

    International Nuclear Information System (INIS)

    Depleted 238U is a major by-product of the nuclear fuel cycle for which increasing use is being made in counterweights, radiation shielding, and ordnance applications. This paper (1) summarizes the pertinent literature on natural and depleted uranium in the environment, (2) integrates results of a series of ecological studies conducted at Los Alamos Scientific Laboratory (LASL) in New Mexico where 70,000 kg of depleted and natural uranium has been expended to the environment over the past 34 years, and (3) synthesizes the information into an assessment of the ecological consequences of natural and depleted uranium released to the environment by various means. Results of studies of soil, plant, and animal communities exposed to this radiation and chemical environment over a third of a century provide a means of evaluating the behavior and effects of uranium in many contexts

  10. Fully Depleted Charge-Coupled Devices

    International Nuclear Information System (INIS)

    We have developed fully depleted, back-illuminated CCDs that build upon earlier research and development efforts directed towards technology development of silicon-strip detectors used in high-energy-physics experiments. The CCDs are fabricated on the same type of high-resistivity, float-zone-refined silicon that is used for strip detectors. The use of high-resistivity substrates allows for thick depletion regions, on the order of 200-300 um, with corresponding high detection efficiency for near-infrared and soft x-ray photons. We compare the fully depleted CCD to the p-i-n diode upon which it is based, and describe the use of fully depleted CCDs in astronomical and x-ray imaging applications

  11. Synthesis and antimicrobial activity of squalamine analogue.

    Science.gov (United States)

    Kim, H S; Choi, B S; Kwon, K C; Lee, S O; Kwak, H J; Lee, C H

    2000-08-01

    Synthesis and antimicrobial activity of squalamine analogue 2 are reported. The synthesis of 2 was accomplished from bisnoralcohol 3. The spermidine moiety was introduced via reductive amination of an appropriately functionalized 3beta-aminosterol with spermidinyl aldehyde 17 utilizing sodium triacetoxyborohydride as the reducing agent. Compound 2 shows weaker antimicrobial activity than squalamine. PMID:11003150

  12. Somatostatin analogue scintigraphy and tuberculosis: case report

    International Nuclear Information System (INIS)

    Scintigraphy using a radiolabelled somatostatin analogue (111 In-pentetreotide) is useful in the detection of neuroendocrine tumors. But this radiopharmaceutical accumulates also in solid tumours or in inflammatory diseases such as granulomatosis. We present a case of 111 In-pentetreotide uptake in a tuberculous adenopathy. (author)

  13. Prussian Blue Analogues of Reduced Dimensionality

    NARCIS (Netherlands)

    Gengler, Regis Y. N.; Toma, Luminita M.; Pardo, Emilio; Lloret, Francesc; Ke, Xiaoxing; Van Tendeloo, Gustaaf; Gournis, Dimitrios; Rudolf, Petra

    2012-01-01

    Mixed-valence polycyanides (Prussian Blue analogues) possess a rich palette of properties spanning from room-temperature ferromagnetism to zero thermal expansion, which can be tuned by chemical modifications or the application of external stimuli (temperature, pressure, light irradiation). While mol

  14. The glaciogenic reservoir analogue studies project (GRASP)

    DEFF Research Database (Denmark)

    Moscariello, A.; Moreau, Julien; Vegt, P. van der;

    increasing the risk associated with developing effectively these reservoirs. Therefore a analogue-based predictive stratigraphical and sedimentological model can help to steer drilling strategy and reduce uncertainties and associated risks. For this purpose the GRASP joint industry programme was established...

  15. Phosphate analogues in the dissection of mechanism.

    OpenAIRE

    Heidi J. Korhonen; Conway, Louis P.; Hodgson, David R. W.

    2014-01-01

    Phosphoryl group transfer is central to genetic replication, cellular signalling and many metabolic processes. Understanding the mechanisms of phosphorylation and phosphate ester and anhydride cleavage is key to efforts towards biotechnological and biomedical exploitation of phosphate-handling enzymes. Analogues of phosphate esters and anhydrides are indispensable tools, alongside protein mutagenesis and computational methods, for the dissection of phosphoryl transfer mechanisms. Hydrolysable...

  16. Structural bisphenol analogues differentially target steroidogenesis in murine MA-10 Leydig cells as well as the glucocorticoid receptor.

    Science.gov (United States)

    Roelofs, Maarke J E; van den Berg, Martin; Bovee, Toine F H; Piersma, Aldert H; van Duursen, Majorie B M

    2015-03-01

    Although much information on the endocrine activity of bisphenol A (BPA) is available, a proper human hazard assessment of analogues that are believed to have a less harmful toxicity profile is lacking. Here the possible effects of BPA, bisphenol F (BPF), bisphenol S (BPS), as well as the brominated structural analogue and widely used flame retardant tetrabromobisphenol A (TBBPA) on human glucocorticoid and androgen receptor (GR and AR) activation were assessed. BPA, BPF, and TBBPA showed clear GR and AR antagonism with IC50 values of 67 μM, 60 μM, and 22 nM for GR, and 39 μM, 20 μM, and 982 nM for AR, respectively, whereas BPS did not affect receptor activity. In addition, murine MA-10 Leydig cells exposed to the bisphenol analogues were assessed for changes in secreted steroid hormone levels. Testicular steroidogenesis was altered by all bisphenol analogues tested. TBBPA effects were more directed towards the male end products and induced testosterone synthesis, while BPF and BPS predominantly increased the levels of progestagens that are formed in the beginning of the steroidogenic pathway. The MA-10 Leydig cell assay shows added value over the widely used H295R steroidogenesis assay because of its fetal-like characteristics and specificity for the physiologically more relevant testicular Δ4 steroidogenic pathway. Therefore, adding an in vitro assay covering fetal testicular steroidogenesis, such as the MA-10 cell line, to the panel of tests used to screen potential endocrine disruptors, is highly recommendable.

  17. 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)

  18. Androgen deprivation therapy for prostate cancer:not so simple

    Institute of Scientific and Technical Information of China (English)

    Nicholas N Tadros; Mark Garzotto

    2011-01-01

    @@ Prostate cancer(PC)is the second most diagnosed visceral malignancy in men worldwide, with over 900 000 new diagnoses each year.1 Approximately 50% of patients treated in industrialized nations will receive androgen deprivation therapy(ADT)at some point in their lifetimes.2

  19. Androgen deprivation modulates the inflammatory response induced by irradiation

    International Nuclear Information System (INIS)

    The aim of this study was to determine whether radiation (RT)-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2), TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT) -induced fibrosis. We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT) via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy

  20. Antiandrogens prevent stable DNA-binding of the androgen receptor

    NARCIS (Netherlands)

    P. Farla; R. Hersmus (Remko); J. Trapman (Jan); A.B. Houtsmuller (Adriaan)

    2005-01-01

    textabstractThe androgen receptor (AR) is essential for development of the male gender and in the growth of the majority of prostate cancers. Agonists as well as most antagonists induce translocation of the receptor to the nucleus, whereas only agonists can activate AR function. An

  1. The androgen receptor in hormone-refractory prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hai-Lei Mao; Zhi-Qi Zhu; Charlie Degui Chen

    2009-01-01

    Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling.However,the effect is short-lived,as nearly all tumours progress to a hormone-refractory (HR) state,a lethal stage of the disease.Intuitively,the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR turnouts.However,there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours.AR signalling can be activated in HR turnouts through several mechanisms.First,activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens.Also,mutations in the AR can change AR ligand specificity,thereby allowing it to be activated by non-steroids or anti-androgens.Finally,overexpression of the wild-type AR sensitizes itself to low concentrations of androgens.Therefore,drugs targeting AR signalling could still be effective in treating HRPC.

  2. Expression of androgen receptor target genes in skeletal muscle

    Institute of Scientific and Technical Information of China (English)

    Kesha Rana; Nicole KL Lee; Jeffrey D Zajac; Helen E MacLean

    2014-01-01

    We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor(AR)‑regulated genes ininvitroandinvivomodels. The expression of the myogenic regulatory factormyogenin was signiifcantly 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 thatmyogenin is repressed by the androgen/AR pathway. The ubiquitin ligaseFbxo32 was repressed by 12h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, andc‑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, p57Kip2, Igf2 andcalcineurin Aa, was increased in AR∆ZF2 muscle, and the expression of all butp57Kip2was 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.

  3. Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation.

    Science.gov (United States)

    Liu, Xiaming; Han, Weiwei; Gulla, Sarah; Simon, Nicholas I; Gao, Yanfei; Cai, Changmeng; Yang, Hongmei; Zhang, Xiaoping; Liu, Jihong; Balk, Steven P; Chen, Shaoyong

    2016-01-12

    The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4-2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).

  4. Androgen deprivation modulates the inflammatory response induced by irradiation

    Directory of Open Access Journals (Sweden)

    Lin Paul-Yang

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to determine whether radiation (RT-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. Methods The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2, TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT -induced fibrosis. Results We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. Conclusion When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

  5. 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…

  6. 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.

  7. A theoretical model of atmospheric ozone depletion

    Science.gov (United States)

    Midya, S. K.; Jana, P. K.; Lahiri, T.

    1994-01-01

    A critical study on different ozone depletion and formation processes has been made and following important results are obtained: (i) From analysis it is shown that O3 concentration will decrease very minutely with time for normal atmosphere when [O], [O2] and UV-radiation remain constant. (ii) An empirical equation is established theoretically between the variation of ozone concentration and time. (iii) Special ozone depletion processes are responsible for the dramatic decrease of O3-concentration at Antarctica.

  8. Depleted Uranium and Its Effects on Humans

    Directory of Open Access Journals (Sweden)

    Zdeněk Hon

    2015-04-01

    Full Text Available The article summarizes contemporary scientific knowledge of depleted uranium effects on human health due to its use in military conflicts. The discussion covers cases of minimal risk due to external irradiation resulting from the storage and handling of depleted uranium ammunition and, in contrast, important toxicological and radio-toxicological risks of late effects resulting from the inhalation and ingestion of dust particles produced by the burning of the core of the anti-tank ammunition.

  9. Depleted Uranium and Its Effects on Humans

    OpenAIRE

    Zdeněk Hon; Jan Österreicher; Leoš Navrátil

    2015-01-01

    The article summarizes contemporary scientific knowledge of depleted uranium effects on human health due to its use in military conflicts. The discussion covers cases of minimal risk due to external irradiation resulting from the storage and handling of depleted uranium ammunition and, in contrast, important toxicological and radio-toxicological risks of late effects resulting from the inhalation and ingestion of dust particles produced by the burning of the core of the anti-tank ammunition.

  10. Depleted Bulk Heterojunction Colloidal Quantum Dot Photovoltaics

    KAUST Repository

    Barkhouse, D. Aaron R.

    2011-05-26

    The first solution-processed depleted bulk heterojunction colloidal quantum dot solar cells are presented. The architecture allows for high absorption with full depletion, thereby breaking the photon absorption/carrier extraction compromise inherent in planar devices. A record power conversion of 5.5% under simulated AM 1.5 illumination conditions is reported. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Oral contraceptives as anti-androgenic treatment of acne.

