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Sample records for aromatase gene defines

  1. A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

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    Albaladejo Carlos

    2010-02-01

    Full Text Available Abstract Background Aromatase (CYP19A1 regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC. Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. Methods We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519 and two in the 3'-UTR region (rs10046 and rs4646 were evaluated on DNA obtained from peripheral blood. Results Thirty-five women (36.8% achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03. Eighteen patients (18.9% reported a progression of the disease. Those patients carrying the genetic variants (AC/AA of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686. This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009. Conclusions Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients.

  2. Constitutional genetic variation at the human aromatase gene (Cyp19) and breast cancer risk

    OpenAIRE

    Siegelmann-Danieli, N; Buetow, K H

    1999-01-01

    The activity of the aromatase enzyme, which converts androgens into oestrogens and has a major role in regulating oestrogen levels in the breast, is thought to be a contributing factor in the development of breast cancer. We undertook this study to assess the role of constitutional genetic variation in the human aromatase gene (Cyp19) in the development of this disease. Our genotyping of 348 cases with breast cancer and 145 controls (all Caucasian women) for a published tetranucleotide repeat...

  3. Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.

    Science.gov (United States)

    Muth-Köhne, Elke; Westphal-Settele, Kathi; Brückner, Jasmin; Konradi, Sabine; Schiller, Viktoria; Schäfers, Christoph; Teigeler, Matthias; Fenske, Martina

    2016-07-01

    , this study demonstrated that the existing Adverse Outcome Pathway (AOP) for aromatase inhibition in fish can be translated to the life-stage of sexual differentiation. We were further able to identify MoA-specific marker gene expression which can be instrumental in defining new measurable key events (KE) of existing or new AOPs related to endocrine disruption. PMID:27130971

  4. Differential expression of genes for aromatase and estrogen receptor during the gonadal development in chicken embryos.

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    Nakabayashi, O; Kikuchi, H; Kikuchi, T; Mizuno, S

    1998-04-01

    In birds, differentiation of embryonic gonads is not as strictly determined by the genetic sex as it is in mammals, and can be influenced by early manipulation with a sex steroid hormone. Thus administration of an aromatase inhibitor induces testis development in the genetic female, and administration of estrogen induces a left ovotestis in the genetic male embryo. Another feature of avian gonadogenesis is that only the left ovary develops in most species. Molecular mechanisms underlying these features at the level of gene expression have not been elucidated. In this paper, we present evidence that a gene for aromatase cytochrome P-450, an enzyme required for the last step in the synthesis of estradiol-17beta, is expressed in medullae of the left and right gonads of a female chicken embryo, but not in those of a male chicken embryo, and that an estrogen receptor gene is expressed only in epithelium (and cortex later, in the female) of the left, not the right, gonad of both sexes, but the expression in the male left gonad is temporary and restricted to an early stage of development. Differential expression of these two genes serves well to explain the above features of gonadal development in birds. Furthermore, in ovo administration of estradiol-17beta from the 5th to the 14th day of incubation does not cause expression of the estrogen receptor gene in the right gonad of chicken embryos of either sex, suggesting that the absence of expression of the estrogen receptor gene in the right gonad is not the result of down-regulation, but may be regarded as an important cause of the unilateral ovarian development. PMID:9584834

  5. Frequency of Polymorphism in Aromatase Enzyme Coding Gene with Prostate Cancer Risk in North Indian Population

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    KH Onsory

    2015-10-01

    Full Text Available Background: A series of biochemical reactions are involved in the endogenous production of estrogens. Their final and rate-limiting step is catalyzed by aromatase belonging to the class XIX of cytochrome P450. CYP19 is a key enzyme for estrogen synthesis in males. It catalyzes the irreversible conversion of androstenedione and testosterone to estrone and estradiol-17β, respectively. Aromatase P450 is present in the endoplasmic reticulum of estrogen-reproducing cells in which it is expressed. The effects of the resulting estrogens are mediated through the estrogen receptor. One of the most important polymorphism, is a C to T variation in exon 7 resulting in an Arg264Cys amino acid exchange, has been shown to be very common in Asia. The purpose of this study was to determine the association of CYP19 gene polymorphism with the prostate cancer risk among the studied population. Methods: PCR-RFLP analysis of CYP19 gene was on 100 prostate cancer patients and an equal number of matching controls. The data was analyzed using the computer software SPSS for windows (version 19. Results: The frequency of CT genotype was higher in patients (37% as compared to controls (21.2% and this incidence was statistically significant (OR, 2.10; 95 % CI, 1.02-4.34; P=0.044. Stratification of patients according to the risk factors, resulted in a slightly improved OR in individuals carrying CT compared to CC genotype (OR, 2.35 95% CI, 1.11-4.96; P=0.024. The TT genotype was not significantly associated with prostate cancer risk (OR, 0.63; 95% CI, 0.16-2.50; P=0.519. Conclusion: It seems that CT genotype is more associated with cancer prostate compare with other genotypes. It appears to be an increased risk of prostate cancer associated with the Arg264Cys substitution in the CYP19 gene.

  6. Weight gain and inflammation regulate aromatase expression in male adipose tissue, as evidenced by reporter gene activity.

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    Polari, L; Yatkin, E; Martínez Chacón, M G; Ahotupa, M; Smeds, A; Strauss, L; Zhang, F; Poutanen, M; Saarinen, N; Mäkelä, S I

    2015-09-01

    Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO-Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFα, as well as forskolin and phorbol 12-myristate 13-acetate, upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols attenuates WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men. PMID:26054748

  7. Update on Aromatase Inhibitors

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    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  8. Expression Patterns of Cytochrome P450 Aromatase Genes During Ovary Development and Their Responses to Temperature Stress in Female Yellow Catfish (Pelteobagrus fulvidraco)

    Institute of Scientific and Technical Information of China (English)

    LIU Miao; QI Baoxia; WEN Haishen; HE Feng; LI Jifang; SHI Dan; HU Jian; ZHANG Yuanqing; MA Ruiqin; MU Weijie

    2011-01-01

    Cytochrome P450 aromatase (P450arom) plays a pivotal role in ovary development.In this study,we used semi-quantitative reverse transcription PCR (RT-PCR) to analyze spatiotemporal expressions of two P450arom genes (CYP1gA and CYP19B)and their responses to temperature stress in female yellow catfish (Pelteobagrusfulvidraco).Tissue distribution pattern of CYP19showed that CYP19B was abundantly expressed in fish brain and ovary (brain>ovary),but weakly in intestines,whereas CYP19Awas exclusively expressed in ovary.Semi-quantitative RT-PCR analyses showed high transcript abundance of both CYP19A and CYP19B in the ovarian reproductive cycle,corresponding with serum estradiol-17β (E2) levels.Increases in aromatases,serum E2 and testosterone (T) levels in fish exposed to higher temperature indicated stimulation of ovarian maturation and recrudescence by heat stress in stages Ⅱ and V during the ovarian cycle,whereas associated decreases in stage III suggested vitellogenesis inhibition by heat stress.Gene expression of CYP19 was closely related to levels of serum E2.Results demonstrated CYP19 played a crucial role in the reproductive cycle of female yellow catfish.Different temperature stress affected CYP19 gene expression in the fish ovarian reproductive cycle.Associated P450arom genes could be useful for studying physiological aspects of yellow catfish.

  9. Molecular characterization of aromatase

    OpenAIRE

    Hong, Yanyan; Li, Hongzhi; Yuan, Yate-Ching; Chen, Shiuan

    2009-01-01

    Aromatase is an estrogen synthetase. Estrogens are female sex hormones involved in the development and growth of breast tumors. It has been of significant interest to elucidate the structure-function relationship of aromatase since its inhibitors have shown great promise in fighting breast cancer. Aromatase belongs to the cytochrome P450 family, and forms an electron-transfer complex with its partner, NADPH-cytochrome P450 reductase. Because of the membrane-bound character and heme-binding in...

  10. Pharmacogenomics of tamoxifen and aromatase inhibitors.

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    Ingle, James N

    2008-02-01

    In selection of therapy for women with breast cancer, the focus has been almost exclusively on the characteristics of the tumor, eg, estrogen receptor (ER) and HER-2. Until recently, essentially no attention has been paid to the host and her genetic makeup as it relates to the metabolism of different drugs. The first real clinical application of pharmacogenetics in breast cancer management relates to tamoxifen's biotransformation to active anticancer metabolites. New information has arisen on the metabolism of tamoxifen to the active metabolite, 4 hydroxy-N-desmethyl-tamoxifen (endoxifen). Endoxifen is a metabolite with antitumor activity and affinity for the ER that is similar to 4-hydroxy-tamoxifen, but 1 that is normally present in substantially higher concentrations. CYP2D6 plays a central role in the metabolism to endoxifen and 1 published study shows that genotypic differences in CYP2D6 and use of CYP2D6 inhibitors has an impact on outcomes of women treated with tamoxifen. The aromatase inhibitors represent a major class of drugs in the armamentarium against breast cancer. The aromatase gene has been resequenced and functional genomics have been performed on the identified nonsynonymous coding single nucleotide polymorphisms showing significant decreases in levels of activity. These findings are consistent with a hypothesis that genetic variation in the CYP19 gene might be important in the activity of aromatase inhibitors. Currently, the emphasis is on examining multiple genes (thus pharmacogenomics) in pharmacodynamic and pharmacokinetic pathways in women receiving aromatase inhibitors for breast cancer. PMID:18072234

  11. Potential utility of natural products as regulators of breast cancer-associated aromatase promoters

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    Walker Larry A

    2011-06-01

    Full Text Available Abstract Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7 aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for

  12. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom)

    Energy Technology Data Exchange (ETDEWEB)

    Conte, F.A.; Grumbach, M.M. [Univ. of California, San Francisco, CA (United States); Ito, Y.; Fisher, C.R.; Simpson, E.R. [Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)

    1994-06-01

    The authors report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (<37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris has enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. 32 refs., 6 figs., 2 tabs.

  13. Aromatase expression is increased in BRCA1 mutation carriers

    International Nuclear Information System (INIS)

    Until recently, the molecular mechanisms explaining increased incidence of ovarian and breast cancers in carriers of BRCA1 gene mutations had not been clearly understood. Of significance is the finding that BRCA1 negatively regulates aromatase expression in vitro. Our objective was to characterise aromatase gene (CYP19A1) and its promoter expression in breast adipose and ovarian tissue in BRCA1 mutation carriers and unaffected controls. We measured aromatase transcripts, total and promoter-specific (PII, PI.3, PI.4) in prophylactic oophorectomy or mastectomy, therapeutic mastectomy, ovarian and breast tissue from unaffected women. We demonstrate that the lack of functional BRCA1 protein correlates to higher aromatase levels in 85% of BRCA1 mutation carriers. This increase is mediated by aberrant transcriptional regulation of aromatase; in breast adipose by increases in promoter II/I.3 and I.4-specific transcripts; and in the ovary with elevation in promoter I.3 and II-specific transcripts. Understanding the link between BRCA1 and aromatase is significant in terms of understanding why carcinogenesis is restricted to estrogen-producing tissues in BRCA1 mutation carriers

  14. Aromatase: Contributions to Physiology and Disease in Women and Men.

    Science.gov (United States)

    Blakemore, Jennifer; Naftolin, Fredrick

    2016-07-01

    Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products. PMID:27252161

  15. Genetics Home Reference: aromatase excess syndrome

    Science.gov (United States)

    ... males, the increased aromatase and subsequent conversion of androgens to estrogen are responsible for the gynecomastia and limited bone growth characteristic of aromatase excess syndrome . Increased estrogen in females can cause symptoms ...

  16. Molecular Docking of Aromatase Inhibitors

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    Virapong Prachayasittikul

    2011-04-01

    Full Text Available Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyzes the aromatization of androstenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. The undesirable effects found in aromatase inhibitors (AIs that are in clinical use necessitate the discovery of novel AIs with higher selectivity, less toxicity and improving potency. In this study, we elucidate the binding mode of all three generations of AI drugs to the crystal structure of aromatase by means of molecular docking. It was demonstrated that the docking protocol could reliably reproduce the interaction of aromatase with its substrate with an RMSD of 1.350 Å. The docking study revealed that polar (D309, T310, S478 and M374, aromatic (F134, F221 and W224 and non-polar (A306, A307, V370, L372 and L477 residues were important for interacting with the AIs. The insights gained from the study herein have great potential for the design of novel AIs.

  17. Characterization and expression profile of the ovarian cytochrome P-450 aromatase (cyp19A1) gene during thermolabile sex determination in Pejerrey, Odontesthes bonariensis

    Science.gov (United States)

    Karube, M.; Fernandino, J.I.; Strobl-Mazzulla, P.; Strussmann, C.A.; Yoshizaki, G.; Somoza, G.M.; Patino, R.

    2007-01-01

    Cytochrome P450 aromatase (cyp19) is an enzyme that catalyzes the conversion of androgens to estrogens and may play a role in temperature- dependent sex determination (TSD) of reptiles, amphibians, and fishes. In this study, the ovarian P450 aromatase form (cyp19A1) of pejerrey Odontesthes bonariensis, a teleost with marked TSD, was cloned and its expression profile evaluated during gonadal differentiation at feminizing (17??C, 100% females), mixed-sex producing (24 and 25??C, 73.3 and 26.7% females, respectively), and masculinizing (29??C, 0% females) temperatures. The deduced cyp19A1 amino acid sequence shared high identity (>77.8%) with that from other teleosts but had low identity (sex producing temperatures were bimodal rather than intermediate, showing low and high modal values similar to those at the feminizing and masculinizing temperatures, respectively. The population percentages of high and low expression levels at intermediate temperatures were proportional to the percentage of females and males, respectively, and high levels were first observed at about the time of sex differentiation of females. These results suggest that cyp19A1 is involved in the process of ovarian formation and possibly also in the TSD of pejerrey. ?? 2007 Wiley-Liss, Inc.

  18. Genetics Home Reference: aromatase deficiency

    Science.gov (United States)

    ... regulating bone growth and blood sugar levels. During fetal development, aromatase converts androgens to estrogens in the placenta, ... link between the mother's blood supply and the fetus. This conversion in the ... sexual development in female fetuses. After birth, the conversion of ...

  19. Aromatase in human liver and its diseases

    International Nuclear Information System (INIS)

    Estrogens play important roles in the cell proliferation and invasion of estrogen-dependent human neoplasms. Aromatase overexpression has been also reported in hepatitis and hepatocellular carcinoma (HCC) compared with normal liver but its details in these hepatic disorders have remained unclear. Therefore, in this study, we first immunolocalized aromatase using immunohistochemistry in patients with liver cirrhosis, steatosis, hepatitis, HCC, and metastasis liver carcinoma (MLC) in order to study the detailed status of intrahepatic aromatase. Aromatase immunoreactivity was predominantly detected in nonneoplastic hepatocytes around tumor cells. We then evaluated the effects of an interaction between hepatocytes and carcinoma cells upon aromatase mRNA expression, using HepG2 as a substitute model of hepatocytes by coculture systems. Aromatase mRNA levels in HepG2 were significantly increased by coculture with all carcinoma cell lines examined. We also evaluated alternative splicing of aromatase exon 1 but the same splicing variant was used in HepG2 cells regardless of carcinoma cell lines employed in the coculture system. These findings obtained in HepG2 indicated that carcinoma cells, whether metastatic or primary, induced aromatase expression in adjacent normal hepatocytes possibly through the soluble aromatase inducible factors in human hepatic microenvironments

  20. Natural Products as Aromatase Inhibitors

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purpos...

  1. Overexpression of aromatase alone is sufficient for ovarian development in genetically male chicken embryos.

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    Luke S Lambeth

    Full Text Available Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1 is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.

  2. Defining human insulin-like growth factor I gene regulation.

    Science.gov (United States)

    Mukherjee, Aditi; Alzhanov, Damir; Rotwein, Peter

    2016-08-01

    Growth hormone (GH) plays an essential role in controlling somatic growth and in regulating multiple physiological processes in humans and other species. Insulin-like growth factor I (IGF-I), a conserved, secreted 70-amino acid peptide, is a critical mediator of many of the biological effects of GH. Previous studies have demonstrated that GH rapidly and potently promotes IGF-I gene expression in rodents and in some other mammals through the transcription factor STAT5b, leading to accumulation of IGF-I mRNAs and production of IGF-I. Despite this progress, very little is known about how GH or other trophic factors control human IGF1 gene expression, in large part because of the absence of any cellular model systems that robustly express IGF-I. Here, we have addressed mechanisms of regulation of human IGF-I by GH after generating cells in which the IGF1 chromosomal locus has been incorporated into a mouse cell line. Using this model, we found that physiological levels of GH rapidly stimulate human IGF1 gene transcription and identify several potential transcriptional enhancers in chromatin that bind STAT5b in a GH-regulated way. Each of the putative enhancers also activates a human IGF1 gene promoter in reconstitution experiments in the presence of the GH receptor, STAT5b, and GH. Thus we have developed a novel experimental platform that now may be used to determine how human IGF1 gene expression is controlled under different physiological and pathological conditions. PMID:27406741

  3. Defining the galaxy of gene expression in breast cancer

    OpenAIRE

    Liu, Edison T; Sotiriou, Christos

    2002-01-01

    Recent reports detailing the expression profiles of primary breast cancer have pointed to the utility of this approach in defining subclasses with distinct molecular configurations and clinical behaviour. Some of the subclasses can be predicted by current molecular tests: estrogen receptor status, p53 staining, and HER-2 overexpression. Others, however, are novel subgroups and may represent distinct cellular types. The results from two recent studies suggest common principles of classificatio...

  4. Defining Aggressive Prostate Cancer Using a 12-Gene Model

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    Tarek A. Bismar

    2006-01-01

    Full Text Available The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to predict prostate cancer progression consisted of 12 proteins. Using a separate patient population, transcriptional levels of the 12 genes encoding for these proteins predicted prostate-specific antigen failure in 79 men following surgery for clinically localized prostate cancer (P = .0015. This study demonstrates that cross-platform models can lead to predictive models with the possible advantage of being more robust through this selection process.

  5. Defining Aggressive Prostate Cancer Using a 12-Gene Model1

    OpenAIRE

    Tarek A Bismar; Demichelis, Francesca; Riva, Alberto; Kim, Robert; Varambally, Sooryanarayana; He, Le; Kutok, Jeff; Aster, Jonathan C; Tang, Jeffery; Kuefer, Rainer; Hofer, Matthias D.; Febbo, Phillip G; Arul M Chinnaiyan; Mark A. Rubin

    2006-01-01

    The critical clinical question in prostate cancer research is: How do we develop means of distinguishing aggressive disease from indolent disease? Using a combination of proteomic and expression array data, we identified a set of 36 genes with concordant dysregulation of protein products that could be evaluated in situ by quantitative immunohistochemistry. Another five prostate cancer biomarkers were included using linear discriminant analysis, we determined that the optimal model used to pre...

  6. Defining the galaxy of gene expression in breast cancer

    International Nuclear Information System (INIS)

    Recent reports detailing the expression profiles of primary breast cancer have pointed to the utility of this approach in defining subclasses with distinct molecular configurations and clinical behaviour. Some of the subclasses can be predicted by current molecular tests: estrogen receptor status, p53 staining, and HER-2 overexpression. Others, however, are novel subgroups and may represent distinct cellular types. The results from two recent studies suggest common principles of classification by expression profiling. These principles are examined and the impact of these results on understanding the biology and the clinical behaviour of breast tumors is explored

  7. Chromatin immunoselection defines a TAL-1 target gene.

    OpenAIRE

    Cohen-Kaminsky, S; Maouche-Chrétien, L; Vitelli, L; Vinit, M A; Blanchard, I; M. Yamamoto; Peschle, C; Roméo, P H

    1998-01-01

    Despite the major functions of the basic helix-loop-helix transcription factor TAL-1 in hematopoiesis and T-cell leukemogenesis, no TAL-1 target gene has been identified. Using immunoprecipitation of genomic fragments bound to TAL-1 in the chromatin of murine erythro-leukemia (MEL) cells, we found that 10% of the immunoselected fragments contained a CAGATG or a CAGGTG E-box, followed by a GATA site. We studied one of these fragments containing two E-boxes, CAGATG and CAGGTC, followed by a GAT...

  8. Aromatase inhibitors in the treatment of endometriosis.

    Science.gov (United States)

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  9. Aromatase inhibitors in the treatment of endometriosis

    Science.gov (United States)

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  10. Post-proliferative immature radial glial cells female-specifically express aromatase in the medaka optic tectum.

    Directory of Open Access Journals (Sweden)

    Akio Takeuchi

    Full Text Available Aromatase, the key enzyme responsible for estrogen biosynthesis, is present in the brain of all vertebrates. Much evidence has accumulated that aromatase is highly and exclusively expressed in proliferating mature radial glial cells in the brain of teleost fish even in adulthood, unlike in other vertebrates. However, the physiological significance of this expression remains unknown. We recently found that aromatase is female-specifically expressed in the optic tectum of adult medaka fish. In the present study, we demonstrated that, contrary to the accepted view of the teleost brain, female-specific aromatase-expressing cells in the medaka optic tectum represent a transient subset of post-proliferative immature radial glial cells in the neural stem cell lineage. This finding led us to hypothesize that female-specific aromatase expression and consequent estrogen production causes some sex difference in the life cycle of tectal cells. As expected, the female tectum exhibited higher expression of genes indicative of cell proliferation and radial glial maturation and lower expression of an anti-apoptotic gene than did the male tectum, suggesting a female-biased acceleration of the cell life cycle. Complicating the interpretation of this result, however, is the additional observation that estrogen administration masculinized the expression of these genes in the optic tectum, while simultaneously stimulating aromatase expression. Taken together, these results provide evidence that a unique subpopulation of neural stem cells female-specifically express aromatase in the optic tectum and suggest that this aromatase expression and resultant estrogen synthesis have an impact on the life cycle of tectal cells, whether stimulatory or inhibitory.

  11. Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

    DEFF Research Database (Denmark)

    Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun;

    2014-01-01

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism....... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...

  12. Thyroid hormone receptors bind to defined regions of the growth hormone and placental lactogen genes.

    OpenAIRE

    Barlow, J W; Voz, M L; Eliard, P H; Mathy-Harter, M; De Nayer, Philippe; Economidis, I V; Belayew, A; Martial, J A; Rousseau, Guy

    1986-01-01

    The intracellular receptor for thyroid hormone is a protein found in chromatin. Since thyroid hormone stimulates transcription of the growth hormone gene through an unknown mechanism, the hypothesis that the thyroid hormone-receptor complex interacts with defined regions of this gene has been investigated in a cell-free system. Nuclear extracts from human lymphoblastoid IM-9 cells containing thyroid hormone receptors were incubated with L-3,5,3'-tri[125I]iodothyronine and calf thymus DNA-cell...

  13. Quantitative determination, by real-time reverse transcription polymerase chain reaction, of aromatase mRNA in invasive ductal carcinoma of the breast

    International Nuclear Information System (INIS)

    Estrogen is a mitogenic factor that is implicated in the genesis and progression of breast cancer via its binding to estrogen receptor (ER)-α. Synthesis of estrogen in situ is believed to be catalyzed mainly by aromatase. Previous studies comparing the relative contributions from tumor cells and stromal cells to local estrogen synthesis, as assessed by immunohistochemical analysis, were quite controversial and no consistent relationship was found between the presence of aromatase and any clinicopathologic factor. In addition, previous studies into aromatase gene expression and clinicopathologic factors are limited. We assessed the level of expression of aromatase mRNA, using quantitative real-time RT-PCR, in 162 cases of invasive ductal carcinoma of the breast. Associations between aromatase expression and different clinicopathologic factors were sought. It was found that aromatase mRNA was expressed at significantly higher levels in patients older than 50 years, in those without axillary lymph node involvement, in those with tumor size less than 2 cm, and in ER-α positive tumors. However, no relationship was found between aromatase mRNA expression and any other clinicopathologic factor, including histologic grade and progesterone receptor status. Patients with high levels of expression of aromatase mRNA tended to have a better prognosis than did those patients with low expression. These findings imply that ER-α and aromatase may be coexpressed in endocrine responsive patients. They may also indicate that aromatase expression could be a marker of endocrine responsiveness, and it may have prognostic implications for breast cancer progression

  14. Characterization of Aromatase Expression in the Adult Male and Female Mouse Brain. I. Coexistence with Oestrogen Receptors α and β, and Androgen Receptors

    OpenAIRE

    Davor Stanić; Sydney Dubois; Hui Kheng Chua; Bruce Tonge; Nicole Rinehart; Malcolm K Horne; Wah Chin Boon

    2014-01-01

    Aromatase catalyses the last step of oestrogen synthesis. There is growing evidence that local oestrogens influence many brain regions to modulate brain development and behaviour. We examined, by immunohistochemistry, the expression of aromatase in the adult male and female mouse brain, using mice in which enhanced green fluorescent protein (EGFP) is transcribed following the physiological activation of the Cyp19A1 gene. EGFP-immunoreactive processes were distributed in many brain regions, in...

  15. Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain

    Directory of Open Access Journals (Sweden)

    Anat Biegon

    2012-11-01

    Full Text Available Cigarette smoking continues to be a major public health problem, and while smoking rates in men have shown some decrease over the last few decades, smoking rates among girls and young women are increasing. Practically all of the important aspects of cigarette smoking are sexually dimorphic. Women become addicted more easily than men, while finding it harder to quit. Nicotine replacement appears to be less effective in women. This may be linked to the observation that women are more sensitive than men to non-nicotine cues or ingredients in cigarettes. The reasons for these sex differences are mostly unknown. Several lines of evidence suggest that many of the reported sex differences related to cigarette smoking may stem from the inhibitory effects of nicotine and other tobacco alkaloids on estrogen synthesis via the enzyme aromatase (cyp19a gene product. Aromatase is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogens. This review provides a summary of experimental evidence supporting brain aromatase as a potential mediator and/or modulator of nicotine actions in the brain, contributing to sex differences in smoking behavior. Additional research on the interaction between tobacco smoke, nicotine and aromatase may help devise new, sex specific methods for prevention and treatment of smoking addiction.

  16. Ligula intestinalis infection is associated with alterations of both brain and gonad aromatase expression in roach (Rutilus rutilus).

    Science.gov (United States)

    Boulange-Lecomte, C; Geraudie, P; Forget-Leray, J; Gerbron, M; Minier, C

    2011-09-01

    The tapeworm Ligula intestinalis commonly infests roach (Rutilus rutilus) and is responsible for the inhibition of gonad development. In order to better understand the effect of the plerocercoid on fish physiology, and to discriminate parasitization effects from those of endocrine-disrupting compounds (EDC), Cyp19b and Cyp19a aromatase expression was investigated by real-time quantitative polymerase chain reaction (PCR) in brain and gonads of ligulosed roach, caught from a reference site. Data were compared to reproductive and endocrine endpoints previously reported in a larger cohort study (including the sampled population of the present one), such as gonadosomatic index, Fulton index, gonadal histology, plasma sex steroid levels and brain aromatase activity. A decrease in Cyp19b expression in the brain of infected fish was demonstrated, in agreement with the reduction of aromatase activity previously described. In contrast, Cyp19a expression in the gonads appeared to be enhanced in ligulosed fish, in accordance with the presence of immature but differentiated sexual tissues. Together these results show that: (1) L. intestinalis infestation results in an alteration of aromatase expression which, in particular, may have profound effects on the fish brain; and (2) L. intestinalis infection must be considered as a major confounding factor in ecotoxicological studies using aromatase expression as an EDC biomarker. Moreover, the concordance between activity and expression--investigated for the first time in the same population--gives a functional relevance to the transcript aromatase dosage in the brain. Finally, quantitative PCR was confirmed as a sensitive approach, enabling aromatase status to be defined in the poorly developed gonads of ligulosed individuals. PMID:21062527

  17. Developmental regulation of aromatase activity in the rat hypothalamus

    International Nuclear Information System (INIS)

    The brain of all mammalian species studied thus far contain an enzymatic activity (aromatase) that catalyzes the conversion of androgens to estrogens. The activity is highest during prenatal development and contributes to the establishment of sex differences which determine adult gonadotropin secretion patterns and reproductive behavior. The studies presented in this dissertation represent a systematic effort to elucidate the mechanism(s) that control the initiation of and contribute to maintaining rat hypothalamic aromatase activity during pre- and postnatal development. Aromatase enzyme activity was measured by the 3H2O release assay or by traditional estrogen product isolation. Brain aromatase mRNA was detected by hybridization to a cDNA encoding rat aromatase cytochrome P-450. In both males and females the time of puberty was associated with a decline in hypothalamic aromatase activity. This decline may represent a factor underlying the peri-pubertal decrease in the sensitivity to gonadal steroid feedback that accompanies completion of puberty. The results also indicate that androgens regulate brain aromatase levels during both the prepubertal and peri-pubertal stages of sexual development and that this regulation is transiently lost in young adults. Utilizing a hypothalamic organotypic culture system, aromatase activity in vitro was maintained for as long as two days. The results of studies of a variety of hormonal and metabolic regulators suggest that prenatal aromatase activity is regulated by factor(s) that function independently from the classical cyclic AMP and protein kinase C trans-membrane signaling pathways

  18. Aromatase inhibitors and anti-synthetase syndrome.

    Science.gov (United States)

    Mascella, Fabio; Gianni, Lorenzo; Affatato, Alessandra; Fantini, Manuela

    2016-09-01

    Adjuvant therapy in postmenopausal women with endocrine-responsive breast cancer (BC) is actually centered on the use of anti-aromatase inhibitors (AI). Several reports, however, are emerging in literature associating the use of this drugs to rheumatic disorders. This case report describes the first case of anti-synthetase syndrome diagnosis after treatment with anti-estrogen agents in a patient with pre-existing rheumatoid arthritis. PMID:27225465

  19. Steroid induction of a peptide hormone gene leads to orchestration of a defined behavioral sequence.

    Science.gov (United States)

    Zitnan, D; Ross, L S; Zitnanova, I; Hermesman, J L; Gill, S S; Adams, M E

    1999-07-01

    At the end of each molt, insects shed the old cuticle by performing preecdysis and ecdysis behaviors. Regulation of these centrally patterned movements involves peptide signaling between endocrine Inka cells and the CNS. In Inka cells, we have identified the cDNA and gene encoding preecdysis-triggering hormone (PETH) and ecdysis-triggering hormone (ETH), which activate these behaviors. Prior to behavioral onset, rising ecdysteroid levels induce expression of the ecdysone receptor (EcR) and ETH gene in Inka cells and evoke CNS sensitivity to PETH and ETH. Subsequent ecdysteroid decline is required for peptide release, which initiates three motor patterns in specific order: PETH triggers preecdysis I, while ETH activates preecdysis II and ecdysis. The Inka cell provides a model for linking steroid regulation of peptide hormone expression and release with activation of a defined behavioral sequence. PMID:10433264

  20. Defining the role of the CGGBP1 protein in FMR1 gene expression.

    Science.gov (United States)

    Goracci, Martina; Lanni, Stella; Mancano, Giorgia; Palumbo, Federica; Chiurazzi, Pietro; Neri, Giovanni; Tabolacci, Elisabetta

    2016-05-01

    Fragile X syndrome is the most common heritable form of intellectual disability and is caused by the expansion over 200 repeats and subsequent methylation of the CGG triplets at the 5' UTR of the FMR1 gene, leading to its silencing. The epigenetic and molecular mechanisms responsible for FMR1 gene silencing are not fully clarified. To identify structure-specific proteins that could recruit components of the silencing machinery we investigated the role of CGGBP1 in FMR1 gene transcription. CGGBP1 is a highly conserved protein that binds specifically to unmethylated CGG tracts. Its role on FMR1 transcription is yet to be defined. Sequencing analysis and expression studies through quantitative PCR of CGGBP1 were performed in cell lines with different allele expansions: wild type, premutation, methylated full mutation and unmethylated full mutation, demonstrating no differences between them. ChIP assays clearly demonstrated that CGGBP1 binds to unmethylated CGG triplets of the FMR1 gene, but not to methylated CGGs. We also observed that CGGBP1 binding to the FMR1 locus was restored after pharmacological demethylation, with 5-azadC, of alleles, carriers of methylated full mutation, suggesting a possible role for CGGBP1 in FMR1 expression. CGGBP1 silencing with shRNAs (reaching ~98% of CGGBP1-mRNA depletion) did not affect FMR1 transcription and CGG expansion stability in expanded alleles. Although the strong binding to the CGG tract could suggest a relevant role of CGGBP1 on FMR1 gene expression, our results demonstrate that CGGBP1 has no direct effect on FMR1 transcription and CGG repeat stability. PMID:26306647

  1. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    Energy Technology Data Exchange (ETDEWEB)

    Kjeldsen, Lisbeth Stigaard; Ghisari, Mandana; Bonefeld-Jørgensen, Eva Cecilie, E-mail: ebj@mil.au.dk

    2013-10-15

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [{sup 3}H]{sub 2}O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks

  2. Currently used pesticides and their mixtures affect the function of sex hormone receptors and aromatase enzyme activity

    International Nuclear Information System (INIS)

    The endocrine-disrupting potential of pesticides is of health concern, since they are found ubiquitously in the environment and in food items. We investigated in vitro effects on estrogen receptor (ER) and androgen receptor (AR) transactivity, and aromatase enzyme activity, of the following pesticides: 2-methyl-4-chlorophenoxyacetic acid (MCPA), terbuthylazine, iodosulfuron-methyl-sodium, mesosulfuron-methyl, metsulfuron-methyl, chlormequat chloride, bitertanol, propiconazole, prothioconazole, mancozeb, cypermethrin, tau fluvalinate, malathion and the metabolite ethylene thiourea (ETU). The pesticides were analyzed alone and in selected mixtures. Effects of the pesticides on ER and AR function were assessed in human breast carcinoma MVLN cells and hamster ovary CHO-K1 cells, respectively, using luciferase reporter gene assays. Effects on aromatase enzyme activity were analyzed in human choriocarcinoma JEG-3 cells, employing the classical [3H]2O method. Five pesticides (terbuthylazine, propiconazole, prothioconazole, cypermethrin and malathion) weakly induced the ER transactivity, and three pesticides (bitertanol, propiconazole and mancozeb) antagonized the AR activity in a concentration-dependent manner. Three pesticides (terbuthylazine, propiconazole and prothioconazole) weakly induced the aromatase activity. In addition, two mixtures, consisting of three pesticides (bitertanol, propiconazole, cypermethrin) and five pesticides (terbuthylazine, bitertanol, propiconazole, cypermethrin, malathion), respectively, induced the ER transactivity and aromatase activity, and additively antagonized the AR transactivity. In conclusion, our data suggest that currently used pesticides possess endocrine-disrupting potential in vitro which can be mediated via ER, AR and aromatase activities. The observed mixture effects emphasize the importance of considering the combined action of pesticides in order to assure proper estimations of related health effect risks. - Highlights:

  3. Aromatase imaging with [N-methyl-C-11]vorozole PET in healthy men and women

    International Nuclear Information System (INIS)

    Aromatase, the last and obligatory enzyme catalyzing estrogen biosynthesis from androgenic precursors, can be labeled in vivo with (11)C-vorozole. Aromatase inhibitors are widely used in breast cancer and other endocrine conditions. The present study aims to provide baseline information defining aromatase distribution in healthy men and women, against which its perturbation in pathological situations can be studied. Methods: (11)C-vorozole (111-296 MBq/subject) was injected I.V in 13 men and 20 women (age range 23 to 67). PET data were acquired over a 90 minute period. Each subject had 4 scans, 2/day separated by 2-6 weeks, including brain and torso or pelvis scans. Young women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned following pretreatment with a clinical dose of the aromatase inhibitor letrozole.Time activity curves were obtained and standard uptake values (SUV) calculated for major organs including brain, heart, lungs, liver, kidneys, spleen, muscle, bone and male and female reproductive organs (penis, testes, uterus, ovaries). Organ and whole body radiation exposures were calculated using Olinda software. Results: Liver uptake was higher than all other organs, but was not blocked by pretreatment with letrozole. Mean SUVs in men were higher than in women, and brain uptake was blocked by letrozole. Male brain SUVs were also higher than all other organs (ranging from 0.48±0.05 in lungs to 1.5±0.13 in kidneys). Mean ovarian SUVs (3.08±0.7) were comparable to brain levels and higher than all other organs. Furthermore, ovarian SUVs In young women around the time of ovulation (midcycle) were significantly higher than those measured in the late luteal phase, while aging and cigarette smoking reduced (11)C-vorozole uptake. Conclusions: PET with (11)C-vorozole is useful for assessing physiological changes in estrogen synthesis capacity in the human body. Baseline levels in

  4. The TALE class homeobox gene Smed-prep defines the anterior compartment for head regeneration.

    Science.gov (United States)

    Felix, Daniel A; Aboobaker, A Aziz

    2010-04-01

    Planaria continue to blossom as a model system for understanding all aspects of regeneration. They provide an opportunity to understand how the replacement of missing tissues from preexisting adult tissue is orchestrated at the molecular level. When amputated along any plane, planaria are capable of regenerating all missing tissue and rescaling all structures to the new size of the animal. Recently, rapid progress has been made in understanding the developmental pathways that control planarian regeneration. In particular Wnt/beta-catenin signaling is central in promoting posterior fates and inhibiting anterior identity. Currently the mechanisms that actively promote anterior identity remain unknown. Here, Smed-prep, encoding a TALE class homeodomain, is described as the first gene necessary for correct anterior fate and patterning during planarian regeneration. Smed-prep is expressed at high levels in the anterior portion of whole animals, and Smed-prep(RNAi) leads to loss of the whole brain during anterior regeneration, but not during lateral regeneration or homeostasis in intact worms. Expression of markers of different anterior fated cells are greatly reduced or lost in Smed-prep(RNAi) animals. We find that the ectopic anterior structures induced by abrogation of Wnt signaling also require Smed-prep to form. We use double knockdown experiments with the S. mediterranea ortholog of nou-darake (that when knocked down induces ectopic brain formation) to show that Smed-prep defines an anterior fated compartment within which stem cells are permitted to assume brain fate, but is not required directly for this differentiation process. Smed-prep is the first gene clearly implicated as being necessary for promoting anterior fate and the first homeobox gene implicated in establishing positional identity during regeneration. Together our results suggest that Smed-prep is required in stem cell progeny as they form the anterior regenerative blastema and is required for