    Science.gov (United States)

    Lemay, André; Poulin, Yves

    2002-07-01

    Although acne is seldom associated with high serum levels of androgens, it has been shown that female acne patients have definite increases in ovarian and adrenal androgen levels when compared to appropriate controls. As shown in several pilot and in multiple open and comparative studies, oral contraceptives (OCs) are effective in causing a significant regression of mild to moderate acne. These results have been confirmed by multicentre randomized trials where low-dose OCs did not cause side effects different from those of the placebo-controlled group. The beneficial effect of OCs is related to a decrease in ovarian and adrenal androgen precursors; to an increase in sex hormone-binding globulin (SHBG), which limits free testosterone; and to a decrease in 3a-androstenediol glucuronide conjugate, the catabolite of dihydrotestosterone (DHT) formed in peripheral tissues. The estrogen-progestin combination containing cyproterone acetate (CPA) is particularly effective in treating acne, since this progestin also has a direct peripheral anti-androgenic action in blocking the androgen receptor. Only two open studies and one randomized study on small numbers of patients have reported some efficacy of spironolactone used alone or in combination with an OC in the treatment of acne. The new non-steroidal anti-androgens flutamide and finasteride are being evaluated for the treatment of hirsutism. Oral antibiotics are prescribed to patients with inflammatory lesions, where they are effective in decreasing the activity of microbes, the activity of microbial enzymes, and leukocyte chemotaxis. Concomitant intake of an OC and an antibiotic usually prescribed for acne does not impair the contraceptive efficacy of the OC. A second effective contraceptive method should be used whenever there would be decreased absorption or efficacy of the OC (digestive problems, breakthrough bleeding), lack of compliance and use of a type or dose of antibiotic different from that usually prescribed

  12. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    Science.gov (United States)

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment.

  13. [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1.

    Science.gov (United States)

    Cai, Yunxin; Lu, Dandan; Chen, Zhen; Ding, Yi; Chung, Nga N; Li, Tingyou; Schiller, Peter W

    2016-08-01

    Analogues of [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt=2',6'-dimethyltyrosine), a potent μ opioid agonist peptide with mitochondria-targeted antioxidant activity were prepared by replacing Dmt with various 2',6'-dialkylated Tyr analogues, including 2',4',6'-trimethyltyrosine (Tmt), 2'-ethyl-6'-methyltyrosine (Emt), 2'-isopropyl-6'-methyltyrosine (Imt) and 2',6'-diethyltyrosine (Det). All compounds were selective μ opioid agonists and the Tmt(1)-, Emt(1) and Det(1)-analogues showed subnanomolar μ opioid receptor binding affinities. The Tmt(1)- and Emt(1)-analogues showed improved antioxidant activity compared to the Dmt(1)-parent peptide in the DPPH radical-scavenging capacity assay, and thus are of interest as drug candidates for neuropathic pain treatment. PMID:27301366

  14. Development of Monte Carlo depletion code MCDEP

    Energy Technology Data Exchange (ETDEWEB)

    Kim, K. S.; Kim, K. Y.; Lee, J. C.; Ji, S. K. [KAERI, Taejon (Korea, Republic of)

    2003-07-01

    Monte Carlo neutron transport calculation has been used to obtain a reference solution in reactor physics analysis. The typical and widely-used Monte Carlo transport code is MCNP (Monte Carlo N-Particle Transport Code) developed in Los Alamos National Laboratory. The drawbacks of Monte-Carlo transport codes are the lacks of the capacities for the depletion and temperature dependent calculations. In this research we developed MCDEP (Monte Carlo Depletion Code Package) using MCNP with the capacity of the depletion calculation. This code package is the integration of MCNP and depletion module of ORIGEN-2 using the matrix exponential method. This code package enables the automatic MCNP and depletion calculations only with the initial MCNP and MCDEP inputs prepared by users. Depletion chains were simplified for the efficiency of computing time and the treatment of short-lived nuclides without cross section data. The results of MCDEP showed that the reactivity and pin power distributions for the PWR fuel pins and assemblies are consistent with those of CASMO-3 and HELIOS.

  15. Anogenital distance as a marker of androgen exposure in humans.

    Science.gov (United States)

    Thankamony, A; Pasterski, V; Ong, K K; Acerini, C L; Hughes, I A

    2016-07-01

    Abnormal foetal testis development has been proposed to underlie common disorders of the male reproductive system such as cryptorchidism, hypospadias, reduced semen quality and testicular germ cell tumour, which are regarded as components of a 'testicular dysgenesis syndrome'. The increasing trends and geographical variation in their incidence have been suggested to result from in utero exposure to environmental chemicals acting as endocrine disruptors. In rodents, the anogenital distance (AGD), measured from the anus to the base of genital tubercle, is a sensitive biomarker of androgen exposure during a critical embryonic window of testis development. In humans, several epidemiological studies have shown alterations in AGD associated with prenatal exposure to several chemicals with potential endocrine disrupting activity. However, the link between AGD and androgen exposure in humans is not well-defined. This review focuses on the current evidence for such a relationship. As in rodents, a clear gender difference is detected during foetal development of the AGD in humans which is maintained thereafter. Reduced AGD in association with clinically relevant outcomes of potential environmental exposures, such as cryptorchidism or hypospadias, is in keeping with AGD as a marker of foetal testicular function. Furthermore, AGD may reflect variations in prenatal androgen exposure in healthy children as shorter AGD at birth is associated with reduced masculine play behaviour in preschool boys. Several studies provide evidence linking shorter AGD with lower fertility, semen quality and testosterone levels in selected groups of adults attending andrology clinics. Overall, the observational data in humans are consistent with experimental studies in animals and support the use of AGD as a biomarker of foetal androgen exposure. Future studies evaluating AGD in relation to reproductive hormones in both infants and adults, and to gene polymorphisms, will help to further delineate

  16. 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.

  17. Radiative characteristics of depleted uranium bomb and it is protection

    International Nuclear Information System (INIS)

    Based on the developing process of depleted uranium bombs described in the first part, the radiative characteristics and mechanism of depleted uranium bombs are analyzed emphatically. The deeper discussion on protection of depleted uranium bombs is proceeded

  18. Recent advances in topoisomerase I-targeting agents, camptothecin analogues.

    Science.gov (United States)

    Kim, Dae-Kee; Lee, Namkyu

    2002-12-01

    The present review concentrates on camptothecin (CPT) analogues, the most extensively studied topoisomerase I (topo I) inhibitors, and provides concise information on the structural features of human topo I enzyme, mechanisms of interaction of CPT with topo I, structure-activity relationship study of CPT analogues including the influence of lactone stability on antitumor activity, and recent updates of valuable CPT analogues. PMID:12370044

  19. In Silico and In Vitro Investigation of the Piperine's Male Contraceptive Effect: Docking and Molecular Dynamics Simulation Studies in Androgen-Binding Protein and Androgen Receptor.

    Science.gov (United States)

    Chinta, Gopichand; Ramya Chandar Charles, Mariasoosai; Klopčič, Ivana; Sollner Dolenc, Marija; Periyasamy, Latha; Selvaraj Coumar, Mohane

    2015-07-01

    Understanding the molecular mechanism of action of traditional medicines is an important step towards developing marketable drugs from them. Piperine, an active constituent present in the Piper species, is used extensively in Ayurvedic medicines (practiced on the Indian subcontinent). Among others, piperine is known to possess a male contraceptive effect; however, the molecular mechanism of action for this effect is not very clear. In this regard, detailed docking and molecular dynamics simulation studies of piperine with the androgen-binding protein and androgen receptors were carried out. Androgen receptors control male sexual behavior and fertility, while the androgen-binding protein binds testosterone and maintains its concentration at optimal levels to stimulate spermatogenesis in the testis. It was found that piperine docks to the androgen-binding protein, similar to dihydrotestosterone, and to androgen receptors, similar to cyproterone acetate (antagonist). Also, the piperine-androgen-binding protein and piperine-androgen receptors interactions were found to be stable throughout 30 ns of molecular dynamics simulation. Further, two independent simulations for 10 ns each also confirmed the stability of these interactions. Detailed analysis of the piperine-androgen-binding protein interactions shows that piperine interacts with Ser42 of the androgen-binding protein and could block the binding with its natural ligands dihydrotestosterone/testosterone. Moreover, piperine interacts with Thr577 of the androgen receptors in a manner similar to the antagonist cyproterone acetate. Based on the in silico results, piperine was tested in the MDA-kb2 cell line using the luciferase reporter gene assay and was found to antagonize the effect of dihydrotestosterone at nanomolar concentrations. Further detailed biochemical experiments could help to develop piperine as an effective male contraceptive agent in the future.

  20. Development of an endogenous androgen receptor-mediated luciferase expression assay (AR-LUX) for interactive androgenic action

    NARCIS (Netherlands)

    Blankvoort, B.M.G.

    2003-01-01

    The research described in this thesis was aimed at developing an in vitro cell-based reporter gene system applicable to the detection of the illegal use of androgenic growth promoters in cattle, and the presence of potential endocrine disrupters present in surface waters and interfering with androge

  1. Androgens Regulate T47D Cells Motility and Invasion through Actin Cytoskeleton Remodeling

    Science.gov (United States)

    Montt-Guevara, Maria Magdalena; Shortrede, Jorge Eduardo; Giretti, Maria Silvia; Giannini, Andrea; Mannella, Paolo; Russo, Eleonora; Genazzani, Alessandro David; Simoncini, Tommaso

    2016-01-01

    The relationship between androgens and breast cancer is controversial. Androgens have complex effects on breast cancer progression and metastasis. Moreover, androgen 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 remodeling. 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 breast cancer treatment. PMID:27746764

  2. Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gorin Frederic A

    2005-03-01

    Full Text Available Abstract Background Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. Methods We investigated the effects of androgen on glycogen phosphorylase (GP, glycogen synthase (GS and on glycogen accumulation in the androgen-receptor (AR reconstituted PC3 cell line containing either an empty vector (PC3-AR-V or vector with HPV-E7 (PC3-AR-E7 and the LNCaP cell line. Results Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. Conclusion Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.

  3. Complete androgen insensitivity syndrome due to a new frameshift deletion in exon 4 of the androgen receptor gene: Functional analysis of the mutant receptor

    NARCIS (Netherlands)

    J.M. Lobaccaro; S. Lumbroso; N. Poujol (Nicolas); V. Georget; A.O. Brinkmann (Albert); G. Malpuech (Georges); C. Sultan

    1995-01-01

    textabstractWe studied the androgen receptor gene in a large kindred with complete androgen insensitivity syndrome and negative receptor-binding activity, single-strand conformation polymorphism (SSCP) analysis and sequencing identified a 13 base pair deletion within exon 4. This was responsible for

  4. Clinical, cytogenetic and molecular analysis of androgen insensitivity syndromes from south Indian cohort and detection and in-silico characterization of androgen receptor gene mutations.

    Science.gov (United States)

    V G, Abilash; S, Radha; K M, Marimuthu; K, Thangaraj; S, Arun; S, Nishu; A, Mohana Priya; J, Meena; D, Anuradha

    2016-01-30

    Rare cases of 9 complete androgen insensitivity syndromes, 9 cases of partial androgen insensitivity syndromes and equal number of male control samples were selected for this study. Few strong variations in clinical features were noticed; Giemsa banded metaphase revealed a 46,XY karyotype and the frequency of chromosome aberrations were significantly higher when compared with control samples. DNA sequence analysis of the androgen receptor gene of androgen insensitivity syndromes revealed three missense mutations - c.C1713>G resulting in the replacement of a highly conserved histidine residue with glutamine p.(His571Glu) in DNA-binding domain, c.A1715>G resulting in the replacement of a highly conserved tyrosine residue with cysteine p.(Tyr572Cys) in DNA-binding domain and c.G2599>A resulting in the replacement of a highly conserved valine residue with methionine p.(Val867Met) in ligand-binding domain of androgen receptor gene respectively. The heterozygous type of mutations c.C1713>G and c.G2599>A observed in mothers of the patients for familial cases concluding that the mutation was inherited from the mother. The novel mutation c.C1713>G is reported first time in androgen insensitivity syndrome. In-silico analysis of mutations observed in androgen receptor gene of androgen insensitivity syndrome predicted that the substitution at Y572C and V867M could probably disrupt the protein structure and function. PMID:26688387

  5. [Insulin analogues: modifications in the structure, molecular and metabolic consequences].