  5. The TALE class homeobox gene Smed-prep defines the anterior compartment for head regeneration.

    Directory of Open Access Journals (Sweden)

    Daniel A Felix

    2010-04-01

    Full Text Available Planaria continue to blossom as a model system for understanding all aspects of regeneration. They provide an opportunity to understand how the replacement of missing tissues from preexisting adult tissue is orchestrated at the molecular level. When amputated along any plane, planaria are capable of regenerating all missing tissue and rescaling all structures to the new size of the animal. Recently, rapid progress has been made in understanding the developmental pathways that control planarian regeneration. In particular Wnt/beta-catenin signaling is central in promoting posterior fates and inhibiting anterior identity. Currently the mechanisms that actively promote anterior identity remain unknown. Here, Smed-prep, encoding a TALE class homeodomain, is described as the first gene necessary for correct anterior fate and patterning during planarian regeneration. Smed-prep is expressed at high levels in the anterior portion of whole animals, and Smed-prep(RNAi leads to loss of the whole brain during anterior regeneration, but not during lateral regeneration or homeostasis in intact worms. Expression of markers of different anterior fated cells are greatly reduced or lost in Smed-prep(RNAi animals. We find that the ectopic anterior structures induced by abrogation of Wnt signaling also require Smed-prep to form. We use double knockdown experiments with the S. mediterranea ortholog of nou-darake (that when knocked down induces ectopic brain formation to show that Smed-prep defines an anterior fated compartment within which stem cells are permitted to assume brain fate, but is not required directly for this differentiation process. Smed-prep is the first gene clearly implicated as being necessary for promoting anterior fate and the first homeobox gene implicated in establishing positional identity during regeneration. Together our results suggest that Smed-prep is required in stem cell progeny as they form the anterior regenerative blastema and is

  6. Origin of aromatase inhibitory activity via proteochemometric modeling.

    Science.gov (United States)

    Simeon, Saw; Spjuth, Ola; Lapins, Maris; Nabu, Sunanta; Anuwongcharoen, Nuttapat; Prachayasittikul, Virapong; Wikberg, Jarl E S; Nantasenamat, Chanin

    2016-01-01

    Aromatase, the rate-limiting enzyme that catalyzes the conversion of androgen to estrogen, plays an essential role in the development of estrogen-dependent breast cancer. Side effects due to aromatase inhibitors (AIs) necessitate the pursuit of novel inhibitor candidates with high selectivity, lower toxicity and increased potency. Designing a novel therapeutic agent against aromatase could be achieved computationally by means of ligand-based and structure-based methods. For over a decade, we have utilized both approaches to design potential AIs for which quantitative structure-activity relationships and molecular docking were used to explore inhibitory mechanisms of AIs towards aromatase. However, such approaches do not consider the effects that aromatase variants have on different AIs. In this study, proteochemometrics modeling was applied to analyze the interaction space between AIs and aromatase variants as a function of their substructural and amino acid features. Good predictive performance was achieved, as rigorously verified by 10-fold cross-validation, external validation, leave-one-compound-out cross-validation, leave-one-protein-out cross-validation and Y-scrambling tests. The investigations presented herein provide important insights into the mechanisms of aromatase inhibitory activity that could aid in the design of novel potent AIs as breast cancer therapeutic agents. PMID:27190705

  7. Three-Dimensional Gene Map of Cancer Cell Types: Structural Entropy Minimisation Principle for Defining Tumour Subtypes

    Science.gov (United States)

    Li, Angsheng; Yin, Xianchen; Pan, Yicheng

    2016-02-01

    In this study, we propose a method for constructing cell sample networks from gene expression profiles, and a structural entropy minimisation principle for detecting natural structure of networks and for identifying cancer cell subtypes. Our method establishes a three-dimensional gene map of cancer cell types and subtypes. The identified subtypes are defined by a unique gene expression pattern, and a three-dimensional gene map is established by defining the unique gene expression pattern for each identified subtype for cancers, including acute leukaemia, lymphoma, multi-tissue, lung cancer and healthy tissue. Our three-dimensional gene map demonstrates that a true tumour type may be divided into subtypes, each defined by a unique gene expression pattern. Clinical data analyses demonstrate that most cell samples of an identified subtype share similar survival times, survival indicators and International Prognostic Index (IPI) scores and indicate that distinct subtypes identified by our algorithms exhibit different overall survival times, survival ratios and IPI scores. Our three-dimensional gene map establishes a high-definition, one-to-one map between the biologically and medically meaningful tumour subtypes and the gene expression patterns, and identifies remarkable cells that form singleton submodules.

  8. Neuroinflammation induces glial aromatase expression in the uninjured songbird brain

    Directory of Open Access Journals (Sweden)

    Saldanha Colin J

    2011-07-01

    Full Text Available Abstract Background Estrogens from peripheral sources as well as central aromatization are neuroprotective in the vertebrate brain. Under normal conditions, aromatase is only expressed in neurons, however following anoxic/ischemic or mechanical brain injury; aromatase is also found in astroglia. This increased glial aromatization and the consequent estrogen synthesis is neuroprotective and may promote neuronal survival and repair. While the effects of estradiol on neuroprotection are well studied, what induces glial aromatase expression remains unknown. Methods Adult male zebra finches (Taeniopygia guttata were given a penetrating injury to the entopallium. At several timepoints later, expression of aromatase, IL-1β-like, and IL-6-like were examined using immunohisotchemistry. A second set of zebra birds were exposed to phytohemagglutinin (PHA, an inflammatory agent, directly on the dorsal surface of the telencephalon without creating a penetrating injury. Expression of aromatase, IL-1β-like, and IL-6-like were examined using both quantitative real-time polymerase chain reaction to examine mRNA expression and immunohistochemistry to determine cellular expression. Statistical significance was determined using t-test or one-way analysis of variance followed by the Tukey Kramers post hoc test. Results Following injury in the zebra finch brain, cytokine expression occurs prior to aromatase expression. This temporal pattern suggests that cytokines may induce aromatase expression in the damaged zebra finch brain. Furthermore, evoking a neuroinflammatory response characterized by an increase in cytokine expression in the uninjured brain is sufficient to induce glial aromatase expression. Conclusions These studies are among the first to examine a neuroinflammatory response in the songbird brain following mechanical brain injury and to describe a novel neuroimmune signal to initiate aromatase expression in glia.

  9. Committee Opinion No. 663: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214191

  10. Committee Opinion No. 663 Summary: Aromatase Inhibitors in Gynecologic Practice.

    Science.gov (United States)

    2016-06-01

    Aromatase inhibitors have been used for the treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions. For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency. Based on long-term adverse effects and complication safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding. For women with polycystic ovary syndrome and a body mass index greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged. Aromatase inhibitors are a promising therapeutic option that may be helpful for the management of endometriosis-associated pain in combination therapy with progestins. PMID:27214185

  11. Aromatase inhibitor strategies in metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Heather L McArthur

    2009-07-01

    Full Text Available Heather L McArthur, Patrick G MorrisBreast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Despite ongoing therapeutic innovations, metastatic breast cancer (MBC remains a treatable but incurable disease. In the developed world, a diagnosis of MBC without a preceding diagnosis of early stage disease is a rare event. However, approximately one-third of women with early stage breast cancer ultimately experience a distant recurrence. Because the majority of breast cancers express estrogen and/or progesterone receptors and are accordingly considered hormone-sensitive, therapeutic strategies that interfere with hormone-mediated tumorigenesis have been a cornerstone of the breast cancer management paradigm for decades. Historically, the selective estrogen receptor modulator tamoxifen has been the most extensively studied and widely used hormone maneuver in breast cancer. However, a recent therapeutic innovation, namely the successful development of third-generation aromatase inhibitors (AIs, has had a dramatic impact on the treatment paradigm for women with hormone-sensitive MBC. Because of the demonstrated efficacy in postmenopausal breast cancer patients, the generally favorable side-effect profile, and the convenience of oral administration, AIs are now in widespread clinical use. Currently, there are three clinically available third-generation AIs: two reversible, nonsteroidal AIs, letrozole and anastrozole; and one irreversible, steroidal AI, exemestane. All three agents are at least as efficacious as tamoxifen as monotherapy for postmenopausal women with hormone-sensitive MBC. Current clinical research aims to improve upon existing strategies by evaluating AIs in combination with systemic chemotherapy regimens and/or novel targeted agents. It is hoped that these therapeutic innovations will lead to ongoing improvements in quality of life parameters and ideally survival for women

  12. Aromatase inhibitors and antiepileptic drugs: a computational systems biology analysis

    Directory of Open Access Journals (Sweden)

    Mustata Gabriela

    2011-06-01

    Full Text Available Abstract Background The present study compares antiepileptic drugs and aromatase (CYP19 inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs are needed, especially since every individual responds differently to given treatment options. Methods Through a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits. Results The pharmacophore model returned 73% (19 out of 26 of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62 of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses. Conclusions This study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity

  13. Cytochrome P450 aromatase expression in human seminoma

    OpenAIRE

    Montanaro Daniela; Aquila Saveria; Romeo Francesco; Rago Vittoria; Andò Sebastiano; Carpino Amalia

    2005-01-01

    Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression ...

  14. DBA-Lectin Reactivity Defines Mouse Uterine Natural Killer Cell Subsets with Biased Gene Expression 1

    Science.gov (United States)

    Chen, Zhilin; Zhang, Jianhong; Hatta, Kota; Lima, Patricia D. A.; Yadi, Hakim; Colucci, Francesco; Yamada, Aureo T.; Croy, B. Anne

    2012-01-01

    Endometrial decidualization, a process essential for blastocyst implantation in species with hemochorial placentation, is accompanied by an enormous but transient influx of Natural Killer (NK) cells. Mouse uterine (u)NK cell subsets have been defined by diameter and cytoplasmic granule number, reflecting stage of maturity and by histochemical reactivity with Periodic Acid Schiff’s (PAS) reagent, with or without co-reactivity with Dolichos biflorus agglutinin (DBA) lectin. We asked whether DBA− and DBA+ mouse uNK cells were equivalent using quantitative (q)RT-PCR analyses of flow separated, midpregnancy (gestation day (gd)10) cells and using immunohistochemistry. CD3E (CD3)-IL2RB (CD122)+DBA− cells were identified as the dominant Ifng transcript source. Skewed IFNG production by uNK cell subsets was confirmed by analysis of uNK cells from eYFP-tagged IFNG-reporter mice. In contrast, CD3E-IL2RB+DBA+ uNK cells expressed genes compatible with significantly greater potential for IL22 synthesis, angiogenesis and participation in regulation mediated by the renin-angiotensin system (RAS). CD3E-IL2RB+DBA+ cells were further divided into VEGFA+ and VEGFA− subsets. CD3E-IL2RB+DBA+ uNK cells but not CD3E-IL2RB+DBA− uNK cells arose from circulating, bone marrow-derived progenitor cells by gd6. These findings indicate the heterogeneous nature of mouse uNK cells and suggest that studies using only DBA + uNK cells will give biased data that does not fully represent the uNK cell population. PMID:22875907

  15. Defining the expression of marker genes in equine mesenchymal stromal cells

    Directory of Open Access Journals (Sweden)

    Deborah J Guest

    2008-11-01

    Full Text Available Deborah J Guest1, Jennifer C Ousey1, Matthew RW Smith21Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU; 2Reynolds House Referrals, Greenwood Ellis and Partners, 166 High Street, Newmarket, Suffolk, CB8 9WS, UKAbstract: Mesenchymal stromal (MS cells have been derived from multiple sources in the horse including bone marrow, adipose tissue and umbilical cord blood. To date these cells have been investigated for their differentiation potential and are currently being used to treat damage to horse musculoskeletal tissues. However, no work has been done in horse MS cells to examine the expression profile of proteins and cell surface antigens that are expressed in human MS cells. The identification of such profiles in the horse will allow the comparison of putative MS cells isolated from different laboratories and different tissues. At present it is difficult to ascertain whether equivalent cells are being used in different reports. Here, we report on the expression of a range of markers used to define human MS cells. Using immunocytochemistry we show that horse MS cells homogenously express collagens, alkaline phosphatase activity, CD44, CD90 and CD29. In contrast, CD14, CD79α and the embryonic stem cell markers Oct-4, SSEA (stage specific embryonic antigen -1, -3, -4, TRA (tumor rejection antigen -1–60 and -1–81 are not expressed. The MS cells also express MHC class I antigens but do not express class II antigens, although they are inducible by treatment with interferon gamma (IFN-γ.Keywords: mesenchymal stem cells, equine, gene expression

  16. Defining the cutoff value of MGMT gene promoter methylation and its predictive capacity in glioblastoma.

    Science.gov (United States)

    Brigliadori, Giovanni; Foca, Flavia; Dall'Agata, Monia; Rengucci, Claudia; Melegari, Elisabetta; Cerasoli, Serenella; Amadori, Dino; Calistri, Daniele; Faedi, Marina

    2016-06-01

    Despite advances in the treatment of glioblastoma (GBM), median survival is 12-15 months. O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation status is acknowledged as a predictive marker for temozolomide (TMZ) treatment. When MGMT promoter values fall into a "methylated" range, a better response to chemotherapy is expected. However, a cutoff that discriminates between "methylated" and "unmethylated" status has yet to be defined. We aimed to identify the best cutoff value and to find out whether variability in methylation profiles influences the predictive capacity of MGMT promoter methylation. Data from 105 GBM patients treated between 2008 and 2013 were analyzed. MGMT promoter methylation status was determined by analyzing 10 CpG islands by pyrosequencing. Patients were treated with radiotherapy followed by TMZ. MGMT promoter methylation status was classified into unmethylated 0-9 %, methylated 10-29 % and methylated 30-100 %. Statistical analysis showed that an assumed methylation cutoff of 9 % led to an overestimation of responders. All patients in the 10-29 % methylation group relapsed before the 18-month evaluation. Patients with a methylation status ≥30 % showed a median overall survival of 25.2 months compared to 15.2 months in all other patients, confirming this value as the best methylation cutoff. Despite wide variability among individual profiles, single CpG island analysis did not reveal any correlation between single CpG island methylation values and relapse or death. Specific CpG island methylation status did not influence the predictive value of MGMT. The predictive role of MGMT promoter methylation was maintained only with a cutoff value ≥30 %. PMID:27029617

  17. Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition.

    Science.gov (United States)

    Dean, Afshan; Nilsen, Margaret; Loughlin, Lynn; Salt, Ian P; MacLean, Margaret R

    2016-08-01

    Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase. PMID:27296990

  18. New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

    Directory of Open Access Journals (Sweden)

    Roleira Fernanda MF

    2008-07-01

    Full Text Available Abstract Background Aromatase, the cytochrome P-450 enzyme (CYP19 responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI, which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds 3a and 4a, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells. Results The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G0/G1 phase and inducing cell death with features of apoptosis and autophagic cell death. Conclusion Our in vitro studies showed that the two steroidal AIs, 3a and 4a, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G0/G1 phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.

  19. Gene expression patterns to define stages of post-harvest senescence in Alstroemeria petals.

    Science.gov (United States)

    Breeze, Emily; Wagstaff, Carol; Harrison, Elizabeth; Bramke, Irene; Rogers, Hilary; Stead, Anthony; Thomas, Brian; Buchanan-Wollaston, Vicky

    2004-03-01

    Petal senescence in many species is regulated by ethylene but some flowers, such as those on the monocotyledonous plant Alstroemeria, var. Rebecca are ethylene insensitive. Changes in gene expression during the post-harvest senescence of Alstroemeria flowers were investigated using several different techniques. Suppressive subtractive hybridization (SSH) was used to obtain cDNA libraries enriched for genes expressed at selected stages of petal senescence. Sequencing of the EST clones obtained resulted in over 1000 sequences that represent approximately 500 different genes. Analysis of the potential functions of these genes provides a snapshot of the processes that are taking place during petal development. Both cell wall related genes and genes involved in metabolism were present at a higher proportion in the earlier stages. Genes encoding metal binding proteins (mostly metallothionein-like) were the major component of senescence enhanced libraries. This limited the diversity of genes identified showing differential expression at the later stages. Changes in the expression of all genes were analysed using microarray hybridization, and genes showing either up or down-regulation were identified. The expression pattern of a selection of genes was confirmed using Northern hybridization. Northern hybridization confirmed the up-regulation of metallothioneins after floral opening, however, this was not detected by the microarray analysis, indicating the importance of using a combination of methods to investigate gene expression patterns. Considerably more genes were up-regulated than down-regulated. This may reflect the need during Alstroemeria petal senescence for the expression of a whole new set of genes involved with degradation and mobilization. The potential uses of expression profiling to improve floral quality in breeding programmes or as a diagnostic tool are discussed. PMID:17147607

  20. Categorizer: a tool to categorize genes into user-defined biological groups based on semantic similarity

    OpenAIRE

    Na, Dokyun; Son, Hyungbin; Gsponer, Jörg

    2014-01-01

    Background Communalities between large sets of genes obtained from high-throughput experiments are often identified by searching for enrichments of genes with the same Gene Ontology (GO) annotations. The GO analysis tools used for these enrichment analyses assume that GO terms are independent and the semantic distances between all parent–child terms are identical, which is not true in a biological sense. In addition these tools output lists of often redundant or too specific GO terms, which a...

  1. A Mutation Affecting the Regulation of a Seca-Lacz Fusion Defines a New Sec Gene

    OpenAIRE

    Riggs, P. D.; Derman, A. I.; Beckwith, J

    1988-01-01

    It was shown previously that the secA gene of Escherichia coli is derepressed in cells that have a defect in protein export. Here it is demonstrated that the β-galactosidase produced by a secA-lacZ gene fusion strain is regulated in the same way. Studies on the fusion strain reveal that the promoter or a site involved in regulation of the secA gene is located considerably upstream from the structural gene. The properties of the fusion strain provide a new selection for mutants that are defect...

  2. CAGE-defined promoter regions of the genes implicated in Rett Syndrome

    DEFF Research Database (Denmark)

    Vitezic, Morana; Bertin, Nicolas; Andersson, Robin;

    2014-01-01

    BACKGROUND: Mutations in three functionally diverse genes cause Rett Syndrome. Although the functions of Forkhead box G1 (FOXG1), Methyl CpG binding protein 2 (MECP2) and Cyclin-dependent kinase-like 5 (CDKL5) have been studied individually, not much is known about their relation to each other with...... each gene and the common transcription factors likely to regulate the three genes. Our data imply Polycomb Repressive Complex 2 (PRC2) mediated silencing of Foxg1 in cerebellum CONCLUSIONS: Our analyses provide a comprehensive picture of the regulatory regions of the three genes involved in Rett...... Syndrome....