    Science.gov (United States)

    de Luis, D A; Romero, E

    2013-01-01

    Recombinant DNA technology has provided insulin analogues for the treatment of diabetes mellitus, with an efficacy and safety that has improved the treatment of this disease. We briefly review the principal characteristics of the insulin analogues currently available. Both rapid-acting (lispro, aspart and glulisine) and long acting (glargine and determir) insulin analogues are included in this review. We describe the pharmacology of each insulin analogue, their differences with the human insulin, the administration, indication, efficacy and safety. In addition we discussed the main controversies of the use of these insulin analogues. In particular, those related with the risk of cancer and retinopathy, and their use in pregnant women. PMID:23517895

  6. Depletion sensitivity predicts unhealthy snack purchases.

    Science.gov (United States)

    Salmon, Stefanie J; Adriaanse, Marieke A; Fennis, Bob M; De Vet, Emely; De Ridder, Denise T D

    2016-01-01

    The aim of the present research is to examine the relation between depletion sensitivity - a novel construct referring to the speed or ease by which one's self-control resources are drained - and snack purchase behavior. In addition, interactions between depletion sensitivity and the goal to lose weight on snack purchase behavior were explored. Participants included in the study were instructed to report every snack they bought over the course of one week. The dependent variables were the number of healthy and unhealthy snacks purchased. The results of the present study demonstrate that depletion sensitivity predicts the amount of unhealthy (but not healthy) snacks bought. The more sensitive people are to depletion, the more unhealthy snacks they buy. Moreover, there was some tentative evidence that this relation is more pronounced for people with a weak as opposed to a strong goal to lose weight, suggesting that a strong goal to lose weight may function as a motivational buffer against self-control failures. All in all, these findings provide evidence for the external validity of depletion sensitivity and the relevance of this construct in the domain of eating behavior. PMID:26321417

  7. The New MCNP6 Depletion Capability

    Energy Technology Data Exchange (ETDEWEB)

    Fensin, Michael Lorne [Los Alamos National Laboratory; James, Michael R. [Los Alamos National Laboratory; Hendricks, John S. [Los Alamos National Laboratory; Goorley, John T. [Los Alamos National Laboratory

    2012-06-19

    The first MCNP based inline Monte Carlo depletion capability was officially released from the Radiation Safety Information and Computational Center as MCNPX 2.6.0. Both the MCNP5 and MCNPX codes have historically provided a successful combinatorial geometry based, continuous energy, Monte Carlo radiation transport solution for advanced reactor modeling and simulation. However, due to separate development pathways, useful simulation capabilities were dispersed between both codes and not unified in a single technology. MCNP6, the next evolution in the MCNP suite of codes, now combines the capability of both simulation tools, as well as providing new advanced technology, in a single radiation transport code. We describe here the new capabilities of the MCNP6 depletion code dating from the official RSICC release MCNPX 2.6.0, reported previously, to the now current state of MCNP6. NEA/OECD benchmark results are also reported. The MCNP6 depletion capability enhancements beyond MCNPX 2.6.0 reported here include: (1) new performance enhancing parallel architecture that implements both shared and distributed memory constructs; (2) enhanced memory management that maximizes calculation fidelity; and (3) improved burnup physics for better nuclide prediction. MCNP6 depletion enables complete, relatively easy-to-use depletion calculations in a single Monte Carlo code. The enhancements described here help provide a powerful capability as well as dictate a path forward for future development to improve the usefulness of the technology.

  8. Holographic Fluids with Vorticity and Analogue Gravity

    CERN Document Server

    Leigh, Robert G; Petropoulos, P Marios

    2012-01-01

    We study holographic three-dimensional fluids with vorticity in local equilibrium and discuss their relevance to analogue gravity systems. The Fefferman-Graham expansion leads to the fluid's description in terms of a comoving and rotating Papapetrou-Randers frame. A suitable Lorentz transformation brings the fluid to the non-inertial Zermelo frame, which clarifies its interpretation as moving media for light/sound propagation. We apply our general results to the Lorentzian Kerr-AdS_4 and Taub-NUT-AdS_4 geometries that describe fluids in cyclonic and vortex flows respectively. In the latter case we associate the appearance of closed timelike curves to analogue optical horizons. In addition, we derive the classical rotational Hall viscosity of three-dimensional fluids with vorticity. Our formula remarkably resembles the corresponding result in magnetized plasmas.

  9. Design and synthesis of new fluconazole analogues.

    Science.gov (United States)

    Pore, Vandana S; Agalave, Sandip G; Singh, Pratiksha; Shukla, Praveen K; Kumar, Vikash; Siddiqi, Mohammad I

    2015-06-21

    We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemolysis study of the most active compounds 6e and 13j showed that both compounds did not cause any hemolysis at the dilutions tested. These compounds did not exhibit any toxicity to L929 cells at MIC and lower concentrations. In the docking study, the overall binding mode of 6e and 13j appeared to be reasonable and provided a good insight into the structural basis of inhibition of Candida albicans Cyp51 by these compounds. PMID:25975803

  10. Somatostatin analogues for acute bleeding oesophageal varices

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C.; Hrobjartsson, A.

    2008-01-01

    BACKGROUND: Somatostatin and its derivatives are sometimes used for emergency treatment of bleeding oesophageal varices in patients with cirrhosis of the liver. OBJECTIVES: To study whether somatostatin or its analogues improve survival or reduce the need for blood transfusions in patients...... with bleeding oesophageal varices. SEARCH STRATEGY: PubMed and The Cochrane Library were searched (November 2007). Reference lists of publications, contacts with authors. SELECTION CRITERIA: All randomised trials comparing somatostatin or analogues with placebo or no treatment in patients suspected of acute...... or recent bleeding from oesophageal varices. DATA COLLECTION AND ANALYSIS: The outcome measures extracted were: mortality, blood transfusions, use of balloon tamponade, initial haemostasis and rebleeding. Intention-to-treat analyses including all randomised patients were conducted if possible; a random...

  11. Studies of natural analogues and geological systems

    International Nuclear Information System (INIS)

    This review has involved studies of natural analogues and natural geological systems leading to the identification and quantification of processes and features of importance to the performance and safety of repositories for radioactive waste. The features and processes selected for the study comprise general geochemical issues related to the performance of the near- and far-field, the performance and durability of construction materials and the effects of glaciation. For each of these areas a number of potentially important processes for repository performance have been described, and evidence for their existence, as well as quantification of parameters of models describing the processes have been sought from major natural analogue studies and site investigations. The review has aimed at covering a relatively broad range of issues at the expense of in-depth analysis. The quantitative data presented are in most cases compilations of data from the literature; in a few cases results of evaluations made within the current project are included

  12. SYNTHESIS AND BIOEVALUATION OF KETOCONAZOLE THIOSEMICARBAZONE ANALOGUES

    OpenAIRE

    Y. Murti

    2011-01-01

    Ketoconazole (KTZ) is a synthetic antifungal drug used to prevent and treat fungal infections, especially in immunocompromised patients such as those with AIDS. Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including C. albicans. Thus new effective agents with less toxicity against fungal infection are urgently required. With this view, ketoconazole thiosemicarbazone analogues (Compounds 1-10) were synthesized wherein condensation of different thiosemic...

  13. Electromagnetic wave analogue of electronic diode

    OpenAIRE

    Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.; Fedotov, Vassili A.; Zheludev, Nikolay I.

    2010-01-01

    An electronic diode is a nonlinear semiconductor circuit component that allows conduction of electrical current in one direction only. A component with similar functionality for electromagnetic waves, an electromagnetic isolator, is based on the Faraday effect of the polarization state rotation and is also a key component of optical and microwave systems. Here we demonstrate a chiral electromagnetic diode, which is a direct analogue of an electronic diode: its functionality is underpinned by ...

  14. Applying Acylated Fucose Analogues to Metabolic Glycoengineering

    OpenAIRE

    Julia Rosenlöcher; Verena Böhrsch; Michael Sacharjat; Véronique Blanchard; Christoph Giese; Volker Sandig; Christian P R Hackenberger; Stephan Hinderlich

    2015-01-01

    Manipulations of cell surface glycosylation or glycan decoration of selected proteins hold immense potential for exploring structure-activity relations or increasing glycoprotein quality. Metabolic glycoengineering describes the strategy where exogenously supplied sugar analogues intercept biosynthetic pathways and are incorporated into glycoconjugates. Low membrane permeability, which so far limited the large-scale adaption of this technology, can be addressed by the introduction of acylated...

  15. The Brookhaven electron analogue, 1953--1957

    Energy Technology Data Exchange (ETDEWEB)

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  16. Instructional influences on analogue functional analysis outcomes.

    OpenAIRE

    Northup, John; Kodak, Tiffany; Grow, Laura; Lee, Jennifer; Coyne, Amanda

    2004-01-01

    Analogue assessments were conducted with a common contingency (escape from tasks) that varied only by three different instructions describing the contingency. In one condition, the contingency was described as "taking a break," in another condition it was described as "time-out," and no description of the contingency was provided in a third condition. The participant was a typically developing 5-year-old child with a diagnosis of attention deficit hyperactivity disorder. Rates of inappropriat...

  17. Analogue memories for high speed detectors signals

    CERN Document Server

    Caponetto, L H

    2000-01-01

    An analogue memory chip family has been developed as a switched capacitor cell array. The family is an ongoing prototyping project within the readout system of the silicon drift detectors for the Inner Tracker System of the ALICE experiment. All chips consist of several capturing channels whose cells number is varying within the family. Chips design choices and performances are briefly discussed here. (5 refs).

  18. Synthesis of a Cyclic Analogue of Galardin

    Institute of Scientific and Technical Information of China (English)

    马大为; 吴问根; 钱静; 郎深慧; 叶其壮

    2001-01-01

    A cyclic analogue 4 of galardin,a known MMP inhibitor,is designed to improve its selectivity.The synthesis of 4starts from dimethyl(S)-malate using diaselective alkylation and subsequent cyclization and amide formation as key steps.The compound 4 showed MMP inhibitory activity on all MMPs tested with IC50 ranging from 20.1 μM to 104 μM.

  19. The Brookhaven electron analogue, 1953--1957

    International Nuclear Information System (INIS)

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary

  20. Platinum analogues in preclinical and clinical development.

    Science.gov (United States)

    Hamilton, T C; O'Dwyer, P J; Ozols, R F

    1993-11-01

    The impact of cisplatin on chemotherapy for solid tumors has led to the synthesis of many molecules with platinum as their central building block. These so-called platinum analogues have been developed with the obvious goals of improving the antitumor activity of cisplatin and hopefully, at the same time, altering the dose-limiting side effects of the prototype drug. At least 10 such molecules are in clinical development, whereas several others are at various stages of preclinical testing. PMID:8305533

  1. h-analogue of Fibonacci Numbers

    OpenAIRE

    Benaoum, H. B.

    2009-01-01

    In this paper, we introduce the h-analogue of Fibonacci numbers for non-commutative h-plane. For h h'= 1 and h = 0, these are just the usual Fibonacci numbers as it should be. We also derive a collection of identities for these numbers. Furthermore, h-Binet's formula for the h-Fibonacci numbers is found and the generating function that generates these numbers is obtained.

  2. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    Science.gov (United States)

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion. PMID:27241617

  3. The modality effect of ego depletion: Auditory task modality reduces ego depletion.

    Science.gov (United States)

    Li, Qiong; Wang, Zhenhong

    2016-08-01

    An initial act of self-control that impairs subsequent acts of self-control is called ego depletion. The ego depletion phenomenon has been observed consistently. The modality effect refers to the effect of the presentation modality on the processing of stimuli. The modality effect was also robustly found in a large body of research. However, no study to date has examined the modality effects of ego depletion. This issue was addressed in the current study. In Experiment 1, after all participants completed a handgrip task, one group's participants completed a visual attention regulation task and the other group's participants completed an auditory attention regulation task, and then all participants again completed a handgrip task. The ego depletion phenomenon was observed in both the visual and the auditory attention regulation task. Moreover, participants who completed the visual task performed worse on the handgrip task than participants who completed the auditory task, which indicated that there was high ego depletion in the visual task condition. In Experiment 2, participants completed an initial task that either did or did not deplete self-control resources, and then they completed a second visual or auditory attention control task. The results indicated that depleted participants performed better on the auditory attention control task than the visual attention control task. These findings suggest that altering task modality may reduce ego depletion.

  4. Depleted uranium and the Gulf War syndrome

    International Nuclear Information System (INIS)

    Some military personnel involved in the 1991Gulf War have complained of continuing stress-like symptoms for which no obvious cause has been found. These symptoms have at times been attributed to the use of depleted uranium (DU) in shell casings which are believed to have caused toxic effects. Depleted uranium is natural uranium which is depleted in the rarer U-235 isotope. It is a heavy metal and in common with other heavy metals is chemically toxic. It is also slightly radioactive and could give rise to a radiological hazard if dispersed in finely divided form so that it was inhaled. In response to concerns, the possible effects of DU have been extensively studied along with other possible contributors to Gulf War sickness. This article looks at the results of some of the research that has been done on DU. (author)

  5. Ozone depletion and chlorine loading potentials

    Science.gov (United States)

    Pyle, John A.; Wuebbles, Donald J.; Solomon, Susan; Zvenigorodsky, Sergei; Connell, Peter; Ko, Malcolm K. W.; Fisher, Donald A.; Stordal, Frode; Weisenstein, Debra

    1991-01-01

    The recognition of the roles of chlorine and bromine compounds in ozone depletion has led to the regulation or their source gases. Some source gases are expected to be more damaging to the ozone layer than others, so that scientific guidance regarding their relative impacts is needed for regulatory purposes. Parameters used for this purpose include the steady-state and time-dependent chlorine loading potential (CLP) and the ozone depletion potential (ODP). Chlorine loading potentials depend upon the estimated value and accuracy of atmospheric lifetimes and are subject to significant (approximately 20-50 percent) uncertainties for many gases. Ozone depletion potentials depend on the same factors, as well as the evaluation of the release of reactive chlorine and bromine from each source gas and corresponding ozone destruction within the stratosphere.

  6. Molten-Salt Depleted-Uranium Reactor

    CERN Document Server

    Dong, Bao-Guo; Gu, Ji-Yuan

    2015-01-01

    The supercritical, reactor core melting and nuclear fuel leaking accidents have troubled fission reactors for decades, and greatly limit their extensive applications. Now these troubles are still open. Here we first show a possible perfect reactor, Molten-Salt Depleted-Uranium Reactor which is no above accident trouble. We found this reactor could be realized in practical applications in terms of all of the scientific principle, principle of operation, technology, and engineering. Our results demonstrate how these reactors can possess and realize extraordinary excellent characteristics, no prompt critical, long-term safe and stable operation with negative feedback, closed uranium-plutonium cycle chain within the vessel, normal operation only with depleted-uranium, and depleted-uranium high burnup in reality, to realize with fission nuclear energy sufficiently satisfying humanity long-term energy resource needs, as well as thoroughly solve the challenges of nuclear criticality safety, uranium resource insuffic...

  7. Plasmonic nanoprobes for stimulated emission depletion microscopy

    CERN Document Server

    Cortes, Emiliano; Sinclair, Hugo G; Guldbrand, Stina; Peveler, William J; Davies, Timothy; Parrinello, Simona; Görlitz, Frederik; Dunsby, Chris; Neil, Mark A A; Sivan, Yonatan; Parkin, Ivan P; French, Paul M; Maier, Stefan A

    2016-01-01

    Plasmonic nanoparticles influence the absorption and emission processes of nearby emitters due to local enhancements of the illuminating radiation and the photonic density of states. Here, we use the plasmon resonance of metal nanoparticles in order to enhance the stimulated depletion of excited molecules for super-resolved microscopy. We demonstrate stimulated emission depletion (STED) microscopy with gold nanorods with a long axis of only 26 nm and a width of 8 nm that provide an enhancement of the resolution compared to fluorescent-only probes without plasmonic components irradiated with the same depletion power. These novel nanoparticle-assisted STED probes represent a ~2x10^3 reduction in probe volume compared to previously used nanoparticles and we demonstrate their application to the first plasmon-assisted STED cellular imaging. We also discuss their current limitations.

  8. Thymidine Analogues for Tracking DNA Synthesis

    Directory of Open Access Journals (Sweden)

    Brenton L. Cavanagh

    2011-09-01

    Full Text Available Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in “tagging DNA synthesis” is the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU. The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using ‘Huisgen’s reaction’ (1,3-dipolar cycloaddition or ‘click chemistry’. This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other “unnatural bases”. These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored.

  9. Department of Energy depleted uranium recycle

    International Nuclear Information System (INIS)

    With its strategic supply of depleted uranium, the Department of Energy is studying reuse of the material in nuclear radiation shields, military hardware, and commercial applications. the study is expected to warrant a more detailed uranium recycle plan which would include consideration of a demonstration program and a program implementation decision. Such a program, if implemented, would become the largest nuclear material recycle program in the history of the Department of Energy. The bulk of the current inventory of depleted uranium is stored in 14-ton cylinders in the form of solid uranium hexafluoride (UF6). The radioactive 235U content has been reduced to a concentration of 0.2% to 0.4%. Present estimates indicate there are about 55,000 UF6-filled cylinders in inventory and planned operations will provide another 2,500 cylinders of depleted uranium each year. The United States government, under the auspices of the Department of Energy, considers the depleted uranium a highly-refined strategic resource of significant value. A possible utilization of a large portion of the depleted uranium inventory is as radiation shielding for spent reactor fuels and high-level radioactive waste. To this end, the Department of Energy study to-date has included a preliminary technical review to ascertain DOE chemical forms useful for commercial products. The presentation summarized the information including preliminary cost estimates. The status of commercial uranium processing is discussed. With a shrinking market, the number of chemical conversion and fabrication plants is reduced; however, the commercial capability does exist for chemical conversion of the UF6 to the metal form and for the fabrication of uranium radiation shields and other uranium products. Department of Energy facilities no longer possess a capability for depleted uranium chemical conversion

  10. Gammaspectrometric determination of depleted uranium in soil

    International Nuclear Information System (INIS)

    Full text: Three years of monitoring the content of natural radionuclides as well as radionuclides of artificial origin in all samples in the south part of the Republic of Serbia and Montenegro indicated that there was widespread, low-level contamination by depleted uranium at this region. High activity of depleted uranium was found in the soil samples taken at the points where the penetrators were found. We used high resolution gamma spectrometry measurements, because of their simplicity and accuracy. Aims of the control were to asses the increase of radioactivity above the natural levels in the immediate and near vicinity of the bomb craters, to asses the corresponding effect of changed natural radioactivity on the health of the population living in these places and finding unexploded depleted uranium bullets. The collected soil samples were cleaned of plants and stones, dried at 105 deg. C - 110 deg. C till constant weight for 24-48 h. After this, the samples were ground, sieved, and measure in cylindrical geometry. Gamma activity was determined by gamma spectrometry measurements using HP Ge detector (ORTEC), with relative efficiency of 25% and energy resolution of 1.85 keV (1332.5 keV 60Co). The analyser system conducts a peak search, energy assignment, quantification and nuclide identification in acquired spectra. Time of measurement varied from 60000 s to 250000 s. Depleted uranium was found in the soil samples from Vranje region and cape Arza (Montenegro). There are four fenced areas in Vranje region (Pljackovica, Bratoselce, Borovac and Reljan) and one in the Montenegro (cape Arza) where we have found depleted uranium penetrators. The 238U and 235U specific activities and their isotopic composition correspond to depleted uranium (238U/235U ratio from 35 to 77). (author)

  11. The use of digit ratios as markers for perinatal androgen action

    Directory of Open Access Journals (Sweden)

    McIntyre Matthew H

    2006-02-01

    Full Text Available Abstract Since the ratio of the second-to-fourth finger length was first proposed as a marker for prenatal androgen action in 1998, over 100 studies have been published that have either further tested the association between the digit ratio and prenatal androgens, or employed digit ratios as a marker to investigate the association between prenatal androgens and a variety of outcomes, including behavior, fertility, and disease risks. Despite the clear demand for an adult marker of prenatal androgen action and increased use of digit ratios as such a marker, its validity remains controversial. This review (1 evaluates current evidence for the relationship between digit ratios and prenatal androgens (using experimentation with animal models, amniotic testosterone, and congenital adrenal hyperplasia case-control studies, (2 describes opportunities for future validation tests, and (3 compares the potential advantages and disadvantages of digit ratio measures with more established methods for studying the effects of prenatal androgens.

  12. The Chemistry and Toxicology of Depleted Uranium

    OpenAIRE

    Katz, Sidney A.

    2014-01-01

    Natural uranium is comprised of three radioactive isotopes: 238U, 235U, and 234U. Depleted uranium (DU) is a byproduct of the processes for the enrichment of the naturally occurring 235U isotope. The world wide stock pile contains some 1½ million tons of depleted uranium. Some of it has been used to dilute weapons grade uranium (~90% 235U) down to reactor grade uranium (~5% 235U), and some of it has been used for heavy tank armor and for the fabrication of armor-piercing bullets and missiles....

  13. Toxicological issues after depleted uranium weapons attacked

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is a byproduct of the uranium enrichment for producing nuclear reactor or nuclear weapon. DU is used in the military as an armor-piercing projectile due to its hardness, strength, and density. A lot of DU weapons were fired in the Gulf War, and bring about critical environmental and internal contamination. Therefore, DU becomes suddenly a hot issue. Some toxicological problems after DU weapons attacked have been reviewed, which include features of internal DU contamination. Hazard of wound contamination and inhalation with insoluble uranium, and other urgent toxicological issues. The healthy effects of implanted with depleted uranium pellets were illustrated in particular

  14. 3-bromopyruvate inhibits glycolysis, depletes cellular glutathione, and compromises the viability of cultured primary rat astrocytes.

    Science.gov (United States)

    Ehrke, Eric; Arend, Christian; Dringen, Ralf

    2015-07-01

    The pyruvate analogue 3-bromopyruvate (3-BP) is an electrophilic alkylator that is considered a promising anticancer drug because it has been shown to kill cancer cells efficiently while having little toxic effect on nontumor cells. To test for potential adverse effects of 3-BP on brain cells, we exposed cultured primary rat astrocytes to 3-BP and investigated the effects of this compound on cell viability, glucose metabolism, and glutathione (GSH) content. The presence of 3-BP severely compromised cell viability and slowed cellular glucose consumption and lactate production in a time- and concentration-dependent manner, with half-maximal effects observed at about 100 µM 3-BP after 4 hr of incubation. The cellular hexokinase activity was not affected in 3-BP-treated astrocytes, whereas within 30 min after application of 3-BP the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was inhibited, and cellular GSH content was depleted in a concentration-dependent manner, with half-maximal effects observed at about 30 µM 3-BP. The depletion of cellular GSH after exposure to 100 µM 3-BP was not prevented by the presence of 10 mM of the monocarboxylates lactate or pyruvate, suggesting that 3-BP is not taken up into astrocytes predominantly by monocarboxylate transporters. The data suggest that inhibition of glycolysis by inactivation of GAPDH and GSH depletion contributes to the toxicity that was observed for 3-BP-treated cultured astrocytes. PMID:25196479

  15. 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.

  16. Laparoscopic Gonadectomy for Complete Androgen Insensitivity Syndrome: A Case Report

    Directory of Open Access Journals (Sweden)

    Eraydın E et al.