  3. Gene Expression Correlations in Human Cancer Cell Lines Define Molecular Interaction Networks for Epithelial Phenotype

    OpenAIRE

    Kohn, Kurt W.; Zeeberg, Barry M.; Reinhold, William C.; Pommier, Yves

    2014-01-01

    Using gene expression data to enhance our knowledge of control networks relevant to cancer biology and therapy is a challenging but urgent task. Based on the premise that genes that are expressed together in a variety of cell types are likely to functions together, we derived mutually correlated genes that function together in various processes in epithelial-like tumor cells. Expression-correlated genes were derived from data for the NCI-60 human tumor cell lines, as well as data from the Bro...

  4. Therapeutic targets for olive pollen allergy defined by gene markers modulated by Ole e 1-derived peptides.

    Science.gov (United States)

    Calzada, David; Aguerri, Miriam; Baos, Selene; Montaner, David; Mata, Manuel; Dopazo, Joaquín; Quiralte, Joaquín; Florido, Fernando; Lahoz, Carlos; Cárdaba, Blanca

    2015-04-01

    Two regions of Ole e 1, the major olive-pollen allergen, have been characterized as T-cell epitopes, one as immunodominant region (aa91-130) and the other, as mainly recognized by non-allergic subjects (aa10-31). This report tries to characterize the specific relevance of these epitopes in the allergic response to olive pollen by analyzing the secreted cytokines and the gene expression profiles induced after specific stimulation of peripheral blood mononuclear cells (PBMCs). PBMCs from olive pollen-allergic and non-allergic control subjects were stimulated with olive-pollen extract and Ole e 1 dodecapeptides containing relevant T-cell epitopes. Levels of cytokines were measured in cellular supernatants and gene expression was determined by microarrays, on the RNAs extracted from PBMCs. One hundred eighty-nine differential genes (fold change >2 or <-2, P<0.05) were validated by qRT-PCR in a large population. It was not possible to define a pattern of response according the overall cytokine results but interesting differences were observed, mainly in the regulatory cytokines. Principal component (PCA) gene-expression analysis defined clusters that correlated with the experimental conditions in the group of allergic subjects. Gene expression and functional analyses revealed differential genes and pathways among the experimental conditions. A set of 51 genes (many essential to T-cell tolerance and homeostasis) correlated with the response to aa10-31 of Ole e 1. In conclusion, two peptides derived from Ole e 1 could regulate the immune response in allergic patients, by gene-expression modification of several regulation-related genes. These results open new research ways to the regulation of allergy by Oleaceae family members. PMID:25553522

  5. Two differentially regulated Arabidopsis genes define a new branch of the DFR superfamily

    DEFF Research Database (Denmark)

    Østergaard, L; Lauvergeat, V; Naested, H;

    2001-01-01

    resembling the expression pattern of late embryogenic abundant ABA-responsive genes. Differential expression of the two genes during plant development was confirmed in plants expressing transcriptional fusions between the two promoters and the Escherichia coli beta-glucuronidase reporter gene. This showed...... that, whereas high expression of AtCRL1 in mature seeds declines during subsequent vegetative growth, transcriptional activity from the AtCRL2 promoter increases during vegetative growth. Expression of both genes is restricted to vascular tissue. Based upon their homology to proteins involved in lignin...... synthesis, we propose that AtCRL2 is involved in generating conducting tissue late in development, while AtCRL1 is involved in vascular tissue differentiation and/or synthesis in the germinating embryos....

  6. Data-driven asthma endotypes defined from blood biomarker and gene expression data

    Science.gov (United States)

    The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-section...

  7. Aromatase inhibitors in stimulated IVF cycles

    Directory of Open Access Journals (Sweden)

    Tournaye Herman

    2011-06-01

    Full Text Available Abstract Aromatase inhibitors have been introduced as a new treatment modality that could challenge clomiphene citrate as an ovulation induction regiment in patients with PCOS. Although several randomized trials have been conducted regarding their use as ovulation induction agents, only few trials are available regarding their efficacy in IVF stimulated cycles. Current available evidence support that letrozole may have a promising role in stimulated IVF cycles, either when administered during the follicular phase for ovarian stimulation. Especially for women with poor ovarian response, letrozole appears to have the potential to increase clinical pregnancy rates when combined with gonadotropins, whereas at the same time reduces the total gonadotropin dose required for ovarian stimulation. However, given that in all of the trials letrozole has been administered in GnRH antagonist cycles, it is intriguing to test in the future how it may perform when used in GnRH agonist cycles. Finally administration of letrozole during luteal phase in IVF cycles offers another treatment modality for patients at high risk for OHSS taking into account that it drastically reduces estradiol levels

  8. Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy.

    Science.gov (United States)

    Hicks, Debbie; Farsani, Golara Torabi; Laval, Steven; Collins, James; Sarkozy, Anna; Martoni, Elena; Shah, Ashoke; Zou, Yaqun; Koch, Manuel; Bönnemann, Carsten G; Roberts, Mark; Lochmüller, Hanns; Bushby, Kate; Straub, Volker

    2014-05-01

    Bethlem myopathy (BM) [MIM 158810] is a slowly progressive muscle disease characterized by contractures and proximal weakness, which can be caused by mutations in one of the collagen VI genes (COL6A1, COL6A2 and COL6A3). However, there may be additional causal genes to identify as in ∼50% of BM cases no mutations in the COL6 genes are identified. In a cohort of -24 patients with a BM-like phenotype, we first sequenced 12 candidate genes based on their function, including genes for known binding partners of collagen VI, and those enzymes involved in its correct post-translational modification, assembly and secretion. Proceeding to whole-exome sequencing (WES), we identified mutations in the COL12A1 gene, a member of the FACIT collagens (fibril-associated collagens with interrupted triple helices) in five individuals from two families. Both families showed dominant inheritance with a clinical phenotype resembling classical BM. Family 1 had a single-base substitution that led to the replacement of one glycine residue in the triple-helical domain, breaking the Gly-X-Y repeating pattern, and Family 2 had a missense mutation, which created a mutant protein with an unpaired cysteine residue. Abnormality at the protein level was confirmed in both families by the intracellular retention of collagen XII in patient dermal fibroblasts. The mutation in Family 2 leads to the up-regulation of genes associated with the unfolded protein response (UPR) pathway and swollen, dysmorphic rough-ER. We conclude that the spectrum of causative genes in extracellular matrix (ECM)-related myopathies be extended to include COL12A1. PMID:24334769

  9. Defining the minimal length of sequence homology required for selective gene isolation by TAR cloning

    OpenAIRE

    Noskov, V. N.; Koriabine, M.; Solomon, G.; Randolph, M; Barrett, J C; Leem, S.-H.; Stubbs, L; Kouprina, N; Larionov, V.

    2001-01-01

    The transformation-associated recombination (TAR) cloning technique allows selective and accurate isolation of chromosomal regions and genes from complex genomes. The technique is based on in vivo recombination between genomic DNA and a linearized vector containing homologous sequences, or hooks, to the gene of interest. The recombination occurs during transformation of yeast spheroplasts that results in the generation of a yeast artificial chromosome (YAC) contain...

  10. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

    OpenAIRE

    Sosnay, Patrick R.; Siklosi, Karen R; Van Goor, Fredrick; Kaniecki, Kyle; Yu, Haihui; Sharma, Neeraj; Ramalho, Anabela S; Amaral, Margarida D.; Dorfman, Ruslan; Zielenski, Julian; Masica, David L.; Karchin, Rachel; Millen, Linda; Thomas, Philip J.; George P. Patrinos

    2013-01-01

    Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR varia...

  11. Defining the optimal animal model for translational research using gene set enrichment analysis.

    Science.gov (United States)

    Weidner, Christopher; Steinfath, Matthias; Opitz, Elisa; Oelgeschläger, Michael; Schönfelder, Gilbert

    2016-01-01

    The mouse is the main model organism used to study the functions of human genes because most biological processes in the mouse are highly conserved in humans. Recent reports that compared identical transcriptomic datasets of human inflammatory diseases with datasets from mouse models using traditional gene-to-gene comparison techniques resulted in contradictory conclusions regarding the relevance of animal models for translational research. To reduce susceptibility to biased interpretation, all genes of interest for the biological question under investigation should be considered. Thus, standardized approaches for systematic data analysis are needed. We analyzed the same datasets using gene set enrichment analysis focusing on pathways assigned to inflammatory processes in either humans or mice. The analyses revealed a moderate overlap between all human and mouse datasets, with average positive and negative predictive values of 48 and 57% significant correlations. Subgroups of the septic mouse models (i.e., Staphylococcus aureus injection) correlated very well with most human studies. These findings support the applicability of targeted strategies to identify the optimal animal model and protocol to improve the success of translational research. PMID:27311961

  12. Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis.

    Science.gov (United States)

    Carpino, A; Romeo, F; Rago, V

    2004-03-01

    Abstract Cytochrome P450 aromatase is a terminal enzyme that catalyses the conversion of androgens into oestrogens. This study investigated the immunohistochemical localization of aromatase in human efferent ductules and proximal ductus epididymis using a mouse anti-human monoclonal P450arom IgG as primary antibody and a goat anti-mouse biotinylated IgG as secondary antibody. A strong immunoreaction was observed in the epithelial cell cytoplasm of both ductuli efferentes and proximal ductus epididymis, whereas the smooth muscle cells were immunonegative in the two regions. The results show, for the first time in humans, that epithelial cells of ductuli efferentes and proximal caput epididymis express aromatase, suggesting that locally produced oestrogens may have a role in epididymal function. PMID:15032911

  13. Chromosomal alterations detected by comparative genomic hybridization in subgroups of gene expression-defined Burkitt's lymphoma

    NARCIS (Netherlands)

    Salaverria, Itziar; Zettl, Andreas; Bea, Silvia; Hartmann, Elena M.; Dave, Sandeep S.; Wright, George W.; Boerma, Evert-Jan; Kluin, Philip M.; Ott, German; Chan, Wing C.; Weisenburger, Dennis D.; Lopez-Guillermo, Armando; Gascoyne, Randy D.; Delabie, Jan; Rimsza, Lisa M.; Braziel, Rita M.; Jaffe, Elaine S.; Staudt, Louis M.; Mueller-Hermelink, Hans Konrad; Campo, Elias; Rosenwald, Andreas

    2008-01-01

    Background Burkitt's lymphoma is an aggressive B-cell lymphoma characterized by typical morph 0 logical, immunophenotypic and molecular features. Gene expression profiling provided a molecular signature of Burkitt's lymphoma, but also demonstrated that a subset of aggressive B-cell lymphomas not ful

  14. Data-driven asthma endotypes defined from blood biomarker and gene expression data.

    Directory of Open Access Journals (Sweden)

    Barbara Jane George

    Full Text Available The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels.

  15. The effects of diabetes on placental aromatase activity.

    Science.gov (United States)

    McRobie, D J; Korzekwa, K R; Glover, D D; Tracy, T S

    1997-01-01

    Diabetes complicates 2-3% of all pregnancies and is associated with an increase in both perinatal morbidity and mortality, though reasons for these adverse outcomes are unknown. Estrogen biosynthesis is a critical factor during pregnancy and is carried out in the placenta via aromatase (cytochrome P450 19A1), which catalyzes the conversion of C-19 androgens to C-18 estrogens. Previous studies have shown that hormones such as insulin-like growth factors and insulin regulate aromatase activity when studied in vitro. Interestingly, levels of these hormones are altered in patients with diabetes. Thus, we hypothesized that the presence of maternal diabetes may alter placental aromatase activity and thus estrogen biosynthesis, possibly serving as one factor in the adverse outcomes of babies born to mothers with diabetes. To this end, we measured the production of 19-hydroxyandrostenedione, 19-oxoadrostenedione and estrone in 30 placental tissues from diabetic patients, using [7-3H]androst-4-ene-3,17-dione as a model substrate for aromatase (P450 19A1). A statistical difference was detected in the percentage of 19-oxoandrostenedione formed between the overt and control groups (P < 0.05). Additionally, NADPH P450-reductase levels were measured in these same tissues to determine whether alterations in this enzyme necessary for aromatase activity could be affected by diabetes. No differences in reductase levels were detected among the patient groups. However, a statistical correlation was found between NADPH P450-reductase activity and the formation velocities of all three estrogen products (P < 0.05). Thus, it appears that the presence of diabetes does not affect placental aromatase activity. PMID:9449216

  16. Seminiferous tubule transfection in vitro to define post-meiotic gene regulation

    Directory of Open Access Journals (Sweden)

    Kirchhoff Christiane

    2009-06-01

    Full Text Available Abstract Background Post-meiotically expressed genes in the testis are essential for the proper progression of spermatogenesis, and yet, aside from the construction of individual transgenic mice using specific promoters to drive reporter plasmids, there are only very limited possibilities for relevant and quantitative analysis of gene promoters. This is due to the special nature of post-meiotic haploid cells, which to date are not represented in any appropriate cell-lines. This article reports the development of novel methodology using isolated and cultured rat seminiferous tubules in a multiwell format, into which promoter-reporter constructs can be introduced by a combination of microinjection and electroporation. Methods Culture conditions were developed which allowed the continued incubation of isolated rat seminiferous tubules for up to 48 h without obvious cell death and loss of post-meiotic cells. Transfection of intact seminiferous tubules by microinjection and electroporation was optimized to achieve high expression efficiencies of control plasmids, using either fluorescent protein or luciferase as reporters, thereby allowing both morphological as well as quantitative assessment. Results Successful transfection was achieved into all cell types except for mature spermatozoa. However, there appeared to be only limited cell-type specificity for the promoters used, even though these had appeared to be specific when used in transgenic animals. Conclusion We have devised a methodology which allows relatively high throughput analysis of post-meiotic gene promoters into primary cells of intact seminiferous tubules. An apparent lack of cell-type specificity suggests that the gene fragments used do not contain sufficient targeting information, or that the transient episomal expression of the constructs does not encourage appropriate expression specificity. The results also highlight the doubtful interpretation of many studies using heterologous

  17. A defined chromosome 6q fragment (at D6S310) harbors a putative tumor suppressor gene for breast cancer.

    Science.gov (United States)

    Theile, M; Seitz, S; Arnold, W; Jandrig, B; Frege, R; Schlag, P M; Haensch, W; Guski, H; Winzer, K J; Barrett, J C; Scherneck, S

    1996-08-15

    Recent evidence obtained by cytogenetic and molecular studies indicates that in breast cancer chromosome 6q is often affected by genetic changes suggesting the existence of putative tumor suppressor genes (TSGs). However the function of gene(s) on this chromosome in breast cancer suppression is not understood. To substantiate further the presence of breast cancer related TSGs at 6q and to define their location, we first performed microcell-mediated transfer of chromosome 6 to CAL51 breast cancer cells for studying possible suppression of malignant phenotype and secondly, we analysed DNAs from 46 primary breast cancers for loss of constitutive heterozygosity (LOH) using 24 poly-morphic microsatellite markers. The chromosome transfer resulted in loss of tumorigenicity and reversion of other neoplastic properties of the microcell hybrids. Polymorphism analysis of single hybrids revealed that they harbored only a small donor chromosome fragment defined by the marker D6S310 (6q23.3-q25) and flanked by D6S292 and D6S311. The LOH data suggest that four tumor suppressor gene loci mapped to the central and distal portion of 6q may be independently deleted in breast cancer. One of these regions corresponds to the region identified by chromosome transfer. PMID:8761288

  18. The hangover gene defines a stress pathway required for ethanol tolerance development

    OpenAIRE

    Scholz, Henrike; Franz, Mirjam; Heberlein, Ulrike

    2005-01-01

    Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioral effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction1–3. Previous studies showed that Drosophila develop ethanol tolerance with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the fun...

  19. DBA-Lectin Reactivity Defines Mouse Uterine Natural Killer Cell Subsets with Biased Gene Expression 1

    OpenAIRE

    Chen, Zhilin; Zhang, Jianhong; Hatta, Kota; Lima, Patricia D.A.; Yadi, Hakim; Colucci, Francesco; Yamada, Aureo T.; Croy, B. Anne

    2012-01-01

    Endometrial decidualization, a process essential for blastocyst implantation in species with hemochorial placentation, is accompanied by an enormous but transient influx of Natural Killer (NK) cells. Mouse uterine (u)NK cell subsets have been defined by diameter and cytoplasmic granule number, reflecting stage of maturity and by histochemical reactivity with Periodic Acid Schiff’s (PAS) reagent, with or without co-reactivity with Dolichos biflorus agglutinin (DBA) lectin. We asked whether DBA...

  20. Defining an innovative and safe non-viral gene delivery system: perspective analysis for gene therapy applications

    OpenAIRE

    Turchiano,

    2013-01-01

    The Sleeping Beauty (SB) transposon-based integration system is a valuable tool for functional genomics in several model organisms and represent a promising vector for gene therapy in humans. The SB transposase was found to bind the inverted repeats of regenerated salmonid transposons in a substrate-specific manner, and to mediate precise cut-and-paste transposition in fish as well as in mouse and human cells. However, a major bottleneck of any transposon-based application is the efficiency o...

  1. Defined DNA-mediated assemblies of gene-expressing giant unilamellar vesicles

    DEFF Research Database (Denmark)

    Hadorn, M.; Boenzli, E.; Sørensen, Kristian T.;

    2013-01-01

    soft matter assemblies and that the highly sensitive gene-expression machinery remains intact and active during multiple experimental steps. An in silico model recapitulates the experiments performed in vitro and covers additional experimental setups highlighting the parameters that control the DNA...... of giant unilamellar vesicles functionalized with a basic cellular machinery to express green fluorescent protein and specified neighbor-to-neighbor interactions. We show both that the local and programmable DNA pairing rules on the nanoscale are able to direct the microscale vesicles into macroscale...

  2. The analysis of the human hemopexin promoter defines a new class of liver-specific genes.

    OpenAIRE

    Poli, V.; Silengo, L; Altruda, F; Cortese, R

    1989-01-01

    Hemopexin (Hpx) is a plasma glycoprotein which is expressed only in the liver. It is synthesized at a lower rate in the fetal liver than in the adult, and its level increases during acute infections. As shown here, a fragment of the human hemopexin promoter spanning from positions -130 to +22 relative to the cap site is sufficient to direct cell-specific transcription of a reporter gene. Within this segment a short sequence, located between positions -120 and -104, is responsible for this eff...

  3. Well-Defined Peapod-like Magnetic Nanoparticles and Their Controlled Modification for Effective Imaging Guided Gene Therapy.

    Science.gov (United States)

    Wang, Ranran; Hu, Yang; Zhao, Nana; Xu, Fu-Jian

    2016-05-11

    Due to their unique properties, one-dimensional (1D) magnetic nanostructures are of great significance for biorelated applications. A facile and straightforward strategy to fabricate 1D magnetic structure with special shapes is highly desirable. In this work, well-defined peapod-like 1D magnetic nanoparticles (Fe3O4@SiO2, p-FS) are readily synthesized by a facile method without assistance of any templates, magnetic string or magnetic field. There are few reports on 1D gene carriers based on Fe3O4 nanoparticles. BUCT-PGEA (ethanolamine-functionalized poly(glycidyl methacrylate) is subsequently grafted from the surface of p-FS nanoparticles by atom transfer radical polymerization to construct highly efficient gene vectors (p-FS-PGEA) for effective biomedical applications. Peapod-like p-FS nanoparticles were proven to largely improve gene transfection performance compared with ordinary spherical Fe3O4@SiO2 nanoparticles (s-FS). External magnetic field was also utilized to further enhance the transfection efficiency. Moreover, the as-prepared p-FS-PGEA gene carriers could combine the magnetic characteristics of p-FS to well achieve noninvasive magnetic resonance imaging (MRI). We show here novel and multifunctional magnetic nanostructures fabricated for biomedical applications that realized efficient gene delivery and real-time imaging at the same time. PMID:27100466

  4. RNA-Seq defines novel genes, RNA processing patterns and enhancer maps for the early stages of nephrogenesis: Hox supergenes.

    Science.gov (United States)

    Brunskill, Eric W; Potter, S Steven

    2012-08-01

    During kidney development the cap mesenchyme progenitor cells both self renew and differentiate into nephrons. The balance between renewal and differentiation determines the final nephron count, which is of considerable medical importance. An important goal is to create a precise genetic definition of the early differentiation of cap mesenchyme progenitors. We used RNA-Seq to transcriptional profile the cap mesenchyme progenitors and their first epithelial derivative, the renal vesicles. The results provide a global view of the changing gene expression program during this key period, defining expression levels for all transcription factors, growth factors, and receptors. The RNA-Seq was performed using two different biochemistries, with one examining only polyadenylated RNA and the other total RNA. This allowed the analysis of noncanonical transcripts, which for many genes were more abundant than standard exonic RNAs. Since a large fraction of enhancers are now known to be transcribed the results also provide global maps of potential enhancers. Further, the RNA-Seq data defined hundreds of novel splice patterns and large numbers of new genes. Particularly striking was the extensive sense/antisense transcription and changing RNA processing complexities of the Hox clusters. PMID:22664176

  5. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Halling-Sørensen, Bent; Birkved, Franziska Maria A Kramer

    2008-01-01

    Antiepileptic drugs and epilepsy are often associated with sexual disorder in women such as hyperandrogenism, menstrual disorders and ovarian cysts. In children, until puberty, a hormone imbalance may influence many aspects of development, e.g. growth and sexual maturation. The aromatase complex is...

  6. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    NARCIS (Netherlands)

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C.

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that wer

  7. Which patients benefit most from adjuvant aromatase inhibitors?

    DEFF Research Database (Denmark)

    Viale, G; Regan, M M; Dell'Orto, P;

    2011-01-01

    On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which...

  8. Long-term safety of aromatase inhibitors in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    Jean-Marc A Nabholtz

    2008-03-01

    Full Text Available Jean-Marc A NabholtzBreast Cancer Research Institute La Prandie, Valojoulx, FranceAbstract: Following promising data for metastatic breast cancer in terms of efficacy and safety profile, third-generation aromatase inhibitors (AI, anastrozole, letrozole, and exemestane, underwent a full development in early setting. If recent results consistently show the superiority of these agents over tamoxifen, the therapeutic strategies of AIs in adjuvant setting are still debated. Beyond the choice of clinical strategy, the long duration of exposure to AI in adjuvant setting required a full determination of the long-term toxicity profile of these agents. While all three AIs have either favorable (decreased incidence of hot flashes, gynecologic and thromboembolic side-effects or unfavorable (skeletal complications, arthralgia, musculoskeletal pain, sexual dysfunction class adverse events, some variability between AIs has been reported in side-effects as well as gastrointestinal, urogenital, neurologic, and visual disturbances, confirming the lack of interchangeability between the three AIs. The overall therapeutic index of AIs appears today superior to that of tamoxifen with proven improved efficacy and better toxicity profile. This review will explore the results from the available adjuvant AIs trials with a particular emphasis on safety profiles, quality of life, and therapeutic index, helping to define the present role of AIs in the adjuvant management of postmenopausal patients with breast cancer.Keywords: breast cancer, aromatase inhibitors, adjuvant, safety profile

  9. Gene expression profiling defined pathways correlated with fibroblast cell proliferation induced by Opisthorchis viverrini excretory/secretory product

    Institute of Scientific and Technical Information of China (English)

    Chanitra Thuwajit; Peti Thuwajit; Kazuhiko Uchida; Daoyot Daorueang; Sasithorn Kaewkes; Sopit Wongkham; Masanao Miwa

    2006-01-01

    AIM: To investigate the mechanism of fibroblast cell proliferation stimulated by the Opisthorchis viverrini excretory/secretory (ES) product.METHODS: NIH-3T3, mouse fibroblast cells were treated with O. viverrini ES product by non-contact co-cultured with the adult parasites. Total RNA from NIH-3T3 treated and untreated with O. viverrini was extracted, reverse transcribed and hybridized with the mouse 15K complementary DNA (cDNA) array. The result was analyzed by ArrayVision version 5 and GeneSpring version 5 softwares. After normalization, the ratios of gene expression of parasite treated to untreated NIH3T3 cells of 2-and more-fold upregulated was defined as the differentially expressed genes. The expression levels of the signal transduction genes were validated by semiquantitative SYBR-based real-time RT-PCR.RESULTS: Among a total of 15 000 genes/ESTs, 239genes with established cell proliferation-related function were 2 fold-and more-up-regulated by O. viverrini ES product compared to those in cells without exposure to the parasitic product. These genes were classified into groups including energy and metabolism, signal transduction, protein synthesis and translation, matrix and structural protein, transcription control, cell cycle and DNA replication. Moreover, the expressions of serinethreonine kinase receptor, receptor tyrosine kinase and collagen production-related genes were up-regulated by O. viverrini ES product. The expression level of signal transduction genes; pkC, pdgfrα, jak 1, eps 8, tgfβ 1/4,strap and h ras measured by real-time RT-PCR confirmed their expression levels to those obtained from cDNA array. However, only the up-regulated expression of pkC, eps 8 and tgfβ 1/4 which are the downstream signaling molecules of either epidermal growth factor (EGF) or transforming growth factor-β (TGF-β) showed statistical significance (P < 0.05). CONCLUSION: O. viverrini ES product stimulates the significant changes of gene expression in several

  10. Analysis of Azotobacter vinelandii strains containing defined deletions in the nifD and nifK genes.

    OpenAIRE

    J. G. LI; Tal, S; Robinson, A. C.; Dang, V; Burgess, B. K.

    1990-01-01

    Strains of Azotobacter vinelandii which contain defined deletions within the nifD and nifK genes which encode, respectively, the alpha and beta subunits of the MoFe protein of nitrogenase were analyzed. When synthesized without its partner, the beta subunit accumulated as a soluble beta 4 tetramer. In contrast, when the alpha subunit was present without its partner, it accumulated primarily as an insoluble aggregate. The solubility of this protein was increased by the presence of a form of th...

  11. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene.

    Science.gov (United States)

    Juhlin, C Christofer; Stenman, Adam; Haglund, Felix; Clark, Victoria E; Brown, Taylor C; Baranoski, Jacob; Bilguvar, Kaya; Goh, Gerald; Welander, Jenny; Svahn, Fredrika; Rubinstein, Jill C; Caramuta, Stefano; Yasuno, Katsuhito; Günel, Murat; Bäckdahl, Martin; Gimm, Oliver; Söderkvist, Peter; Prasad, Manju L; Korah, Reju; Lifton, Richard P; Carling, Tobias

    2015-09-01

    As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. PMID:26032282

  12. Age-related decrease in aromatase and estrogen receptor(ERαand ERβ) expression in rat testes: protective effect of low caloric diets

    Institute of Scientific and Technical Information of China (English)

    Khaled Hamden; Dorothee Silandre; Christelle Delalande; Abdefattah El Feki; Serge Carreau

    2008-01-01

    Aim: To examine the effects on rat aging of caloric restriction (CR1) and undernutrition (CR2) on the body and on testicular weights, on two enzymatic antioxidants (superoxide dismutase and catalase), on lipid peroxidation and on the expression of testicular aromatase and estrogen receptors (ER). Methods: CR was initiated in 1-month-old rats and carried on until the age of 18 months. Results: In control and CR2 rats an age-related decrease of the aromatase and of ER (α and β) gene expression was observed; in parallel a diminution of testicular weights, and of the total number and motility of epididymal spermatozo was recorded. In addition, aging in control and CR2 rats was accom-panied by a significant decrease in testicular superoxide dismutase, catalase activities, and an increase in lipid peroxidation level (thiobarbituric acid reactive substance), associated with alterations of spermatogenesis. Conversely, caloric restriction-treatment exerted a protective effect and all the parameters were less affected by aging. Conclusion:These results indicate that during aging, a low caloric diet (not undernutrition) is beneficial for spermatogenesis and likely improves the protection of the cells via an increase of the cellular antioxidant defense system in which aromatase/ER could play a role.

  13. Defining reference sequences for Nocardia species by similarity and clustering analyses of 16S rRNA gene sequence data.

    Directory of Open Access Journals (Sweden)

    Manal Helal

    Full Text Available BACKGROUND: The intra- and inter-species genetic diversity of bacteria and the absence of 'reference', or the most representative, sequences of individual species present a significant challenge for sequence-based identification. The aims of this study were to determine the utility, and compare the performance of several clustering and classification algorithms to identify the species of 364 sequences of 16S rRNA gene with a defined species in GenBank, and 110 sequences of 16S rRNA gene with no defined species, all within the genus Nocardia. METHODS: A total of 364 16S rRNA gene sequences of Nocardia species were studied. In addition, 110 16S rRNA gene sequences assigned only to the Nocardia genus level at the time of submission to GenBank were used for machine learning classification experiments. Different clustering algorithms were compared with a novel algorithm or the linear mapping (LM of the distance matrix. Principal Components Analysis was used for the dimensionality reduction and visualization. RESULTS: The LM algorithm achieved the highest performance and classified the set of 364 16S rRNA sequences into 80 clusters, the majority of which (83.52% corresponded with the original species. The most representative 16S rRNA sequences for individual Nocardia species have been identified as 'centroids' in respective clusters from which the distances to all other sequences were minimized; 110 16S rRNA gene sequences with identifications recorded only at the genus level were classified using machine learning methods. Simple kNN machine learning demonstrated the highest performance and classified Nocardia species sequences with an accuracy of 92.7% and a mean frequency of 0.578. CONCLUSION: The identification of centroids of 16S rRNA gene sequence clusters using novel distance matrix clustering enables the identification of the most representative sequences for each individual species of Nocardia and allows the quantitation of inter- and intra

  14. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation

    OpenAIRE

    Asadabadi, Ebrahim Barzegari; Chupani, Latifeh; Jamalan, Mostafa; Mirzaie, Sako; Shahverdi, Ahmad Reza

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of arom...

  15. The ferrous-oxy complex of human aromatase

    International Nuclear Information System (INIS)

    In this communication, we document the self-assembly of heterologously expressed truncated human aromatase (CYP19) into nanometer scale phospholipids bilayers (Nanodiscs). The resulting P450 CYP19 preparation is stable and can tightly associate with the substrate androstenedione to form a nearly complete high-spin ferric protein. Ferrous CYP19 in Nanodiscs was mixed anaerobically in a rapid-scan stopped-flow with atmospheric dioxygen and the formation of the ferrous-oxy complex observed. First order decay of the oxy-complex to release superoxide and regenerate the ferric enzyme was monitored kinetically. Surprisingly, the ferrous-oxy complex of aromatase is more stable than that of hepatic CYP3A4, opening the path to precisely determine the biochemical and biophysical properties of the reaction cycle intermediates in this important human drug target

  16. Aromatase inhibitors for subfertile women with polycystic ovary syndrome (Review)

    OpenAIRE

    Franik, S.; Kremer, J.A.M.; Nelen, W.L.D.M.; Farquhar, C

    2014-01-01

    BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a novel class of drugs that were introduced for ovulation induction in 2001. Over the last ten years clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line tr...

  17. Cytochrome P450 aromatase expression in human seminoma

    Directory of Open Access Journals (Sweden)

    Montanaro Daniela

    2005-12-01

    Full Text Available Abstract Background The enzyme cytochrome P450 aromatase, catalysing the conversion of androgens into estrogens, has been detected in normal human testicular cells suggesting a physiological role of local estrogen biosynthesis on spermatogenesis control. Estrogens, regulating cell growth and apoptosis, can also be involved in tumorigenesis process, but the possible link between estrogens and testicular neoplastic process is, up to now, scarcely known. This study examined aromatase expression in human seminoma, which is the most common germ cell tumour of the testis. Methods The tumour-bearing testes were obtained from 20 patients with classic seminoma undergoing to therapeutic orchidectomy. Paraffin embedded tissues were processed for immunohistochemistry using a mouse monoclonal antibody generated against human placental cytochrome P450 arom, as primary antibody, and a biotinylated goat-anti-mouse IgG, as secondary antibody. Furthermore, Western blot analysis of seminoma extracts was carried out. Results Intense P450 arom immunoreactivity was observed in the seminoma cells and Western blot analysis confirmed the immunodetection. A strong immunostaining was also detected in cells of intratubular germ cell neoplasia (IGCN, adjacent to seminoma. Conclusion The present study demonstrated, for the first time in human, aromatase expression in neoplastic cells of seminoma suggesting a relation between local estrogen biosynthesis and germ cell tumorigenesis. The P450 arom immunolocalization in the cells of IGCN, representing the common precursor of most germ cell tumors, seems to support these findings.

  18. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Muenke, M.; Gripp, K.W.; McDonald-McGinn, D.M. [Univ. of Pennsylvania, Philadelphia, PA (United States)] [and others

    1997-03-01

    The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis. 54 refs., 4 figs., 2 tabs.

  19. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome

    Science.gov (United States)

    Muenke, M.; Gripp, K. W.; McDonald-McGinn, D. M.; Gaudenz, K.; Whitaker, L. A.; Bartlett, S. P.; Markowitz, R. I.; Robin, N. H.; Nwokoro, N.; Mulvihill, J. J.; Losken, H. W.; Mulliken, J. B.; Guttmacher, A. E.; Wilroy, R. S.; Clarke, L. A.; Hollway, G.; Adès, L. C.; Haan, E. A.; Mulley, J. C.; Cohen, M. M.; Bellus, G. A.; Francomano, C. A.; Moloney, D. M.; Wall, S. A.; Wilkie, A. O. M.; Zackai, E. H.

    1997-01-01

    The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis. ImagesFigure 2Figure 3Figure 4 PMID:9042914

  20. Multicolor fluorescent in situ hybridization to define abutting and overlapping gene expression in the embryonic zebrafish brain

    Directory of Open Access Journals (Sweden)

    Hauptmann Giselbert

    2011-04-01

    Full Text Available Abstract Background In recent years, mapping of overlapping and abutting regulatory gene expression domains by chromogenic two-color in situ hybridization has helped define molecular subdivisions of the developing vertebrate brain and shed light on its basic organization. Despite the benefits of this technique, visualization of overlapping transcript distributions by differently colored precipitates remains difficult because of masking of lighter signals by darker color precipitates and lack of three-dimensional visualization properties. Fluorescent detection of transcript distributions may be able to solve these issues. However, despite the use of signal amplification systems for increasing sensitivity, fluorescent detection in whole-mounts suffers from rapid quenching of peroxidase (POD activity compared to alkaline phosphatase chromogenic reactions. Thus, less strongly expressed genes cannot be efficiently detected. Results We developed an optimized procedure for fluorescent detection of transcript distribution in whole-mount zebrafish embryos using tyramide signal amplification (TSA. Conditions for hybridization and POD-TSA reaction were optimized by the application of the viscosity-increasing polymer dextran sulfate and the use of the substituted phenol compounds 4-iodophenol and vanillin as enhancers of POD activity. In combination with highly effective bench-made tyramide substrates, these improvements resulted in dramatically increased signal-to-noise ratios. The strongly enhanced signal intensities permitted fluorescent visualization of less abundant transcripts of tissue-specific regulatory genes. When performing multicolor fluorescent in situ hybridization (FISH experiments, the highly sensitive POD reaction conditions required effective POD inactivation after each detection cycle by glycine-hydrochloric acid treatment. This optimized FISH procedure permitted the simultaneous fluorescent visualization of up to three unique transcripts

  1. Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural Polyphenols

    OpenAIRE

    Neves, Marco A. C.; Dinis, Teresa C. P.; Colombo, Giorgio; Melo, M. Luísa Sá e

    2007-01-01

    Aromatase, an enzyme of the cytochrome P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques bas...

  2. Synthesis of highly-labeled with tritium steroid hormones and their use for estimation of aromatase activity

    International Nuclear Information System (INIS)

    Highly-labeled steroids - progesterone, estradiol, and androsterone are synthesized. They are used for determination of aromatase activity in different pathologies. It is shown that high activity of aromatase in endometrium in patients with endometrium neoplasms without myome deteriorates disease prognosis. At the same time high aromatase activity in endometrium in patients with endometrium neoplasms with myome has frequently opportune result

  3. HLA-A Gene Polymorphism Defined by High-Resolution Sequence Based Typing in 161 Northern Chinese Han People

    Institute of Scientific and Technical Information of China (English)

    Chunxia Yan; Haiyan Sun; Xiuqing Zhang; Jian Wang; Huanming Yang; Shengbin Li; Ruilin Wang; Jingxiang Li; Yajun Deng; Dongying Wu; Hongbo Zhang; Hongxing Zhang; Lidong Wang; Chunrong Zhang

    2003-01-01

    Human leukocyte antigen (HLA) system is the most polymorphic region known in the human genome. In the present study, we analyzed for the first time the HLA-A gene polymorphisms defined by the high-resolution typing methods--sequence-based typing (SBT) in 161 Northern Chinese Han people. A total of 74 different HLA-A gene types and 36 alleles were detected. The most frequent alleles were A*110101 (GF=0.2360), A*24020101 (GF=0.1646), and A*020101 (GF=0.1553); followed by A*3303 (GF=0.1180), A*3001 (GF=0.0590),and A*310102 (GF=0.0404). The frequencies of following alleles, A*0203, A*0205,A*0206, A*0207, A*030101, A*2423, A*2601, A*3201, and A*3301, are all higher than 0.0093. The homozygous alleles include A*020101, A*110101, A*24020101 and A*310102. Heterozygosity (H), polymorphism information content (PIC), discrimination power (DP) and probability of paternity exclusion (PPE) of HLA-A in the samples were calculated and their values were 0.8705, 0.8491, 0.6014, and 0.9475, respectively. These results by SBT analysis of HLA-A polymorphism in Northern Chinese Han population, especially the allele subtypes character, will be of great interest for clinical transplantation, disease-associated study and forensic identification. Implementation of high-resolution typing methods allows a significantly wider spectrum of HLA variation including rare alleles. This spectrum will further be extensively utilized in many fields.