    2011-10-01

    Full Text Available Objective: Our aim was to present and discuss a case with androgen insensitivity syndrome that underwent laparoscopic gonadectomy.Case: A 21 year-old women admitted to our clinic with the complaint of primary amenorrhea and infertility. She had sufficient breast maturation but have scanty pubic and axillar hair. In gynecologic examination vagina was 5 cm in length and ended blindly. In ultrasonographic examination uterus was absent, there were bilateral masses each 3 cm in diameter located near the internal os of the inguinal canals. Her karyotype was 46 XY.Results: The patient underwent laparoscopy. Pelvic inspection revealed no internal genitalia except bilateral gonads appearing as testis. The pedicle of gonads were coagulated with bipolar diathermy and cut with laparoscopic scissors and removed with endobags.Conclusions: Androgen insensitivity syndrome should be suspected in cases with primary amenorrhea and laparoscopic gonadectomy should be performed after puberty.

  17. Cortical venous thrombosis following exogenous androgen use for bodybuilding.

    Science.gov (United States)

    Sveinsson, Olafur; Herrman, Lars

    2013-01-01

    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. PMID:23389726

  18. 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.

  19. Update of the androgen receptor gene mutations database.

    Science.gov (United States)

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

    1999-01-01

    The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 309 to 374 during the past year. We have expanded the database by adding information on AR-interacting proteins; and we have improved the database by identifying those mutation entries that have been updated. Mutations of unknown significance have now been reported in both the 5' and 3' untranslated regions of the AR gene, and in individuals who are somatic mosaics constitutionally. In addition, single nucleotide polymorphisms, including silent mutations, have been discovered in normal individuals and in individuals with male infertility. A mutation hotspot associated with prostatic cancer has been identified in exon 5. The database is 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).

  20. Impact of androgen deprivation therapy on sexual function

    Institute of Scientific and Technical Information of China (English)

    Clarisse R Mazzola; John P Mulhall

    2012-01-01

    Many patients with prostate cancer for whom androgen deprivation therapy (ADT) is indicated are young and desire to remain sexually active.In such patients,the side effects of androgen therapy on sexual function can be a source of serious reduction in overall quality of life.Providing the appropriate treatment options in this patient population is therefore essential.Nevertheless,treating such patients is challenging and an understanding of the underlying mechanisms of sexual physiology and pathophysiology is crucial to optimal patient care.In this paper,we reviewed what was known regarding the effects of ADT on sexual function in animal models and we also provided a detailed review on the effects of ADT on sexual health in humans and its treatment.

  1. Anti-androgen resistance in prostate cancer cells chronically induced by interleukin-1β

    OpenAIRE

    Staverosky, Julia A.; Zhu, Xin-Hua; Ha, Susan; Logan, Susan K.

    2013-01-01

    Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of the androgen receptor gene itself, resulting in the r...

  2. Classical androgen receptors in non-classical sites in the brain

    OpenAIRE

    Sarkey, Sara; Azcoitia, Iñigo; Garcia-Segura, Luis Miguel; Garcia-Ovejero, Daniel; Doncarlos, Lydia L.

    2008-01-01

    Androgen receptors are expressed in many different neuronal populations in the central nervous system where they often act as transcription factors in the cell nucleus. However, recent studies have detected androgen receptor immunoreactivity in neuronal and glial processes of the adult rat neocortex, hippocampal formation, and amygdala as well as in the telencephalon of Eastern Fence and green anole lizards. This review discusses previously published findings on extranuclear androgen receptor...

  3. Biological aspects of the potential interaction between androgen suppression and radiation therapy

    International Nuclear Information System (INIS)

    It is a basic axiom of radiotherapy that the radiation dose required for tumor eradication increases with increasing tumor volume. These Patterns of Care Studies and prospective studies using rebiopsy have shown that this holds true for prostate cancer as well. Despite our best endeavors with conventional dose, there remains a substantial element of local failure following radiotherapy, and this is T-stage related. Unlikely many other solid tumors, a convenient method of volume reduction exists for prostate carcinoma. Approximately 90% demonstrate shrinkage following androgen suppression, an effect that is more pronounced at the primary site than metastatic sites. Transrectal ultrasound studies have shown a median of 40% prostatic tumor volume reduction after 3-4 months of androgen suppression. With more protracted androgen suppression the shrinkage progresses and a small minority of patients may actually have a complete response determined pathologically. Animal models demonstrate clearly that the TCD50 of androgen dependent tumors may be decreased by prior androgen depression. This effect is most pronounced if radiation is deferred until the time of maximal tumor regression. The advantage is lost if the tumor is allowed to regrow in an androgen independent fashion to its original volume. It is not clear whether this benefit of neoadjuvant androgen suppression results solely from volume shrinkage. The potential for synergy exists as both radiation and androgen suppression have an element of apoptosis as a common pathway of cell death. Although apoptosis is certainly the major cause of cell death from androgen suppression its' contribution to radiation cell kill in prostatic adenocarcinomas is yet to be evaluated. If the two effects are additive and not synergistic, then sequence should be unimportant. Animal models, however, demonstrate that the TCD50 of androgen dependent tumors is not significantly reduced by adjuvant androgen suppression. Human data is still

  4. Transcriptional programs activated by exposure of human prostate cancer cells to androgen

    OpenAIRE

    DePrimo, Samuel E; Diehn, Maximilian; Nelson, Joel B.; Reiter, Robert E.; Matese, John; Fero, Mike; Tibshirani, Robert; Brown, Patrick O; James D Brooks

    2002-01-01

    Background Androgens are required for both normal prostate development and prostate carcinogenesis. We used DNA microarrays, representing approximately 18,000 genes, to examine the temporal program of gene expression following treatment of the human prostate cancer cell line LNCaP with a synthetic androgen. Results We observed statistically significant changes in levels of transcripts of more than 500 genes. Many of these genes were previously reported androgen targets, but most were not prev...

  5. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

    OpenAIRE

    Mahajan, Nupam P.; Liu, Yuanbo; Majumder, Samarpan; Warren, Maria R.; Parker, Carol E.; Mohler, James L.; Earp, H. Shelton; Whang, Young E.

    2007-01-01

    Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth o...

  6. Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer

    OpenAIRE

    Osamu Ogawa; Tomomi Kamba; Takahiro Inoue; Takashi Kobayashi

    2013-01-01

    In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent subli...

  7. Keratinocyte Growth Inhibition through the Modification of Wnt Signaling by Androgen in Balding Dermal Papilla Cells

    OpenAIRE

    Kitagawa, Tomoko; Matsuda, Ken-ichi; Inui, Shigeki; Takenaka, Hideya; Katoh, Norito; Itami, Satoshi; Kishimoto, Saburo; Kawata, Mitsuhiro

    2009-01-01

    Context/Objective: Androgen induces androgenetic alopecia (AGA), which has a regressive effect on hair growth from the frontal region of the scalp. Conversely, Wnt proteins are known to positively affect mammalian hair growth. We hypothesized that androgen reduces hair growth via an interaction with the Wnt signaling system. The objective of this study was to investigate the effect of androgen on Wnt signaling in dermal papilla (DP) cells.

  8. Is there a relationship between androgenic alopecia and benign prostatic hyperplasia?

    OpenAIRE

    Ladan Dastgheib; Mehdi Shirazi; Iman Moezzi; Saber Dehghan; Maryam-Sadat Sadati

    2015-01-01

    Androgenic alopecia as a physiologic process and benign prostatic hyperplasia (BPH) as a pathologic process in the older population are androgen-dependent processes influenced by 5-alpha reductase enzyme which converts testosterone to dihydrotestosterone. This cross sectional study was done to evaluate the relationship between androgenic alopecia and BPH. 150 men older than 50 years old, who presented to the free prostate screening clinic, were included. They were asked about urinary symptoms...

  9. Protein-protein Interactions of the Androgen Receptor in Living Cells

    OpenAIRE

    Royen, Martin

    2008-01-01

    markdownabstract__Abstract__ Natural androgens, testosterone (T) and its derivative dihydrotestosterone (DHT) play a crucial role in the development and maintenance of the male phenotype. Androgens are steroids that exert their function via the androgen receptor (AR), a ligand dependent transcription factor. The human AR gene, is located on the X chromosome, and contains 8 exons, coding for a 110 kDa, 919 amino acids protein (Brinkmann et al., 1989; Hughes and Deeb, 2006). In the classical mo...

  10. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    OpenAIRE

    Rennie, Paul S.; Artem Cherkasov; Nada Lallous; Kush Dalal

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the ...

  11. Threat perception and familiarity moderate the androgen response to competition in women

    OpenAIRE

    Oliveira, Rui F.; Oliveira, Gonçalo A.; Sara eUceda; Tania eF. De Oliveira; Alexandre eFernandes; Teresa eGarcia-Marques

    2013-01-01

    Social interactions elicit androgen responses whose function has been posited to be the adjustment of androgen-dependent behaviors to social context. The activation of this androgen response is known to be mediated and moderated by psychological factors. In this study we tested the hypothesis that the testosterone (T) changes after a competition are not simply related to its outcome, but rather to the way the subject evaluates the event. In particular we tested two evaluative dimensions of a ...

  12. Sarcopenia and Androgens: A Link between Pathology and Treatment

    OpenAIRE

    Basualto-Alarcón, Carla; Varela, Diego; Duran, Javier; Maass, Rodrigo; Estrada, Manuel

    2014-01-01

    Sarcopenia, the age-related loss of skeletal muscle mass and function, is becoming more prevalent as the lifespan continues to increase in most populations. As sarcopenia is highly disabling, being associated with increased risk of dependence, falls, fractures, weakness, disability, and death, development of approaches to its prevention and treatment are required. Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developme...

  13. Evidence for an androgen receptor in human testis

    Energy Technology Data Exchange (ETDEWEB)

    Graham, M.L.; Razel, A.J.; Spelsberg, T.C.; Coulam, C.B.

    1984-11-01

    The present study identified and characterized an androgen-binding protein in human testicular tissue. Human testes were homogenized in dilute Tris buffer containing thioglycerol, phenylmethylsulfonylfluoride, and molybdate. The supernatant (termed cytosol) was incubated with radiolabeled androgen methyltrienolone (tritium-labeled R1881), and nonspecific binding was determined by adding 100-fold excess of unlabeled R1881 together with (/sup 3/H)R1881 to cytosol. Specific binding with saturation at 24 hours was observed. Scatchard analysis of the specific binding with the use of increasing concentrations of (/sup 3/H)R1881 alone and (/sup 3/H)R1881 plus 200-fold excess unlabeled R1881 demonstrated a high-affinity (dissociation constant . 2.18 X 10(-10) mol/L), low-capacity (2924 molecules per cell) class of binding sites. A second class of lower-affinity sites was identified with a dissociation constant equaling 1.2 X 10(-8) and 26,300 molecules per cell. The bulk of the higher-affinity class of sites was precipitated at 35% ammonium sulfate. In competitive binding assays, dihydrotestosterone and testosterone greatly diminished binding to this high-affinity class of sites. Progesterone also diminished binding but to a lesser degree. Estradiol, estriol, and estrone failed to compete for these sites. Analysis of the receptor, using sucrose gradients, revealed a major peak in the 4S region and a small peak at 8S. A similar high-affinity (dissociation constant . 4.28 X 10(-9), low-capacity (4860 molecules per cell) binding protein was identified in purified nuclei. Binding to nuclear chromatin was demonstrated in the cell-free binding assay, and nuclear binding was further illustrated in the biopsy assay of intact tissue, suggesting translocation in vivo. These properties are characteristic of the androgen receptor and suggest that human testis is a target tissue for androgen, as has been found in animal tissue.