  4. FBN1 gene mutation defines the profibrillin to fibrillin processing site and segregates with tall stature in a family

    Energy Technology Data Exchange (ETDEWEB)

    Grossfield, J.; Cao, S.; Milewicz, D. [Univ. of Texas Medical School, Houston, TX (United States)] [and others

    1994-09-01

    Dermal fibroblasts from a 13-year-old boy with skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Synthesis and secretion of profibrillin was normal but only half of the secreted profibrillin was converted to fibrillin, an extracellular proteolytic processing that removes a 20 kDa fragment from the protein. All the secreted profibrillin was processed to fibrillin in control cells. Only the processed form of fibrillin was deposited into the extracellular matrix in both the proband`s and the control cells. Electron microscopic examination of rotary shadowed microfibrils made by the proband`s fibroblasts were indistinguishable from control cells. Screening exons in the 3{prime} end of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 5482 of the FBN1 cDNA changing R 1828 to W. This mutation disrupts a known consensus sequence recognized by a cellular protease and is located in the carboxy terminus at a site predicted to remove a 19 kD fragment. The proband and his 22-year-old brother, also heterozygous for the mutation, have had normal echocardiograms and ophthalmologic exams. The mutation segregated in the proband`s three generation family with autosomal dominant inheritance of height (> 90th percentile) and no known cardiovascular or ocular problems, including the 67-year-old grandmother (exams pending). The mutation was not found in 90 chromosomes from unrelated individuals. In summary, (1) the mutation identifies the cleavage site for the conversion of profibrillin to fibrillin; (2) the characterized mutation segregates in the family with tall stature without known cardiovascular or ocular problems; (3) this mutation potentially defines the phenotype associated with a {open_quotes}null{close_quotes} allele for the FBN1 gene.

  5. New insights about the evaluation of human sperm quality: the aromatase example.

    Directory of Open Access Journals (Sweden)

    A Saad

    2010-01-01

    Full Text Available Male contribution to the couple's infertility is at first evaluated by the routine examination of semen parameters upon optical microscopy providing valuable information for a rational initial diagnosis and for a clinical management of infertility. But the different forms of infertility defined according to the WHO criteria especially teratozoospermia are not always related to the chromatin structure or to the fertilization capacity. New investigations at the molecular level (transcript and protein could be developed in order to understand the nature of sperm malformation responsible of human infertility and thus to evaluate the sperm quality. The profile analysis of spermatozoal transcripts could be considered as a fingerprint of the past spermatogenic events. The selection of representative transcripts of normal spermatozoa remains complex because a differential expression (increased, decreased or not modified levels of specific transcripts has been revealed between immotile and motile sperm fractions issued from normozoospermic donors. Microarrays tests or real-time quantitative PCR could be helpful for the identification of factors involved in the male infertility. Differences in the expression of specific transcripts have been reported between normal and abnormal semen samples. With the aromatase example, we have noted a negative strong correlation between the amount of transcript and the percentage of abnormal forms especially in presence of head defects. Immunocytochemical procedures using fluorescent probes associated with either confocal microscopy or flow cytometry can be also helpful to proceed with further investigations about the localization of proteins in the compartmentalized spermatozoa or the acrosome reaction. The dual location of aromatase both in the equatorial segment, the mid-piece and the tail could explain the double role of this enzyme in acrosome reaction and motility.

  6. Imaging of aromatase distribution in rat and rhesus monkey brains with [{sup 11}C]vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Kayo [Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala SE-75124 (Sweden); Uppsala Imanet, Uppsala SE-75109 (Sweden)]. E-mail: kayo.takahashi@uppsala.imanet.se; Bergstroem, Mats [Uppsala Imanet, Uppsala SE-75109 (Sweden); Department of Pharmaceutical Biosciences, Uppsala University, Uppsala SE-75124 (Sweden); Fraendberg, Pernilla [Uppsala Imanet, Uppsala SE-75109 (Sweden); Vesstroem, Eva-Lotta [Uppsala Imanet, Uppsala SE-75109 (Sweden); Watanabe, Yasuyoshi [Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585 (Japan); Langstroem, Bengt [Uppsala Imanet, Uppsala SE-75109 (Sweden)

    2006-07-15

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [{sup 11}C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K {sub d} of [{sup 11}C]vorozole binding to aromatase in MA was determined to be 0.60{+-}0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [{sup 11}C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.

  7. Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole

    International Nuclear Information System (INIS)

    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [11C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K d of [11C]vorozole binding to aromatase in MA was determined to be 0.60±0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [11C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons

  8. Aromatase Expression in the Hippocampus of AD Patients and 5xFAD Mice

    Science.gov (United States)

    Prange-Kiel, Janine; Dudzinski, Danuta A.; Pröls, Felicitas; Glatzel, Markus; Matschke, Jakob; Rune, Gabriele M.

    2016-01-01

    Numerous studies show that 17β-estradiol (E2) protects against Alzheimer's disease (AD) induced neurodegeneration. The E2-synthesizing enzyme aromatase is expressed in healthy hippocampi, but although the hippocampus is severely affected in AD, little is known about the expression of hippocampal aromatase in AD. To better understand the role of hippocampal aromatase in AD, we studied its expression in postmortem material from patients with AD and in a mouse model for AD (5xFAD mice). In human hippocampi, aromatase-immunoreactivity was observed in the vast majority of principal neurons and signal quantification revealed higher expression of aromatase protein in AD patients compared to age- and sex-matched controls. The tissue-specific first exons of aromatase I.f, PII, I.3, and I.6 were detected in hippocampi of controls and AD patients by RT-PCR. In contrast, 3-month-old, female 5xFAD mice showed lower expression of aromatase mRNA and protein (measured by qRT-PCR and semiquantitative immunohistochemistry) than WT controls; no such differences were observed in male mice. Our findings stress the importance of hippocampal aromatase expression in neurodegenerative diseases. PMID:27298742

  9. Uso de inibidores da aromatase no tratamento do câncer de mama e osteoporose = The use of aromatase inhibitors for breast cancer treatment and osteoporosis

    Directory of Open Access Journals (Sweden)

    Cassol, Lina Barbosa

    2005-01-01

    Conclusão: Estratégias diagnósticas, preventivas e, eventualmente, terapêuticas de osteoporose devem ser empregadas precocemente em pacientes com câncer de mama tratadas com inibidores da aromatase

  10. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    International Nuclear Information System (INIS)

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor (11C)vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in (11C)vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  11. Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.-W.; Logan, J.; Hooker, J.M.; Muench, L.; Fowler, J.S.

    2010-01-12

    Cigarette smoking and nicotine have complex effects on human physiology and behavior, including some effects similar to those elicited by inhibition of aromatase, the last enzyme in estrogen biosynthesis. We report the first in vivo primate study to determine whether there is a direct effect of nicotine administration on brain aromatase. Brain aromatase availability was examined with positron emission tomography and the selective aromatase inhibitor [{sup 11}C]vorozole in six baboons before and after exposure to IV nicotine at .015 and .03 mg/kg. Nicotine administration produced significant, dose-dependent reductions in [{sup 11}C]vorozole binding. The amygdala and preoptic area showed the largest reductions. Plasma levels of nicotine and its major metabolite cotinine were similar to those found in cigarette smokers. Nicotine interacts in vivo with primate brain aromatase in regions involved in mood, aggression, and sexual behavior.

  12. Expression and clinical significance of genes frequently mutated in small cell lung cancers defined by whole exome/RNA sequencing

    OpenAIRE

    Iwakawa, Reika; Kohno, Takashi; Totoki, Yasushi; Shibata, Tatsuhiro; Tsuchihara, Katsuya; Mimaki, Sachiyo; Tsuta, Koji; NARITA, Yoshitaka; Nishikawa, Ryo; Noguchi, Masayuki; Harris, Curtis C.; Robles, Ana I.; Yamaguchi, Rui; Imoto, Seiya; Miyano, Satoru

    2015-01-01

    We identified the TMEM132D, SPTA1 and VPS13B genes as frequently mutated and expressed in any progression stage of SCLC, in addition to known tumor suppressor genes, TP53, RB1 and PTEN. These genes could be involved in SCLC development, and their mutated gene products will be promising therapeutic targets in SCLC patients.

  13. Characterization of a Defined 2,3,5,6-Tetrachlorobiphenyl-ortho-Dechlorinating Microbial Community by Comparative Sequence Analysis of Genes Coding for 16S rRNA

    OpenAIRE

    Pulliam Holoman, Tracey R; Elberson, Margaret A.; Cutter, Leah A.; May, Harold D.; Sowers, Kevin R.

    1998-01-01

    Defined microbial communities were developed by combining selective enrichment with molecular monitoring of total community genes coding for 16S rRNAs (16S rDNAs) to identify potential polychlorinated biphenyl (PCB)-dechlorinating anaerobes that ortho dechlorinate 2,3,5,6-tetrachlorobiphenyl. In enrichment cultures that contained a defined estuarine medium, three fatty acids, and sterile sediment, a Clostridium sp. was predominant in the absence of added PCB, but undescribed species in the δ ...

  14. Analysis of gene expression patterns by microarray hybridization in blood mononuclear cells of SLA-DRB1 defined Canadian Yorkshire pigs

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    Bridle Byram

    2008-06-01

    Full Text Available Abstract Background The Swine Leukocyte Antigen (SLA system encodes molecules for self-nonself discrimination and is associated with immune responses and disease resistance. Three lines of pigs defined by their SLA-DRB1 alleles were developed at the University of Guelph for xenotransplantation and immune response studies. The aim of this project was to explore the potential association between defined SLA-DRB1 alleles and gene transcriptional patterns of other immune-related genes in blood mononuclear cells. Findings Three SLA-DRB1 alleles were characterized using a RT-PCR-based sequencing method. The loci represented included a new allele, DRB1*04ns01. Next, microarray heterologous (bovine-porcine hybridization together with qPCR were used to explore differential gene expression between SLA-DRB1-defined groups. Microarray analysis showed significant (p Conclusion A new SLA-DRB1 allele was characterized. A potential association was found between SLA-DRB1 alleles and inflammation-related genes. However, the influence of other genes cannot be ruled out. These preliminary findings agree with other studies linking MHC haplotypes and inflammation processes, including autoimmune disease. The study provides an initial view of the biological interactions between the SLA complex and other immune-related genes. Future studies will focus on characterization of SLA-haplotypes associated with these particular alleles and the dynamics of the immune response to antigenic challenges.

  15. Aromatase inhibitors in the treatment of deep endometriosis

    Directory of Open Access Journals (Sweden)

    Simone Ferrero

    2009-09-01

    Full Text Available Recent case reports and pilot studies suggested that aromatase inhibitors might be effective in treating pain symptoms related to the presence of endometriosis. We present the case of a 32-year-old woman who suffered dysmenorrhea, dyspareunia, chronic pelvic pain, and dyschezia caused by rectovaginal endometriosis. Pain symptoms recurred after treatment with the oral contraceptive pill; the patient refused surgery. Therefore a double-drug regimen including letrozole (2.5 mg/day and norethisterone acetate (2.5 mg/day was offered to the patient. The scheduled length of treatment was six months. This double-drug regimen determined a quick and significant improvement in all pain symptoms. During treatment, the patient complained mild arthralgia. After the interruption of treatment, pain symptoms quickly recurred and at 6-month follow-up their intensity was similar to baseline values. Operative laparoscopy was performed, the presence of rectovaginal endometriosis was confirmed and all visible endometriotic lesions were excised. Aromatase inhibitors might be offered when pain symptoms caused by endometriosis persist during the administration of other hormonal therapies and the patient refuses surgery. However, women must be informed that these drugs determine only a temporary relief of pain symptoms and might cause adverse effects (such as arthralgia.

  16. Activity, reconstitution, and accumulation of nitrogenase components in Azotobacter vinelandii mutant strains containing defined deletions within the nitrogenase structural gene cluster.

    OpenAIRE

    Robinson, A. C.; Burgess, B. K.; Dean, D R

    1986-01-01

    The Azotobacter vinelandii genes encoding the nitrogenase structural components are clustered and ordered: nifH (Fe protein)-nifD (MoFe protein alpha subunit)-nifK (MoFe protein beta subunit). In this study various A. vinelandii mutant strains which contain defined deletions within the nitrogenase structural genes were isolated and studied. Mutants deleted for the nifD or nifK genes were still able to accumulate significant amounts of the unaltered MoFe protein subunit as well as active Fe pr...

  17. The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth.

    OpenAIRE

    Zhan, Q.; Lord, K A; Alamo, I; Hollander, M C; Carrier, F.; Ron, D; KOHN, K. W.; Hoffman, B; Liebermann, D A; Fornace, A J

    1994-01-01

    A remarkable overlap was observed between the gadd genes, a group of often coordinately expressed genes that are induced by genotoxic stress and certain other growth arrest signals, and the MyD genes, a set of myeloid differentiation primary response genes. The MyD116 gene was found to be the murine homolog of the hamster gadd34 gene, whereas MyD118 and gadd45 were found to represent two separate but closely related genes. Furthermore, gadd34/MyD116, gadd45, MyD118, and gadd153 encode acidic ...

  18. Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer.

    Science.gov (United States)

    Abdalla, Mohamed M; Al-Omar, Mohamed A; Bhat, Mashooq A; Amr, Abdel-Galil E; Al-Mohizea, Abdullah M

    2012-05-01

    The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone(®)). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC(50) of 80 μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer. PMID:22361454

  19. The iron/heme regulated genes of Haemophilus influenzae: comparative transcriptional profiling as a tool to define the species core modulon

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    Morton Daniel J

    2009-01-01

    Full Text Available Abstract Background Haemophilus influenzae requires heme for aerobic growth and possesses multiple mechanisms to obtain this essential nutrient. Although an understanding of the heme acquisition mechanisms of H. influenzae is emerging, significant gaps in our knowledge remain. Unresolved issues include the identities of all genes exhibiting altered transcription in response to iron and heme availability, the fraction of such genes functioning in iron/heme acquisition, and the heterogeneity of this gene set among clinical isolates. Previously we utilized H. influenzae strain Rd KW20 to demonstrate the utility of transcriptional profiling in defining the genes exhibiting altered transcription in response to environmental iron and heme levels. The current study expands upon those observations by determining the iron/heme modulons of two clinical isolates, the type b isolate 10810 and the nontypeable isolate R2866. These data are used to begin to define the core iron/heme modulon of the species. Results Microarray studies were performed to compare gene expression on transition from iron/heme-restricted to iron/heme-replete conditions for each isolate. Of 1820 ORFs on the array corresponding to R2866 genes, 363 were significantly differentially expressed: 233 were maximally transcribed under iron/heme-replete conditions and 130 under iron/heme-restricted conditions. Of the 1883 ORFs representing genes of strain 10810, 353 were significantly differentially transcribed: 150 were preferentially transcribed under iron/heme-replete conditions and 203 under iron/heme-restricted conditions. Comparison of the data sets indicated that 163 genes exhibited similar regulation in both isolates and that 74 of these exhibited similar patterns of regulation in Rd KW20. These comprise the putative core iron/heme modulon. Conclusion This study provides evidence for a conserved core of H. influenzae genes the transcription of which is altered by the availability of

  20. Potential role of aromatase inhibitors in the treatment of endometriosis

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    Abu Hashim H

    2014-07-01

    Full Text Available Hatem Abu HashimDepartment of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, EgyptAbstract: Endometriosis is an estrogen-dependent chronic inflammatory disease affecting 5%–10% of reproductive-age women, with a prevalence of 5%–50% in infertile women and >33% of women with chronic pelvic pain. Third-generation aromatase inhibitors (AIs are approved adjuvants for the treatment of estrogen receptor-positive breast cancer. Molecular studies have revealed the presence of aromatase P450, the key enzyme in the biosynthesis of ovarian estradiol, inside the endometriotic tissue, indicating local synthesis of estradiol. Thereby, AIs represent an appealing medical option for the management of different aspects of this enigmatic disease, especially pelvic pain and infertility. Accordingly, this review aims to evaluate the potential role of AIs in the treatment of endometriosis-associated symptoms, mainly pain and infertility. Notably, several studies have demonstrated that the combination of AIs with conventional therapy as oral contraceptive pills, progestins, or gonadotropin-releasing hormone analogs can be used to control endometriosis-associated pain and pain recurrence in premenopausal women, particularly those with pain due to rectovaginal endometriosis refractory to other medical or surgical treatment. Some case reports have shown promising results in the treatment of postmenopausal endometriosis as first-line treatment, when surgery is contraindicated, or as second-line treatment in the case of postoperative recurrence. Third-generation AIs, especially letrozole, have challenged clomiphene citrate as an ovulation-induction agent in patients with polycystic ovary syndrome and in cases of unexplained infertility. However, few studies are available regarding the use of AIs to treat endometriosis-associated infertility. Therefore, larger multicenter randomized trials using AIs for the treatment of endometriosis

  1. Hepatic transcriptome analysis of hepatitis C virus infection in chimpanzees defines unique gene expression patterns associated with viral clearance.

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    Santosh Nanda

    Full Text Available Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3 and cytotoxic granule-associated RNA binding protein (TIA1, associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a "danger signal" leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection.

  2. Sequential waves of gene expression in patients with clinically defined dengue illnesses reveal subtle disease phases and predict disease severity.

    Directory of Open Access Journals (Sweden)

    Peifang Sun

    Full Text Available BACKGROUND: Dengue virus (DENV infection can range in severity from mild dengue fever (DF to severe dengue hemorrhagic fever (DHF or dengue shock syndrome (DSS. Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51 and DHF (n = 13 from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the "early" group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0-1 and declined on day 3-4; the second "late" group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5-6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0-3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1. CONCLUSIONS/SIGNIFICANCE: Our study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1-3 may have

  3. Gene expression profiling of mouse p53-deficient epidermal carcinoma defines molecular determinants of human cancer malignancy

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    Buitrago-Pérez Águeda

    2010-07-01

    Full Text Available Abstract Background The epidermal specific ablation of Trp53 gene leads to the spontaneous development of aggressive tumors in mice through a process that is accelerated by the simultaneous ablation of Rb gene. Since alterations of p53-dependent pathway are common hallmarks of aggressive, poor prognostic human cancers, these mouse models can recapitulate the molecular features of some of these human malignancies. Results To evaluate this possibility, gene expression microarray analysis was performed in mouse samples. The mouse tumors display increased expression of cell cycle and chromosomal instability associated genes. Remarkably, they are also enriched in human embryonic stem cell gene signatures, a characteristic feature of human aggressive tumors. Using cross-species comparison and meta-analytical approaches, we also observed that spontaneous mouse tumors display robust similarities with gene expression profiles of human tumors bearing mutated TP53, or displaying poor prognostic outcome, from multiple body tissues. We have obtained a 20-gene signature whose genes are overexpressed in mouse tumors and can identify human tumors with poor outcome from breast cancer, astrocytoma and multiple myeloma. This signature was consistently overexpressed in additional mouse tumors using microarray analysis. Two of the genes of this signature, AURKA and UBE2C, were validated in human breast and cervical cancer as potential biomarkers of malignancy. Conclusions Our analyses demonstrate that these mouse models are promising preclinical tools aimed to search for malignancy biomarkers and to test targeted therapies of prospective use in human aggressive tumors and/or with p53 mutation or inactivation.

  4. ORGAN BOUNDARY1 defines a gene expressed at the junction between the shoot apical meristem and lateral organs

    OpenAIRE

    Cho, Euna; Zambryski, Patricia C.