  14. Evidence for an androgen receptor in human testis

    International Nuclear Information System (INIS)

    The present study identified and characterized an androgen-binding protein in human testicular tissue. Human testes were homogenized in dilute Tris buffer containing thioglycerol, phenylmethylsulfonylfluoride, and molybdate. The supernatant (termed cytosol) was incubated with radiolabeled androgen methyltrienolone (tritium-labeled R1881), and nonspecific binding was determined by adding 100-fold excess of unlabeled R1881 together with [3H]R1881 to cytosol. Specific binding with saturation at 24 hours was observed. Scatchard analysis of the specific binding with the use of increasing concentrations of [3H]R1881 alone and [3H]R1881 plus 200-fold excess unlabeled R1881 demonstrated a high-affinity (dissociation constant . 2.18 X 10(-10) mol/L), low-capacity (2924 molecules per cell) class of binding sites. A second class of lower-affinity sites was identified with a dissociation constant equaling 1.2 X 10(-8) and 26,300 molecules per cell. The bulk of the higher-affinity class of sites was precipitated at 35% ammonium sulfate. In competitive binding assays, dihydrotestosterone and testosterone greatly diminished binding to this high-affinity class of sites. Progesterone also diminished binding but to a lesser degree. Estradiol, estriol, and estrone failed to compete for these sites. Analysis of the receptor, using sucrose gradients, revealed a major peak in the 4S region and a small peak at 8S. A similar high-affinity (dissociation constant . 4.28 X 10(-9), low-capacity (4860 molecules per cell) binding protein was identified in purified nuclei. Binding to nuclear chromatin was demonstrated in the cell-free binding assay, and nuclear binding was further illustrated in the biopsy assay of intact tissue, suggesting translocation in vivo. These properties are characteristic of the androgen receptor and suggest that human testis is a target tissue for androgen, as has been found in animal tissue

  15. Cause of Androgenic Alopecia: Crux of the Matter

    OpenAIRE

    Emin Tuncay Ustuner, MD

    2013-01-01

    Summary: What is wrong with the current understanding of etiopatho genesis of androgenic alopecia (AGA)? What is the most important question to ask to understand AGA? Why is that question skimped? Which findings are interpreted incorrectly? Is there anything that has not been discerned about AGA until today? What are the deceptive factors for investigators? Is it possible to snap the whole view uninterruptedly in one clear picture? Answers and an overview with fresh perspectives are provided.

  16. Cause of Androgenic Alopecia: Crux of the Matter

    Directory of Open Access Journals (Sweden)

    Emin Tuncay Ustuner, MD

    2013-10-01

    Full Text Available Summary: What is wrong with the current understanding of etiopatho genesis of androgenic alopecia (AGA? What is the most important question to ask to understand AGA? Why is that question skimped? Which findings are interpreted incorrectly? Is there anything that has not been discerned about AGA until today? What are the deceptive factors for investigators? Is it possible to snap the whole view uninterruptedly in one clear picture? Answers and an overview with fresh perspectives are provided.

  17. Androgen Exposure and Sensation-Seeking in Young Males

    OpenAIRE

    Ellison, Peter; Little, A.; Apicella, Carmel; Dreber, Anna; Gray, Peter B; Campbell, Bruce C

    2008-01-01

    Testosterone is thought to be associated with short attention spans, increased novelty, and thrill seeking and behavioral disinhibition in men. However, there is little empirical evidence for such associations among normal males. Here we test three separate measures of androgenicity; salivary testosterone (current exposure), facial masculinity (pubertal exposure), and 2D:4D digit ratio (prenatal exposure) as predictors of sensation-seeking in young men. Participants were 98 young men between ...

  18. Anabolic androgenic steroids and violence : a medicolegal and experimental study

    OpenAIRE

    Thiblin, Ingemar

    1999-01-01

    Non-medical use of anabolic androgenic steroids (AAS) has been linked to various psychological and behavioural complications in case and survey reports. Judging from these reports, the symptoms most consistently associated with AAS use are extreme irritability, increased aggressiveness and mood swings. There are also a limited number of reports connecting AAS-associated aggressivity with violent acts including homicide, while reports of self-injurious behaviour associated ...

  19. Incomplete androgen insensitivity (Reifenstein syndrome) - a case report

    OpenAIRE

    Turan, Volkan; Yeniel, Özgür; Ergenoğlu, Mete; Terek, Coşan; Ulukuş, Murat

    2010-01-01

    We report a 20 year old case of partial androgen insensitivity syndrome, referred to our clinic with complaints concerning external genital organs and left undescended testicle. The phenotypically male case was first evaluated for secondary sex development. Axillary hair was scanty and no pubic hair was found. There was no breast development. In the gynecological examination, the clitoris was hypertrophic (4.6 cm) and a blind vagina with intact hymen was seen. Abdominopelvic ultrasonography r...

  20. Do circulating androgen levels predict competitiveness in female athletes?

    OpenAIRE

    Romfo, Marit

    2012-01-01

    Objective: In males a correlation between competitiveness and testosterone have been reported. As no such data is available in females we aimed at investigating the possible association between competitiveness and androgen levels in a sample of female top athletes.Method: Thirty one Norwegian female top athletes completed the competitiveness subscale of the Sport Orientation Questionnaire (SOQ), underwent a maximal oxygen consumption (VO2max) test with a following lactate measurement and had ...

  1. Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Sharp, Adam; Welti, Jonathan; Blagg, Julian; de Bono, Johann S

    2016-09-01

    Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2. ©2016 AACRSee related article by Yang et al., p. 4466.

  2. Early androgen influences on human neural and behavioural development

    OpenAIRE

    Hines, Melissa

    2008-01-01

    Gonadal hormones, particularly androgens, influence sexual differentiation of the body, as well as the brain and behaviour. Ante-natal exposure to atypical hormone environments leads to alterations in human behaviours that show sex differences. These include childhood play, sexual orientation, gender identity, and personality characteristics, such as empathy and aggression. Individual variability among healthy children in antenatal hormone exposure show similar relationships to individual var...

  3. Echocardiographic Findings in Power Athletes Abusing Anabolic Androgenic Steroids

    OpenAIRE

    Hajimoradi, Behzad; Kazerani, Hashem

    2012-01-01

    Purpose Anabolic androgenic steroids (AAS) abuse for improving physical appearance and performance in body builders is common and has been considered responsible for serious cardiovascular effects. Due to disagreement about cardiovascular side effects of these drugs in published articles, this case control study was designed to evaluate the echocardiographic findings in body builder athletes who are current and chronic abusers of these drugs. Methods Body builder athletes with continuous prac...

  4. Nonneural Androgen Receptors Affect Sexual Differentiation of Brain and Behavior.

    Science.gov (United States)

    Swift-Gallant, Ashlyn; Coome, Lindsay A; Ramzan, Firyal; Monks, D Ashley

    2016-02-01

    Testosterone, acting via estrogenic and androgenic pathways, is the major endocrine mechanism promoting sexual differentiation of the mammalian nervous system and behavior, but we have an incomplete knowledge of which cells and tissues mediate these effects. To distinguish between neural and nonneural actions of androgens in sexual differentiation of brain and behavior, we generated a loxP-based transgenic mouse, which overexpresses androgen receptors (ARs) when activated by Cre. We used this transgene to overexpress AR globally in all tissues using a cytomegalovirus (CMV)-Cre driver (CMV-AR), and we used a Nestin-Cre driver to overexpress AR only in neural tissue (Nes-AR). We then examined whether neural or global AR overexpression can affect socio-sexual behaviors using a resident-intruder paradigm. We found that both neural and global AR overexpression resulted in decreased aggressive behaviors and increased thrusting during mounting of intruders, consistent with a neural site of action. Global, but not neural, AR overexpression in males led to an increase in same-sex anogenital investigation. Together, these results suggest novel roles for nonneural AR in sexual differentiation of mice, and indicate that excess AR can lead to a paradoxical reduction of male-typical behavior. PMID:26636184

  5. Preliminary investigations into triazole derived androgen receptor antagonists.

    Science.gov (United States)

    Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C

    2014-05-01

    A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.

  6. 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. PMID:24742982

  7. Cues to androgens and quality in male gibbon songs.

    Directory of Open Access Journals (Sweden)

    Claudia Barelli

    Full Text Available Animal vocal signals may provide information about senders and mediate important social interactions like sexual competition, territory maintenance and mate selection. Hence, it is important to understand whether vocal signals provide accurate information about animal attributes or status. Gibbons are non-human primates that produce loud, distinctive and melodious vocalizations resembling more those of birds than of other non-human primates. Wild gibbons are characterized by flexibility in social organization (i.e., pairs and multimale units as well as in mating system (i.e., monogamy and polyandry. Such features make them a suitable model to investigate whether the physiology (hormonal status and socio-demographic features find their correspondence in the structure of their songs. By combining male solo song recordings, endocrine outputs using non-invasive fecal androgen measures and behavioral observations, we studied 14 groups (10 pair-living, 4 multimale of wild white-handed gibbons (Hylobates lar residing at Khao Yai National Park, Thailand. We collected a total of 322 fecal samples and recorded 48 songs from 18 adult animals. Our results confirmed inter-individuality in male gibbon songs, and showed a clear correlation between androgen levels and song structures. Gibbons with higher androgen levels produced calls having higher pitch, and similarly adult individuals produced longer calls than senior males. Thus, it is plausible that gibbon vocalizations provide receivers with information about singers' attributes.

  8. The estrogenic and androgenic potential of pyrethroids in vitro. Review.

    Science.gov (United States)

    Saillenfait, Anne-Marie; Ndiaye, Dieynaba; Sabaté, Jean-Philippe

    2016-08-01

    Synthetic pyrethroids are used worldwide as insecticides. Their metabolites are regularly detected in the urine of adults and children from the general population. There is increasing concern that they may induce sex-hormone disrupting effects. The present work reviews available published information on the (anti)estrogenic and (anti)androgenic activity of pyrethroids in in vitro screening tests. In recent years, a large number of pyrethroids have been evaluated using various common testing methods. In tests using recombinant yeast or mammalian cells, the pyrethroids were found to be essentially negative or weakly estrogenic. More inconsistent results were found regarding their estrogenic action in proliferation tests. Conflicting findings were also reported across studies and/or assays which evaluated their anti-estrogenic or anti-androgenic potential. Some studies have suggested that certain pyrethroids may have potential antagonist activity. However, no strong interaction with the estrogenic or androgenic pathway was reported. The present review confirms the interest in performing a screening battery and in adopting an integrative approach for identifying the potential of different compounds from a chemical family to interfere with the endocrine system. PMID:26921664

  9. Discovery of diarylhydantoins as new selective androgen receptor modulators.

    Science.gov (United States)

    Nique, François; Hebbe, Séverine; Peixoto, Christophe; Annoot, Denis; Lefrançois, Jean-Michel; Duval, Eric; Michoux, Laurence; Triballeau, Nicolas; Lemoullec, Jean-Michel; Mollat, Patrick; Thauvin, Maxime; Prangé, Thierry; Minet, Dominique; Clément-Lacroix, Philippe; Robin-Jagerschmidt, Catherine; Fleury, Damien; Guédin, Denis; Deprez, Pierre

    2012-10-11

    A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.

  10. Recent developments in antiandrogens and selective androgen receptor modulators.

    Science.gov (United States)

    Haendler, Bernard; Cleve, Arwed

    2012-04-16

    The androgens testosterone and dihydrotestosterone play an essential role in the development and maintenance of primary and secondary male characteristics. Androgens bind to a specific androgen receptor (AR), a ligand-dependent transcription factor which controls the expression of a large number of downstream target genes. The AR is an essential player in early and late prostate cancer, and may also be involved in some forms of breast cancer. It also represents a drug target for the treatment of hypogonadism. Recent studies furthermore indicate that targeting the AR in pathologies such as frailty syndrome, cachexia or polycystic ovary syndrome may have clinical benefit. Numerous AR ligands with very different pharmacological properties have been identified in the last 40 years and helped to treat several of these diseases. However, progress still needs to be made in order to find compounds with an improved profile with regard to efficacy, differentiation and side-effects. This will only be achieved through a better understanding of the mechanisms involved in normal and aberrant AR signaling.