    2011-01-01

    We identify a gene, ORGAN BOUNDARY1 (OBO1), by its unique pattern of enhancer- driven GFP expression at the boundaries between the apical meristems and lateral organs in Arabidopsis embryos, seedlings, and mature plants. OBO1 also is expressed at the root apical meristem and in distinct cell files surrounding this area. OBO1 is one of a 10-member plant-specific gene family encoding a single small domain (133 amino acids) with unknown function. One member of this gene family, OBO2, is identica...

  5. Fuzzy tandem repeats containing p53 response elements may define species-specific p53 target genes.

    Directory of Open Access Journals (Sweden)

    Iva Simeonova

    2012-06-01

    Full Text Available Evolutionary forces that shape regulatory networks remain poorly understood. In mammals, the Rb pathway is a classic example of species-specific gene regulation, as a germline mutation in one Rb allele promotes retinoblastoma in humans, but not in mice. Here we show that p53 transactivates the Retinoblastoma-like 2 (Rbl2 gene to produce p130 in murine, but not human, cells. We found intronic fuzzy tandem repeats containing perfect p53 response elements to be important for this regulation. We next identified two other murine genes regulated by p53 via fuzzy tandem repeats: Ncoa1 and Klhl26. The repeats are poorly conserved in evolution, and the p53-dependent regulation of the murine genes is lost in humans. Our results indicate a role for the rapid evolution of tandem repeats in shaping differences in p53 regulatory networks between mammalian species.

  6. Expression and clinical significance of genes frequently mutated in small cell lung cancers defined by whole exome/RNA sequencing.

    Science.gov (United States)

    Iwakawa, Reika; Kohno, Takashi; Totoki, Yasushi; Shibata, Tatsuhiro; Tsuchihara, Katsuya; Mimaki, Sachiyo; Tsuta, Koji; Narita, Yoshitaka; Nishikawa, Ryo; Noguchi, Masayuki; Harris, Curtis C; Robles, Ana I; Yamaguchi, Rui; Imoto, Seiya; Miyano, Satoru; Totsuka, Hirohiko; Yoshida, Teruhiko; Yokota, Jun

    2015-06-01

    Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Only 15% of SCLC patients survive beyond 2 years after diagnosis. Therefore, for the improvement of patients' outcome in this disease, it is necessary to identify genetic alterations applicable as therapeutic targets in SCLC cells. The purpose of this study is the identification of genes frequently mutated and expressed in SCLCs that will be targetable for therapy of SCLC patients. Exome sequencing was performed in 28 primary tumors and 16 metastatic tumors from 38 patients with SCLCs. Expression of mutant alleles was verified in 19 cases by RNA sequencing. TP53, RB1 and PTEN were identified as being significantly mutated genes. Additional 36 genes were identified as being frequently (≥10%) mutated in SCLCs by combining the results of this study and two recent studies. Mutated alleles were expressed in 8 of the 36 genes, TMEM132D, SPTA1, VPS13B, CSMD2, ANK2, ASTN1, ASPM and FBN3. In particular, the TMEM132D, SPTA1 and VPS13B genes were commonly mutated in both early and late stage tumors, primary tumors and metastases, and tumors before and after chemotherapy, as in the case of the TP53 and RB1 genes. Therefore, in addition to TP53, RB1 and PTEN, TMEM132D, SPTA1 and VPS13B could be also involved in SCLC development, with the products from their mutated alleles being potential therapeutic targets in SCLC patients. PMID:25863124

  7. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    OpenAIRE

    JacquesBalthazart; NobuhiroHarada; AnneT.M.Konkle; CornelliaVoigt; GregoryFBall

    2011-01-01

    Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months), brain aromatase activity and transcription are markedly (4-6 fold) increased by genomic actions of se...

  8. Correlation between aromatase expression in the eutopic endometrium of symptomatic patients and the presence of endometriosis

    Directory of Open Access Journals (Sweden)

    Maia Jr H

    2012-02-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1,2, Julio Casoy11CEPARH, 2Itaigara Memorial Day Hospital, Salvador, Bahia, BrazilObjective: To investigate whether aromatase expression in the eutopic endometrium correlates with the presence and severity of endometriosis in patients with infertility and/or dysmenorrhea undergoing laparoscopy and hysteroscopy.Patients: The study involved 106 patients of reproductive age with symptoms of dysmenorrhea and infertility. Sixteen endometriosis-free asymptomatic patients were used as a control group.Methods: Concomitant laparoscopy and hysteroscopy was carried out in all cases. An endometrial biopsy was taken to determine aromatase p450 expression by immunohistochemistry. Endometriosis was staged according to the American Society of Reproductive Medicine classification.Results: Endometriosis was diagnosed by laparoscopy in 92/106 symptomatic patients. In this group, aromatase expression was detected in the eutopic endometrium of 66/92 patients with endometriosis (72% and in 13/14 (95% patients in the symptomatic, endometriosis-free group (P = 0.09. Aromatase expression was not detected in any patients from the control group. In the endometriosis group, aromatase expression was detected in the eutopic endometrium of 28/45 patients (62% with American Society of Reproductive Medicine classification stage 1 of the disease, in 11/14 patients (78% with stage II, 14/20 patients (70% with stage III, and in 12/13 patients (92% with stage IV; however, the difference was only statistically significant between stages I and IV (P = 0.04.Conclusion: Aromatase expression in the endometrium was associated with the presence of dysmenorrhea and infertility irrespective of the presence of endometriosis. When endometriosis was present, however, there was a tendency for aromatase expression to be positively correlated with dysmenorrhea severity.Keywords: aromatase, endometrium, endometriosis, Cox-2, dysmenorrhea

  9. Aromatase inhibitors in breast cancer: the discovery of new computational design and biochemical evaluation

    OpenAIRE

    Neves, Marco André Coelho das

    2009-01-01

    Continuous exposure to high levels of endogenous estrogens is associated with increased risks of developing breast cancer. In this sense, aromatase, the cytochrome P450 enzyme involved in the conversion of androgens, testosterone and androstenedione, into estrogens, estradiol and estrone, is an important target for the endocrine treatment of breast cancer in postmenopausal women. Aromatase inhibition is achieved either with compounds structurally related to the androstenedio...

  10. Acute Stress Differentially Affects Aromatase Activity in Specific Brain Nuclei of Adult Male and Female Quail

    OpenAIRE

    Dickens, Molly J; Cornil, Charlotte; Balthazart, Jacques

    2011-01-01

    The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic level is poorly understood. The enzyme aromatase converts testosterone to estradiol in the brain to activate reproductive behavior in male Japanese quail (Coturnix japonica). The discovery of rapid and reversible modification of aromatase activity (AA) provides a potential mechanism for fast, s...

  11. Two aromatase inhibitors inhibit the ability of a third to promote mating in male rats.

    Science.gov (United States)

    Yahr, Pauline

    2015-09-01

    Aromatase, the enzyme that aromatizes androstenedione (A) to estrone and testosterone (T) to estradiol (E), affects androgen control of male sex behavior in many vertebrates. In male monkeys, rats and quail, E mimics the ability of T to promote mating, and aromatase inhibitors block mating induced by T but not E. Aromatase inhibitors include androgens with different A-rings than T and A, e.g., 1,4,6-androstatriene-3,17-dione (ATD), azoles, e.g., fadrozole, and androgens α-halogenated at carbon 6, e.g., 6α-bromoA, 6α-fluoroA and 6α-fluoroT. 6α-FluoroT is the only 6α-halogenated androgen studied in regard to mating. It promotes mating in male rats and quail and was studied, before it was known to inhibit aromatase, because it cannot be aromatized yet has the same A-ring as T. 6α-FluoroT might promote mating by binding estrogen receptors (ER) directly, i.e., unassisted, or by metabolism to an androgen that binds ER. Since neither process would require aromatase, this study tested both hypotheses by determining how mating induced in castrated male rats by 6α-fluoroT is affected by ATD and fadrozole. Both aromatase inhibitors inhibited the effects of 6α-fluoroT on mating. Thus, 6α-fluoroT does not promote mating by direct ER binding or metabolism to another androgen. Since aromatase underlies a process in which 6α-fluoroT, unlike most nonaromatizable androgens, mimics T effects on male sex behavior, the process must involve a feature that 6α-fluoroT shares with T but not other nonaromatizable androgens. A-ring structure is a candidate. A hypothesis is also offered for how aromatase may participate without aromatizing the androgen. PMID:26232614

  12. A feasibility study of a Nordic walking intervention for women experiencing aromatase inhibitor associated arthralgia

    OpenAIRE

    Fields, Jo

    2015-01-01

    Background: Women taking AIs (Aromatase Inhibitors) as treatment for breast cancer commonly experience joint pain and stiffness (aromatase inhibitor associated arthralgia; AIAA) which can lead to early discontinuation of treatment. Exercise is often recommended and there is preliminary evidence it might prove helpful. Nordic Walking is a popular form of exercise in women with breast cancer, and based on a biopsychosocial model, could provide additional benefits over normal walking alone. Ther...

  13. Bilateral de quervain syndrome after aromatase inhibitor administration: a case report and review of the literature.

    Science.gov (United States)

    Papadimitriou, Konstantinos; Kountourakis, Panteleimon; Morakis, Emmanouil; Vassiliou, Vassilios; Barbounis, Vasileios; Ardavanis, Alexandros

    2012-01-01

    Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs), and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of the relevant literature. PMID:22567020

  14. Bilateral De Quervain Syndrome after Aromatase Inhibitor Administration: A Case Report and Review of the Literature

    OpenAIRE

    Vasileios Barbounis; Vassilios Vassiliou; Emmanouil Morakis; Panteleimon Kountourakis; Konstantinos Papadimitriou; Alexandros Ardavanis

    2012-01-01

    Aromatase inhibitors are widely used as one of the main treatment options of both early and advanced hormone receptor-positive breast cancer in postmenopausal women. Unfortunately, musculoskeletal symptoms are often presented in patients treated with aromatase inhibitors (AIs), and, although the pathogenesis is unknown, postulated mechanisms have been described. Herein, to our knowledge, we present the first report of bilateral De Quervain syndrome related with AIs therapy with a review of th...

  15. Effects of aromatase inhibition on spatial working memory and hippocampal astrocyte numbers

    OpenAIRE

    José I. Arias; Héctor González-Pardo; Nélida M. Conejo; Jorge L. Arias

    2012-01-01

    Sex hormones are known to induce the sexual differentiation of the brain during early development in mammals. Testosterone secreted by males already during gestation is classically believed to contribute to brain and behavioural sexual differentiation thanks to its conversion to estradiol by the enzyme aromatase. However, there is evidence suggesting that aromatase inhibition may also impair cognitive functions in women receiving hormonal treatment for breast cancer. In order to evaluate the ...

  16. Neoplastic and stromal cells contribute to an extracellular matrix gene expression profile defining a breast cancer subtype likely to progress.

    Directory of Open Access Journals (Sweden)

    Tiziana Triulzi

    Full Text Available We recently showed that differential expression of extracellular matrix (ECM genes delineates four subgroups of breast carcinomas (ECM1, -2, -3- and -4 with different clinical outcome. To further investigate the characteristics of ECM signature and its impact on tumor progression, we conducted unsupervised clustering analyses in 6 additional independent datasets of invasive breast tumors from different platforms for a total of 643 samples. Use of four different clustering algorithms identified ECM3 tumors as an independent group in all datasets tested. ECM3 showed a homogeneous gene pattern, consisting of 58 genes encoding 43 structural ECM proteins. From 26 to 41% of the cases were ECM3-enriched, and analysis of datasets relevant to gene expression in neoplastic or corresponding stromal cells showed that both stromal and breast carcinoma cells can coordinately express ECM3 genes. In in vitro experiments, β-estradiol induced ECM3 gene production in ER-positive breast carcinoma cell lines, whereas TGFβ induced upregulation of the genes leading to ECM3 gene classification, especially in ER-negative breast carcinoma cells and in fibroblasts. Multivariate analysis of distant metastasis-free survival in untreated breast tumor patients revealed a significant interaction between ECM3 and histological grade (p = 0.001. Cox models, estimated separately in grade I-II and grade III tumors, indicated a highly significant association between ECM3 and worse survival probability only in grade III tumors (HR = 3.0, 95% CI = 1.3-7.0, p = 0.0098. Gene Set Enrichment analysis of ECM3 compared to non-ECM3 tumors revealed significant enrichment of epithelial-mesenchymal transition (EMT genes in both grade I-II and grade III subsets of ECM3 tumors. Thus, ECM3 is a robust cluster that identifies breast carcinomas with EMT features but with accelerated metastatic potential only in the undifferentiated (grade III phenotype. These findings support the

  17. Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury.

    Directory of Open Access Journals (Sweden)

    Manoj Bhasin

    Full Text Available Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC and medial smooth muscle cells (SMC from canine vein grafts, 2 hours (H to 30 days (D following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12-24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-κB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM-1 signaling, as well as PPARα activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1α, and Insulin Receptor (INSR as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1, a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention.

  18. Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design

    OpenAIRE

    Mirzaie, Sako; Chupani, Latifeh; Asadabadi, Ebrahim Barzegari; Shahverdi, Ahmad Reza; Jamalan, Mostafa

    2013-01-01

    Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromata...

  19. Simultaneous determination of gene expression and bacterial identity in single cells in defined mixtures of pure cultures

    DEFF Research Database (Denmark)

    Poulsen, Lars K.; Dalton, Helen M.; Angels, Mark; Marshall, Kevin C.; Molin, Søren; Goodman, Amanda E.

    1997-01-01

    A protocol was developed to achieve the simultaneous determination of gene expression and bacterial identity at the level of single cells: a chromogenic beta-galactosidase activity assay was combined with in situ hybridization of Fluorescently labelled oligonucleotide probes to rRNA. The method a...

  20. Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian microsomes by various environmental substances.

    Science.gov (United States)

    Hinfray, Nathalie; Porcher, Jean-Marc; Brion, François

    2006-11-01

    Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high microM range depending on the substance: steroidal and non steroidal inhibitors of aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal aromatase assay is suitable for evaluating potential aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish. PMID:17081805

  1. Well-defined Block Copolymers for Gene Delivery to Dendritic Cells: Probing the Effect of Polycation Chain-length

    OpenAIRE

    Tang, Rupei; Palumbo, R. Noelle; Nagarajan, Lakshmi; Krogstad, Emily; Wang, Chun

    2009-01-01

    The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the in...

  2. CREB Targets Define the Gene Expression Signature of Malignancies Having Reduced Levels of the Tumor Suppressor Tristetraprolin

    OpenAIRE

    Mohammad Fallahi; Amelio, Antonio L.; Cleveland, John L.; Rounbehler, Robert J.

    2014-01-01

    The RNA-binding protein Tristetraprolin (TTP, ZFP36) functions as a tumor suppressor that impairs the development and disables the maintenance of MYC-driven lymphoma. In addition, other human cancers expressed reduced levels of TTP, suggesting that it may function as a tumor suppressor in several malignancies. To identify genes that may be associated with TTP tumor suppressor functions in human cancer, we analyzed The Cancer Genome Atlas (TCGA) breast cancer, lung adenocarcinoma, lung squamou...

  3. Defining the robust behaviour of the plant clock gene circuit with absolute RNA timeseries and open infrastructure.

    Science.gov (United States)

    Flis, Anna; Fernández, Aurora Piñas; Zielinski, Tomasz; Mengin, Virginie; Sulpice, Ronan; Stratford, Kevin; Hume, Alastair; Pokhilko, Alexandra; Southern, Megan M; Seaton, Daniel D; McWatters, Harriet G; Stitt, Mark; Halliday, Karen J; Millar, Andrew J

    2015-10-01

    Our understanding of the complex, transcriptional feedback loops in the circadian clock mechanism has depended upon quantitative, timeseries data from disparate sources. We measure clock gene RNA profiles in Arabidopsis thaliana seedlings, grown with or without exogenous sucrose, or in soil-grown plants and in wild-type and mutant backgrounds. The RNA profiles were strikingly robust across the experimental conditions, so current mathematical models are likely to be broadly applicable in leaf tissue. In addition to providing reference data, unexpected behaviours included co-expression of PRR9 and ELF4, and regulation of PRR5 by GI. Absolute RNA quantification revealed low levels of PRR9 transcripts (peak approx. 50 copies cell(-1)) compared with other clock genes, and threefold higher levels of LHY RNA (more than 1500 copies cell(-1)) than of its close relative CCA1. The data are disseminated from BioDare, an online repository for focused timeseries data, which is expected to benefit mechanistic modelling. One data subset successfully constrained clock gene expression in a complex model, using publicly available software on parallel computers, without expert tuning or programming. We outline the empirical and mathematical justification for data aggregation in understanding highly interconnected, dynamic networks such as the clock, and the observed design constraints on the resources required to make this approach widely accessible. PMID:26468131

  4. Comprehensive analysis of cytokine gene polymorphisms defines the association of IL-12 gene with ophthalmopthy in Korean children with autoimmune thyroid disease.

    Science.gov (United States)

    Jang, Jung-Pil; Cho, Won-Kyoung; Baek, In-Cheol; Choi, Eun-Jeong; Shin, Dong-Hwan; Suh, Byung-Kyu; Kim, Tai-Gyu

    2016-05-01

    In early onset autoimmune thyroid disease (AITD) showing a strong genetic tendency, cytokines have been suggested to play a critical role in the development of AITD. To directly compare the influences of several cytokine gene polymorphisms, 25 single nucleotide polymorphisms (SNPs) in 17 cytokine genes were analyzed on 104 Korean children with AITD [Hashimoto's disease (HD) = 44, Graves' disease (GD) = 60 (thyroid-associated ophthalmopathy (TAO) = 29, non-TAO = 31)] and 192 controls. Compared with healthy controls, any significant association with polymorphisms of cytokine genes was not found in HD and GD. Among GD patients, non-TAO group only showed significant associations with IL-12 C allele (rs3212227: A > C) (76.6% vs. 51.6%, OR = 0.3 [0.15-0.71], Pc = 0.007). Particularly, the frequency of IL-12C allele was significantly lower in the non-TAO group than in the TAO group (82.8% vs. 51.6%, Pc = 0.018). Our comprehensive analysis of cytokine gene polymorphisms suggests that IL-12 gene may play impact on specific pathogenesis of ophthalmopathy in Korean children with AITD. PMID:26850223

  5. Zbtb20 Defines a Hippocampal Neuronal Identity Through Direct Repression of Genes That Control Projection Neuron Development in the Isocortex

    DEFF Research Database (Denmark)

    Nielsen, Jakob V; Thomassen, Mads; Møllgård, Kjeld; Noraberg, Jens; Jensen, Niels A

    2014-01-01

    Hippocampal pyramidal neurons are important for encoding and retrieval of spatial maps and episodic memories. While previous work has shown that Zbtb20 is a cell fate determinant for CA1 pyramidal neurons, the regulatory mechanisms governing this process are not known. In this study, we demonstrate...... data reveal a novel regulatory mechanism by which Zbtb20 suppresses the acquisition of an isocortical fate during archicortical neurogenesis to ensure commitment to a CA1 pyramidal neuron fate. We further show that the expression pattern of Zbtb20 is evolutionary conserved in the fetal human...... hippocampus, where it is complementary to the expression pattern of the Zbtb20 target gene Tbr1. Therefore, the disclosed Zbtb20-mediated transcriptional repressor mechanism may be involved in development of the human archicortex....