  11. Analogue to Digital and Digital to Analogue Converters (ADCs and DACs): A Review Update

    CERN Document Server

    Pickering, J

    2015-01-01

    This is a review paper updated from that presented for CAS 2004. Essentially, since then, commercial components have continued to extend their performance boundaries but the basic building blocks and the techniques for choosing the best device and implementing it in a design have not changed. Analogue to digital and digital to analogue converters are crucial components in the continued drive to replace analogue circuitry with more controllable and less costly digital processing. This paper discusses the technologies available to perform in the likely measurement and control applications that arise within accelerators. It covers much of the terminology and 'specmanship' together with an application-oriented analysis of the realisable performance of the various types. Finally, some hints and warnings on system integration problems are given.

  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. Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

    Science.gov (United States)

    Kaur, Satwant; Baynes, Alice; Lockyer, Anne E; Routledge, Edwin J; Jones, Catherine S; Noble, Leslie R; Jobling, Susan

    2016-01-01

    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.

  14. Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata

    Science.gov (United States)

    Lockyer, Anne E.; Routledge, Edwin J.; Jones, Catherine S.; Noble, Leslie R.; Jobling, Susan

    2016-01-01

    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. PMID:27448327

  15. Direct interaction between AR and PAK6 in androgen-stimulated PAK6 activation.

    Science.gov (United States)

    Liu, Xia; Busby, Jennifer; John, Ciny; Wei, Jianning; Yuan, Xin; Lu, Michael L

    2013-01-01

    A p21-activated kinase 6 (PAK6) was previously identified to be an androgen receptor (AR) interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.

  16. Direct interaction between AR and PAK6 in androgen-stimulated PAK6 activation.

    Directory of Open Access Journals (Sweden)

    Xia Liu

    Full Text Available A p21-activated kinase 6 (PAK6 was previously identified to be an androgen receptor (AR interacting protein through a yeast two-hybrid screening. We used hormone responsive prostate cancer LAPC4 and LNCap cell lines as models to study the signaling events associated with androgen stimulation and PAK6. An androgen-stimulated PAK6 kinase activation was observed in LAPC4 cells expressing endogenous PAK6 and in LNCap cells ectopically expressing a wild type PAK6. This activation was likely mediated through a direct interaction between AR and PAK6 since siRNA knock-down of AR in LAPC4 cells downregulated androgen-stimulated PAK6 activation. In addition, LNCap cells expressing a non-AR-interacting PAK6 mutant exhibited dampened androgen-stimulated kinase activation. As a consequence of androgen-stimulated activation, PAK6 was phosphorylated at multiple serine/threonine residues including the AR-interacting domain of PAK6. Furthermore, androgen-stimulation promoted prostate cancer cell motility and invasion were demonstrated in LNCap cells ectopically expressing PAK6-WT. In contrast, LNCap expressing non-AR-interacting mutant PAK6 did not respond to androgen stimulation with increased cell motility and invasion. Our results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion.

  17. Application of backtracking algorithm to depletion calculations

    International Nuclear Information System (INIS)

    Based on the theory of linear chain method for analytical depletion calculations, the burn-up matrix is decoupled by the divide and conquer strategy and the linear chain with Markov characteristic is formed. The density, activity and decay heat of every nuclide in the chain can be calculated by analytical solutions. Every possible reaction path of the nuclide must be considered during the linear chain establishment process. To confirm the calculation precision and efficiency, the algorithm which can cover all the reaction paths of the nuclide and search the paths automatically according to to problem description and precision restrictions should be sought. Through analysis and comparison of several kinds of searching algorithms, the backtracking algorithm was selected to search and calculate the linear chains using Depth First Search (DFS) method. The depletion program can solve the depletion problem adaptively and with high fidelity. The solution space and time complexity of the program were analyzed. The new developed depletion program was coupled with Monte Carlo program MCMG-II to calculate the benchmark burn-up problem of the first core of China Experimental Fast Reactor (CEFR). The initial verification and validation of the program was performed by the calculation. (author)

  18. Global Warming: Lessons from Ozone Depletion

    Science.gov (United States)

    Hobson, Art

    2010-01-01

    My teaching and textbook have always covered many physics-related social issues, including stratospheric ozone depletion and global warming. The ozone saga is an inspiring good-news story that's instructive for solving the similar but bigger problem of global warming. Thus, as soon as students in my physics literacy course at the University of…

  19. How Depleted is the MORB mantle?

    Science.gov (United States)

    Hofmann, A. W.; Hart, S. R.

    2015-12-01

    Knowledge of the degree of mantle depletion of highly incompatible elements is critically important for assessing Earth's internal heat production and Urey number. Current views of the degree of MORB source depletion are dominated by Salters and Stracke (2004), and Workman and Hart (2005). The first is based on an assessment of average MORB compositions, whereas the second considers trace element data of oceanic peridotites. Both require an independent determination of one absolute concentration, Lu (Salters & Stracke), or Nd (Workman & Hart). Both use parent-daughter ratios Lu/Hf, Sm/Nd, and Rb/Sr calculated from MORB isotopes combined with continental-crust extraction models, as well as "canonical" trace element ratios, to boot-strap the full range of trace element abundances. We show that the single most important factor in determining the ultimate degree of incompatible element depletion in the MORB source lies in the assumptions about the timing of continent extraction, exemplified by continuous extraction versus simple two-stage models. Continued crust extraction generates additional, recent mantle depletion, without affecting the isotopic composition of the residual mantle significantly. Previous emphasis on chemical compositions of MORB and/or peridotites has tended to obscure this. We will explore the effect of different continent extraction models on the degree of U, Th, and K depletion in the MORB source. Given the uncertainties of the two most popular models, the uncertainties of U and Th in DMM are at least ±50%, and this impacts the constraints on the terrestrial Urey ratio. Salters, F.J.M. and Stracke, A., 2004, Geochem. Geophys. Geosyst. 5, Q05004. Workman, R.K. and Hart, S.R., 2005, EPSL 231, 53-72.

  20. Radioimmunoassay of the androgen function at healthy children

    International Nuclear Information System (INIS)

    The androgen function at 67 healthy children aged 1-18 years is studied. Three age groups (1-6 yrs., n=28; 7-12 yrs., n=19; 12-18 yrs., n=20) are examined. Measurements have been done of testosterone (T), Δ-4 androstenedione (Δ-4-A) and sex hormone binding globulin (SHBG) by RIA kits of the Merieux. 17-α-hydroxyprogesterone (17α-OHP), the basic precursor os the androgens, has been measured in the serum by the same RIA kits. An increase in T and Δ-4-A levels with age is observed with significantly higher levels for 12-18 year, compared to those of 1 - 6 years (p<0.02, p<0.002) and 7-12 years (p<0.001). There is reliably higher secretion of T and Δ-4-A in boys, compared to that in 12-18 year girls (p<0.01), while in groups of smaller children only a tendency has been established, probably due to the higher SD. Decrease of the SHBG levels with age has been determined. The lowest levels belong to the binding protein in boys of 12-18 (35.93 ± 8.19 nmol/l)), compared to the other boys as well as in girls in the groups of smaller children (p<0.01). SHBG correlates strong inversely with the levels of T and (Δ-4-A in the 12-18 year boys (8.05 ± 4.4 nmol/l; 19.9 ± 5.7 nmol/l). Probably the higher levels of the two androgens determine the decrease to the binding capacity of the SHBG between 7 and 18 age during sexual development in boys. Reliable difference between the levels of 17α OHP in the smaller groups (1 month - 1 yrs.; 7 - 12 yrs.), compared to the group od 12 - 17 yrs. (p<0.01) have been found. The present study determines referent ranges of the serum levels of T, Δ-4-A, SHBG and 17α OHP in healthy children aged 1 - 18 yrs. and provides information about androgen function in this age period. These hormones are important markers of androgen profile in many endocrine diseases in both sexes and the established reference range will serve for a prompt diagnosis and a regular therapeutic control in CAN, PCOS, hyperandrogenism etc

  1. ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor

    International Nuclear Information System (INIS)

    The androgen receptor (AR) acts as an androgen-dependent transcription factor controlling the development of prostate tissue. Upon binding to androgen, AR undergoes a dynamic structural change leading to interaction between the NH2- and COOH-terminal regions of AR (N-C interaction). ARA24/Ran, which is a small GTPase, functions as an AR coactivator. Here, we report that ARA24/Ran enhances the N-C interaction of AR. The constitutively GTP- or GDP-bound form of ARA24/Ran repressed the AR N-C interaction. ARA24/Ran did not enhance the transcriptional activities of AR mutants that disrupt the N-C interaction. ARA24/Ran formed an endogenous protein complex with nuclear AR, but not cytoplasmic AR. Unlike SRC-1 with the positive activity for AR N-C interaction, ARA24/Ran did not enhance the transcriptional activity of the COOH-terminal domain-deleted AR mutant that is constitutively localized in the nucleus. These data demonstrate that ARA24/Ran increases AR transactivation by enhancing the AR N-C interaction in the nucleus

  2. Functional characterisation of a natural androgen receptor missense mutation (N771H) causing human androgen insensitivity syndrome.

    Science.gov (United States)

    Cai, J; Cai, L-Q; Hong, Y; Zhu, Y-S

    2012-05-01

    Androgen insensitivity syndrome (AIS) is an X-linked disorder due to mutations of androgen receptor (AR) gene. Various AR mutations have been identified, and the characterisation of these mutations greatly facilitates our understanding of AR structure-function. In this study, we have analysed an AR missense mutation (N771H) identified in patients with AIS. Functional analysis of the mutant AR was performed by in vitro mutagenesis-cotransfection assays. Compared to the wild-type AR, the dose-response curve of dihydrotestosterone-induced transactivation activity in the mutant AR was greatly shifted to the right and significantly decreased. However, the maximal efficacy of transactivation activity in the mutant AR was similar to that of the wild type. Receptor binding assay indicated that the mutant AR had an approximately 2.5-fold lower binding affinity to dihydrotestosterone compared to the wild type. Western blot analysis showed that the size and the expression level of mutant AR in transfected cells were comparable to the wild type. These data underscore the importance of asparagine at amino acid position 771 of human AR in normal ligand binding and normal receptor function, and a mutation at this position results in androgen insensitivity in affected subjects.

  3. Studies on Androgen Receptor mRNA expression in Pancreas, Hypothalamus and Ovary of Androgen Sterilized Rats

    Institute of Scientific and Technical Information of China (English)

    Li WANG; Jing-wen HOU; Li-min LU; Jin YU; Sui-qi GUI

    2004-01-01

    Objective To investigate the androgen receptor (AR) mRNA expression in pancreas,hypothalamus and ovary of androgen sterilized rats (ASR)Methods ASR model was established by subcutaneous injection of testosterone propionate to SD female rats at the age of 9 days. Around the age of 106 days (proestrus),all rats were killed, serum △ 4-andronestedione (△ 4-A), total testosterone (TT), free testosterone (FT), insulin (Ins) and C-peptide (C-P)were measured by radioimmunoassay (RIA). Total RNA in pancreas, hypothalamus and ovary were extracted and the amount of AR mRNA was quantitatedly analyzed by RT-PCR with single base mutant template as inner standard. Results Serum concentrations of△ 4-A, TT, FT, Ins and C-P in ASR model rats were significantly higher than those in control group (P<0. 05, P<0. 01). The expression of AR mRNA in pancreas, hypothalamus and ovary increased significantly (P<0. 05,P<0. 01) of model rats as compared with control group. Conclusion The elevated serum androgen levels in ASR model could enhance the expression of AR mRNA levels in pancreas, hypothalamus and ovary, which further induce hyperinsulinemia and anovulation.

  4. Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

    Science.gov (United States)

    Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

    2016-07-22

    It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. PMID:27179779

  5. Contributions by the CAG-repeat Polymorphism of the Androgen Receptor Gene and Circulating Androgens to Muscle Size. Odense Androgen Study - A Population-based Study of 20-29 Year-old Danish Men

    DEFF Research Database (Denmark)

    Nielsen, Torben Leo; Hagen, Claus; Wraae, Kristian;

    2007-01-01

    -29 years, who matched the background population as regards body mass index, chronic disease, medication, physical activity, smoking, and sociodemographic parameters. Genotyping was performed in 767 men, whole body DXA in 783 men, and MRI in 406 consecutively included men. Main Outcome Measures: Six......-repeat number correlated inversely with thigh and axial muscle area and with lower and upper extremity lean body mass. Except for upper extremity lean body mass, these findings remained significant in multivariate analyses controlling for circulating androgens, physical activity, smoking, alcohol intake......Context: The number of CAG-repeats within the CAG-repeat polymorphism of the androgen receptor gene is inversely correlated with the transcriptional activity of the androgen receptor. Objective: To study the effect of the CAG-repeat number and circulating androgens on muscle size, to examine...

  6. Uncovering Mass Segregation with Galaxy Analogues in Dark Matter Simulations

    CERN Document Server

    Joshi, Gandhali D; Wadsley, James

    2016-01-01

    We investigate mass segregation in group and cluster environments by identifying galaxy analogues in high-resolution dark matter simulations. Subhalos identified by the AHF and ROCKSTAR halo finders have similar mass functions, independent of resolution, but different radial distributions due to significantly different subhalo hierarchies. We propose a simple way to classify subhalos as galaxy analogues. The radial distributions of galaxy analogues agree well at large halo-centric radii for both AHF and ROCKSTAR but disagree near parent halo centres where the phase-space information used by ROCKSTAR is essential. We see clear mass segregation at small radii (within $0.5\\,r_{vir}$) with average galaxy analogue mass decreasing with radius. Beyond the virial radius, we find a mild trend where the average galaxy analogue mass increases with radius. These mass segregation trends are strongest in small groups and dominated by the segregation of low mass analogues. The lack of mass segregation in massive galaxy anal...

  7. Insulin analogues in pregnancy and specific congenital anomalies

    DEFF Research Database (Denmark)

    de Jong, Josta; Garne, Ester; Wender-Ozegowska, Ewa;

    2016-01-01

    Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant...... women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we...... included 1286 foetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate...

  8. The Greenland analogue project. Yearly report 2010

    Energy Technology Data Exchange (ETDEWEB)

    Harper, J.; Brinkerhoff, D.; Johnson, J. [University of Montana, Missoula (United States); Ruskeeniemi, T.; Engstroem, J.; Kukkonen, I. [Geological Survey of Finland (Finland)] [and others

    2012-04-15

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  9. The Greenland analogue project. Yearly report 2010

    International Nuclear Information System (INIS)

    A four-year field and modelling study of the Greenland ice sheet and subsurface conditions, Greenland Analogue Project (GAP), has been initiated collaboratively by SKB, Posiva and NWMO to advance the understanding of processes associated with glaciation and their impact on the long-term performance of a deep geological repository. The study site encompasses a land terminus portion of the Greenland ice sheet, east of Kangerlussuaq, and is in many ways considered to be an appropriate analogue of the conditions that are expected to prevail in much of Canada and Fennoscandia during future glacial cycles. The project begins in 2009 and is scheduled for completion in 2012. Our current understanding of the hydrological, hydrogeological and hydrogeochemical processes associated with cold climate conditions and glacial cycles, and their impact on the long-term performance of deep geological repositories for spent nuclear fuel, will be significantly improved by studying a modern analogue. The GAP will conduct the first in situ investigations of some of the parameters and processes needed to achieve a better understanding of how an ice sheet may impact a deep repository, and will provide measurements, observations and data that may significantly improve our safety assessments and risk analyses of glaciation scenarios. This report was produced by the GAP team members and presents an overview of the activities within the GAP during the interval January 1 to December 31, 2010, as well as research results obtained during this time frame. Research for the GAP is ongoing, and additional results related to the data presented here may become available in the future and will be presented in subsequent annual reports. (orig.)

  10. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Directory of Open Access Journals (Sweden)

    John M Kokontis

    Full Text Available The majority of prostate cancer (PCa patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC. We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1; and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  11. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Science.gov (United States)

    Kokontis, John M; Lin, Hui-Ping; Jiang, Shih Sheng; Lin, Ching-Yu; Fukuchi, Junichi; Hiipakka, Richard A; Chung, Chi-Jung; Chan, Tzu-Min; Liao, Shutsung; Chang, Chung-Ho; Chuu, Chih-Pin

    2014-01-01

    The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1); and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1) and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  12. A worldwide view of groundwater depletion

    Science.gov (United States)

    van Beek, L. P.; Wada, Y.; van Kempen, C.; Reckman, J. W.; Vasak, S.; Bierkens, M. F.

    2010-12-01

    During the last decades, global water demand has increased two-fold due to increasing population, expanding irrigated area and economic development. Globally such demand can be met by surface water availability (i.e., water in rivers, lakes and reservoirs) but regional variations are large and the absence of sufficient rainfall and run-off increasingly encourages the use of groundwater resources, particularly in the (semi-)arid regions of the world. Excessive abstraction for irrigation frequently leads to overexploitation, i.e. if groundwater abstraction exceeds the natural groundwater recharge over extensive areas and prolonged times, persistent groundwater depletion may occur. Observations and various regional studies have revealed that groundwater depletion is a substantial issue in regions such as Northwest India, Northeast Pakistan, Central USA, Northeast China and Iran. Here we provide a global overview of groundwater depletion from the year 1960 to 2000 at a spatial resolution of 0.5 degree by assessing groundwater recharge with the global hydrological model PCR-GLOBWB and subtracting estimates of groundwater abstraction obtained from IGRAC-GGIS database. PCR-GLOBWB was forced by the CRU climate dataset downscaled to daily time steps using ERA40 re-analysis data. PCR-GLOBWB simulates daily global groundwater recharge (0.5 degree) while considering sub-grid variability of each grid cell (e.g., short and tall vegetation, different soil types, fraction of saturated soil). Country statistics of groundwater abstraction were downscaled to 0.5 degree by using water demand (i.e., agriculture, industry and domestic) as a proxy. To limit problems related to increased capture of discharge and increased recharge due to groundwater pumping, we restricted our analysis to sub-humid to arid areas. The uncertainty in the resulting estimates was assessed by a Monte Carlo analysis of 100 realizations of groundwater recharge and 100 realizations of groundwater abstraction

  13. Health and environmental impact of depleted uranium

    International Nuclear Information System (INIS)

    Depleted Uranium (DU) is 'nuclear waste' produced from the enrichment process and is mostly made up of 238U and is depleted in the fissionable isotope 235U compared to natural uranium (NU). Depleted uranium has about 60% of the radioactivity of natural uranium. Depleted uranium and natural uranium are identical in terms of the chemical toxicity. Uranium's high density gives depleted uranium shells increased range and penetrative power. This density, combined with uranium's pyrophoric nature, results in a high-energy kinetic weapon that can punch and burn through armour plating. Striking a hard target, depleted uranium munitions create extremely high temperatures. The uranium immediately burns and vaporizes into an aerosol, which is easily diffused in the environment. People can inhale the micro-particles of uranium oxide in an aerosol and absorb them mainly from lung. Depleted uranium has both aspects of radiological toxicity and chemical toxicity. The possible synergistic effect of both kinds of toxicities is also pointed out. Animal and cellular studies have been reported the carcinogenic, neurotoxic, immuno-toxic and some other effects of depleted uranium including the damage on reproductive system and foetus. In addition, the health effects of micro/ nano-particles, similar in size of depleted uranium aerosols produced by uranium weapons, have been reported. Aerosolized DU dust can easily spread over the battlefield spreading over civilian areas, sometimes even crossing international borders. Therefore, not only the military personnel but also the civilians can be exposed. The contamination continues after the cessation of hostilities. Taking these aspects into account, DU weapon is illegal under international humanitarian laws and is considered as one of the inhumane weapons of 'indiscriminate destruction'. The international society is now discussing the prohibition of DU weapons based on 'precautionary principle'. The 1991 Gulf War is reportedly the first

  14. Digital and analogue industrial radiography, application fields

    International Nuclear Information System (INIS)

    Full text: Reusable phosphor screens for computer radiography (CR), amorphous selenium screens for direct radiography (DR), film digitalisation (FD) constitute imaging methods accepted by industry and are used for non-destructive radiographic testing (RT). Economic pressures are involving and affecting digital RT technology. Standards and codes for film radiography and radioscopy qualification do no longer cover the wide range of digital RT applications. It will be our task to optimise the performance of digital RT characterisation and to create appropriate examination methods to use all these new and existent technologies. In the meantime, an increasing automation and control of manual methods of analogue radiography can as well be expected. (author)

  15. Technical Considerations in Magnetic Analogue Models

    CERN Document Server

    Adams, Patrick W M

    2016-01-01

    The analogy between vorticity and magnetic fields has been a subject of interest to researchers for a considerable period of time, mainly because of the structural similarities between the systems of equations that govern the evolution of the two fields. We recently presented the analysis of magnetic fields and hydrodynamics vorticity fields and argued for a formal theory of analogue magnetism. This article provides in depth technical details of the relevant considerations for the simulation procedures and extends the analyses to a range of fluids.

  16. Analogues of Euler and Poisson Summation Formulae

    Indian Academy of Sciences (India)

    Vivek V Rane

    2003-08-01

    Euler–Maclaurin and Poisson analogues of the summations $\\sum_{a < n ≤ b}(n)f(n), \\sum_{a < n ≤ b}d(n) f(n), \\sum_{a < n ≤ b}d(n)(n) f(n)$ have been obtained in a unified manner, where (()) is a periodic complex sequence; () is the divisor function and () is a sufficiently smooth function on [, ]. We also state a generalised Abel's summation formula, generalised Euler's summation formula and Euler's summation formula in several variables.

  17. Materials analogue of zero-stiffness structures

    Science.gov (United States)

    Kumar, Arun; Subramaniam, Anandh

    2011-04-01

    Anglepoise lamps and certain tensegrities are examples of zero-stiffness structures. These structures are in a state of neutral equilibrium with respect to changes in configuration of the system. Using Eshelby's example of an edge dislocation in a thin plate that can bend, we report the discovery of a non-trivial new class of material structures as an analogue to zero-stiffness structures. For extended positions of the edge dislocation in these structures, the dislocation experiences a zero image force. Salient features of these material structures along with the key differences from conventional zero-stiffness structures are pointed out.

  18. Satellite television analogue and digital reception techniques

    CERN Document Server

    Benoit, Herve

    1999-01-01

    Satellite television is part of the lives of millions of television viewers worldwide and its influence is set to increase significantly with the launch of digital satellite television services.This comprehensive reference book, written by the author of the highly successful 'Digital Television', provides a technical overview of both analogue and digital satellite TV. Written concisely and thoroughly, it covers all aspects of satellite TV necessary to understand its operation and installation. It also covers the evolution of satellite television, and contains a detailed glossary of tec

  19. Analogue cosmology in a hadronic fluid

    Directory of Open Access Journals (Sweden)

    Bilić Neven

    2014-01-01

    Full Text Available Analog gravity models of general relativity seem promising routes to providing laboratory tests of the foundation of quantum field theory in curved space-time. In contrast to general relativity, where geometry of a spacetime is determined by the Einstein equations, in analog models geometry and evolution of analog spacetime are determined by the equations of fluid mechanics. In this paper we study the analogue gravity model based on massless pions propagating in a expanding hadronic fluid. The analog expanding spacetime takes the form of an FRW universe, with the apparent and trapping horizons defined in the standard way.

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

    International Nuclear Information System (INIS)

    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