  6. Heterogeneous EGFR gene copy number increase is common in colorectal cancer and defines response to anti-EGFR therapy.

    Science.gov (United States)

    Ålgars, Annika; Avoranta, Tuulia; Österlund, Pia; Lintunen, Minnamaija; Sundström, Jari; Jokilehto, Terhi; Ristimäki, Ari; Ristamäki, Raija; Carpén, Olli

    2014-01-01

    Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12-0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC. PMID:24940619

  7. Heterogeneous EGFR Gene Copy Number Increase Is Common in Colorectal Cancer and Defines Response to Anti-EGFR Therapy

    Science.gov (United States)

    Ålgars, Annika; Lintunen, Minnamaija; Sundström, Jari; Jokilehto, Terhi; Ristimäki, Ari; Ristamäki, Raija; Carpén, Olli

    2014-01-01

    Anti-EGFR therapy is commonly used to treat colorectal cancer (CRC), although only a subset of patients benefit from the treatment. While KRAS mutation predicts non-responsiveness, positive predictive markers are not in clinical practice. We previously showed that immunohistochemistry (IHC)-guided EGFR gene copy number (GCN) analysis may identify CRC patients benefiting from anti-EGFR treatment. Here we tested the predictive value of such analysis in chemorefractory metastatic CRC, elucidated EGFR GCN heterogeneity within the tumors, and evaluated the association between EGFR GCN, KRAS status, and anti-EGFR antibody response in CRC cell lines. The chemorefractory patient cohort consisted of 54 KRAS wild-type (WT) metastatic CRC patients. EGFR GCN status was analyzed by silver in situ hybridization using a cut-off value of 4.0 EGFR gene copies/cell. KRAS-WT and KRAS mutant CRC cell lines with different EGFR GCN were used in in vitro studies. The chemorefractory CRC tumors with EGFR GCN increase (≥4.0) responded better to anti-EGFR therapy than EGFR GCN (<4.0) tumors (clinical benefit, P = 0.0004; PFS, HR = 0.23, 95% CI 0.12–0.46). EGFR GCN counted using EGFR IHC guidance was significantly higher than the value from randomly selected areas verifying intratumoral EGFR GCN heterogeneity. In CRC cell lines, EGFR GCN correlated with EGFR expression. Best anti-EGFR response was seen with KRAS-WT, EGFR GCN = 4 cells and poorest response with KRAS-WT, EGFR GCN = 2 cells. Anti-EGFR response was associated with AKT and ERK1/2 phosphorylation, which was effectively inhibited only in cells with KRAS-WT and increased EGFR GCN. In conclusion, IHC-guided EGFR GCN is a promising predictor of anti-EGFR treatment efficacy in chemorefractory CRC. PMID:24940619

  8. Purification of human placental aromatase cytochrome P-450 with monoclonal antibody and its characterization

    International Nuclear Information System (INIS)

    A simple and efficient method is described for the purification of microsomal aromatase cytochrome P-450 from human placenta. The enzyme was solubilized with Emulgen 913 and sodium cholate and subjected to chromatography on a column of Sepharose 4B couples with a specific monoclonal antibody, followed by hydroxyapatite column chromatography. The specific cytochrome P-450 content of purified aromatase was 13.1 (12-14.8) nmol/mg of protein. Aromatase assays were carried out with reconstituted systems of bovine liver P-450 reductase and dilauroyl-L-α-phosphatidylcholine with [1β-3H,4-14C]androstenedione as substrate. The total recovery of purified aromatase activity was 32.2%, and P-450 recovery was 17.6%. The very high Km value for 16α-hydroxytestosterone aromatization gives a reasonable indication that estriol is not the directly aromatized product in the fetoplacental unit of human pregnancy. The aromatase P-450 was subjected to SDS-polyacrylamide gel electrophoresis in increasing quantities. Silver stain detection techniques indicated a single band having a molecular mass of 55 kDa with greater than 97% purity. The stability analysis showed a half-life of over 4 years on storage at -80C

  9. Defining essential genes and identifying virulence factors of Porphyromonas gingivalis by massively-parallel sequencing of transposon libraries (Tn-seq)

    Science.gov (United States)

    Klein, Brian A.; Duncan, Margaret J.; Hu, Linden T.

    2016-01-01

    Summary Porphyromonas gingivalis is a keystone pathogen in the development and progression of periodontal disease. Obstacles to the development of saturated transposon libraries have previously limited transposon mutant-based screens as well as essential gene studies. We have developed a system for efficient transposon mutagenesis of P. gingivalis using a modified mariner transposon. Tn-seq is a technique that allows for quantitative assessment of individual mutants within a transposon mutant library by sequencing the transposon-genome junctions and then compiling mutant presence by mapping to a base genome. Using Tn-seq, it is possible to quickly define all the insertional mutants in a library and thus identify non-essential genes under the conditions in which the library was produced. Identification of fitness of individual mutants under specific conditions can be performed by exposing the library to selective pressures. PMID:25636611

  10. Screening of selected pesticides for inhibition of CYP19 aromatase activity in vitro

    DEFF Research Database (Denmark)

    Vinggaard, A.M.; Hnida, C.; Breinholt, V.;

    2000-01-01

    Many pesticides are able to block or activate the steroid hormone receptors and/or to affect the levels of sex hormones, thereby potentially affecting the development or expression of the male and female reproductive system or both. This emphasizes the relevance of screening pesticides for a wide...... range of hormone-mimicking effects. Twenty-two pesticides were tested for their ability to affect CYP19 aromatase activity in human placental microsomes using the classical [H-3](2)O method. Prochloraz, imazalil, propioconazole, fenarimol, triadimenol, triadimefon tall fungicides), and dicofol tan...... triadimenol were identified as weak aromatase inhibitors. In conclusion, seven out of 22 tested pesticides turned out to be weak to moderate aromatase inhibitors in vitro, indicating the relevance of elucidating the endocrine effects in vivo of these compounds....

  11. Effects of transferrin on aromatase activity in porcine granulosa cells in vitro.

    Directory of Open Access Journals (Sweden)

    Małgorzata Duda

    2009-01-01

    Full Text Available Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor. Recent studies have reported that transferrin plays a crucial role in the local regulation of ovarian function, apart from its iron-binding characteristic. Therefore, the present study was undertaken to explore the possible role of transferrin in porcine granulosa cells function by examining its influence on aromatase activity, the most important indicator of follicular cell differentiation. In the first series of studies, pig granulosa cells isolated from small, immature follicles were cultured in the presence of transferrin alone (10 microg/ml or 100 microg/ml or with the addition of FSH (100ng/ml. The second series of studies was undertaken to determine transferrin-stimulated granulosa cells ability to aromatize exogenous testosterone (1x10(-7M. One hour after the establishment of cultures an aromatase inhibitor CGS16949A was added to test its influence on estradiol production. After 48 hours, cultures were terminated and cells were processed for immunocytochemical staining of aromatase. Media were frozen for further estradiol level analysis. Positive immunostaining for aromatase was found in all granulosa cell cultures. The intensity of immunostaining was always stronger in cultures supplemented with FSH whereas the addition of transferrin had no effect. Granulosa cells in vitro synthesized the highest amount of estradiol after the addition of FSH and exogenous testosterone as measured radioimmunologically. Concomitant treatment with FSH and transferrin caused an inhibition of FSH-stimulated aromatase activity. The production of estradiol also declined in the presence of FSH, testosterone and transferrin. This study demonstrates that transferrin had a dose-dependent inhibitory effect on FSH-stimulated aromatase activity, which was confirmed by radioimmunoassay. Our results indicate

  12. Are separable aromatase systems involved in hormonal regulation of the male brain

    International Nuclear Information System (INIS)

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells

  13. Are separable aromatase systems involved in hormonal regulation of the male brain

    Energy Technology Data Exchange (ETDEWEB)

    Hutchison, J.B.; Schumacher, M.; Steimer, T.; Gahr, M. (Institute of Animal Physiology, Babraham, Cambridge (England))

    1990-07-01

    In vitro study of testosterone (T) metabolism shows that formation of estradiol-17 beta (E2) is regionally specific within the preoptic area (POA) of the male ring dove. The POA is known to be involved in the formation of E2 required for specific components of male sexual behavior. Two sub-areas of high aromatase activity, anterior (aPOA) and posterior preoptic (pPOA) areas, have been identified. Aromatase activity is higher in aPOA than in pPOA. The aromatase activity within the aPOA is also more sensitive to the inductive effects of low circulating T, derived from subcutaneous silastic implants, than the enzyme activity in pPOA. Kinetic analysis of preoptic fractions indicates that a similar high-affinity enzyme occurs in both areas (apparent Km less than 14 nM), but the Vmax of aPOA enzyme activity is higher than pPOA. Cells containing estrogen receptors (ER) are localized in areas of high aromatase activity. There is overlap between immunostained cells in the aPOA and in samples containing inducible aromatase activity measured in vitro. Within the aPOA there is a higher density of ER cells in the nucleus preopticus medialis. The pPOA area also contains ER, notably in the nucleus interstitialis, but at a lower density. We conclude that the hormonal regulation of the male preoptic-anterior hypothalamic region, which is a target for the behavioral action of T, involves at least two inducible aromatase systems with associated estrogen receptor cells.

  14. Sex differences in brain aromatase activity: genomic and non-genomic controls

    Directory of Open Access Journals (Sweden)

    Jacques eBalthazart

    2011-09-01

    Full Text Available Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months, brain aromatase activity and transcription are markedly (4-6 fold increased by genomic actions of sex steroids. Initial work indicated that the preoptic aromatase activity is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of aromatase activity, immunoreactivity and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. Aromatase activity in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in aromatase activity have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral

  15. Xanthones from the Botanical Dietary Supplement Mangosteen (Garcinia mangostana) with Aromatase Inhibitory Activity

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    Twelve xanthone constituents of the botanical dietary supplement, mangosteen (the pericarp of Garcinia mangostina) were screened using a non-cellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D (3), garcinone E (5)α-mangostin (8), and γ-mangostin (9) exhibited dose-dependent inhibitory activity. In a follow-up cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones was γ-mangosti...

  16. 3H- and 14C-labelling of the aromatase inhibitor ZK 138723

    International Nuclear Information System (INIS)

    It has been known for several years that the growth of certain neoplastic disorders - especially breast cancer in women -depends on the serum level of estrogen. One strategy of lowering the estrogen formation is to inhibit the action of the enzyme aromatase, which catalyzes the final step in estrogen biosynthesis in humans. For this purpose nonsteroidal compounds seem to offer advantages as compared to the classical steroid derivatives regarding intensity and duration of effect as well as selectivity to other cytochrome P450 enzymes. The competitive aromatase inhibitor ZK138723 is such a nonsteroidal compound. It was labelled with 3H and 14C to be used for further pharmacological investigations. (author)

  17. Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons.

    Science.gov (United States)

    Robarge, Jason D; Duarte, Djane B; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A; Vasko, Michael R

    2016-07-01

    Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

  18. Define Project

    DEFF Research Database (Denmark)

    Munk-Madsen, Andreas

    2005-01-01

    "Project" is a key concept in IS management. The word is frequently used in textbooks and standards. Yet we seldom find a precise definition of the concept. This paper discusses how to define the concept of a project. The proposed definition covers both heavily formalized projects and informally...... organized, agile projects. Based on the proposed definition popular existing definitions are discussed....

  19. Molecular simulations of aromatase reveal new insights into the mechanism of ligand binding.

    Science.gov (United States)

    Park, Jiho; Czapla, Luke; Amaro, Rommie E

    2013-08-26

    CYP19A1, also known as aromatase or estrogen synthetase, is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Several clinically used breast cancer therapies target aromatase. In this work, explicitly solvated all-atom molecular dynamics simulations of aromatase with a model of the lipid bilayer and the transmembrane helix are performed. The dynamics of aromatase and the role of titration of an important amino acid residue involved in aromatization of androgens are investigated via two 250-ns long simulations. One simulation treats the protonated form of the catalytic aspartate 309, which appears more consistent with crystallographic data for the active site, while the simulation of the deprotonated form shows some notable conformational shifts. Ensemble-based computational solvent mapping experiments indicate possible novel druggable binding sites that could be utilized by next-generation inhibitors. In addition, the effects of protonation on the ligand positioning and channel dynamics are investigated using geometrical models that estimate the opening width of critical channels. Significant differences in channel dynamics between the protonated and deprotonated trajectories are exhibited, suggesting that the mechanism for substrate and product entry and the aromatization process may be coupled to a "locking" mechanism and channel opening. Our results may be particularly relevant in the design of novel drugs, which may be useful therapeutic treatments of cancers such as those of the breast and prostate. PMID:23927370

  20. A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) | Division of Cancer Prevention

    Science.gov (United States)

    E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with AIs due to the development of musculoskeletal symptoms (MSS). Women with stage 1-111 breast cancer who are prescribed the aromatase inhibitor anastrozole as treatment may join. |

  1. Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination

    International Nuclear Information System (INIS)

    Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 μM (except for TBTO and DES, 10 μM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 μM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment

  2. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Kidd, M. [Wren Laboratories, Branford, CT (United States); Modlin, I.M. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Yale School of Medicine, New Haven, CT (United States); Severi, S.; Nicolini, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Drozdov, I. [Bering Limited, London (United Kingdom); Kwekkeboom, D.J.; Krenning, E.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Erasmus Medical Center, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Zentralklinik Bad Berka, Theranostics Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)

    2016-05-15

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with {sup 177}Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 {sup 18}FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ{sup 2} = 27.4; p = 1.2 x 10{sup -7}) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0

  3. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    International Nuclear Information System (INIS)

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with 177Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 18FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ2 = 27.4; p = 1.2 x 10-7) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0.004) for predicting

  4. EFFECTS OF INCUBATION TEMPERATURE AND ESTROGEN EXPOSURE ON AROMATASE ACTIVITY IN THE BRAIN AND GONADS OF EMBRYONIC ALLIGATORS

    Science.gov (United States)

    During embryogenesis, incubation temperature and the hormonal environment influence gonadal differentiation of some reptiles, including all crocodilians. Current evidence suggests that aromatase, the enzyme that converts androgens to estrogens, has a role in sexual differentiatio...

  5. Effects of Pharmaceuticals Used for Breast Cancer Treatment on Reproduction and Aromatase Activity in a Marine Fish

    Science.gov (United States)

    Laboratory experiments were conducted with the marine fish cunner (Tautogolabrus adspersus) to evaluate whether four pharmaceuticals used in breast cancer treatment have an impact on reproduction or aromatase activity. Tamoxifen binds to estrogen receptors, while anastrozole, let...

  6. Investigation of aromatase inhibitory activity of metal complexes of 8-hydroxyquinoline and uracil derivatives

    Directory of Open Access Journals (Sweden)

    Prachayasittikul V

    2014-08-01

    Full Text Available Veda Prachayasittikul,1 Ratchanok Pingaew,2 Chanin Nantasenamat,3 Supaluk Prachayasittikul,3 Somsak Ruchirawat,4,5 Virapong Prachayasittikul1 1Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 2Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand; 3Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand; 4Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 5Chulabhorn Graduate Institute, Bangkok, Thailand Purpose: Estrogens play important roles in the pathogenesis and progression of breast cancer as well as estrogen-related diseases. Aromatase is a key enzyme in the rate-limiting step of estrogen production, in which its inhibition is one strategy for controlling estrogen levels to improve prognosis of estrogen-related cancers and diseases. Herein, a series of metal (Mn, Cu, and Ni complexes of 8-hydroxyquinoline (8HQ and uracil derivatives (4–9 were investigated for their aromatase inhibitory and cytotoxic activities. Methods: The aromatase inhibition assay was performed according to a Gentest™ kit using CYP19 enzyme, wherein ketoconazole and letrozole were used as reference drugs. The cytotoxicity was tested on normal embryonic lung cells (MRC-5 using 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay. Results: Only Cu complexes (6 and 9 exhibited aromatase inhibitory effect with IC50 0.30 and 1.7 µM, respectively. Cytotoxicity test against MRC-5 cells showed that Mn and Cu complexes (5 and 6, as well as free ligand 8HQ, exhibited activity with IC50 range 0.74–6.27 µM. Conclusion: Cu complexes (6 and 9 were found to act as a novel class of aromatase inhibitor. Our findings suggest that these 8HQ–Cu–uracil complexes are promising agents that could be potentially developed as a selective anticancer agent for breast cancer

  7. Design, synthesis, and biological evaluation of resveratrol analogues as aromatase and quinone reductase 2 inhibitors for chemoprevention of cancer

    International Nuclear Information System (INIS)

    A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC50 0.59 μM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC50 70 nM) and 84 (IC50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC50 of 80 μM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC50 1.7 μM and 0.27 μM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.

  8. Immunocytochemical and biochemical evidence for aromatase in neurons of the retina, optic tectum and retinotectal pathways in goldfish.

    Science.gov (United States)

    Gelinas, D; Callard, G V

    1993-12-01

    Using an animal model in which neural aromatase is apparently overexpressed (the goldfish, Carassius auratus) and an anti-human placental antibody which specifically crossreacts with goldfish brain aromatase, aromatase-immunoreactive neuronal cell bodies and fibers have been localized within the retina. These include a subset of horizontal cells, bipolar cells, and amacrine cells of the inner nuclear layer, some fibers of the outer and inner synaptic layers and certain cells of the ganglion cell layer; photoreceptors were never labeled. Some ganglion cell projections to the brain via the optic nerve and optic tract were aromatase-positive, as were small neurons of the stratum periventriculare (SPV) and fibers of two other strata of the optic tectum. Aromatase activity, as measured by [3H]androgen by tissue homogenates and cell cultures, confirmed the presence of aromatase in retina and in brain regions containing the optic tectum. This localization of the rate-limiting enzyme in estrogen biosynthesis suggests that neuroestrogen derived from circulating androgen m ay modulate transmission and integration of visual information important for reproduction in this species. PMID:8680435

  9. Ginkgo biloba extract EGb 761-mediated inhibition of aromatase for the treatment of hormone-dependent breast cancer.

    Science.gov (United States)

    Park, Yong Joo; Ahn, Hui Yeon; Kim, Ha Ryong; Chung, Kyu Hyuck; Oh, Seung Min

    2016-01-01

    Ginkgo biloba has been used in herbal medicines for thousands of years. Although a standard G. biloba extract, EGb 761 has been used to improve cognition in breast cancer patients, its effects on breast cancer are unknown. Therefore, we investigated the antitumorigenic effects of EGb 761 using an in vitro cell model and an in vivo xenograft model. EGb 761 significantly inhibited aromatase activity in aromatase over-expressing MCF-7 cells (MCF-7 AROM). In addition, EGb 761 exposure reduced cytochrome p450 aromatase (CYP19) mRNA and protein expression; CYP19 promoter I.3 and PII expression particularly decreased. These inhibitory effects on aromatase were accompanied by reduced 17β-estradiol levels in MCF-7 AROM cells. For elucidating antitumorigenic effects, MCF-7 AROM cells were implanted in BALB/c nude mice prior to oral EGb 761 treatment for 3 weeks. EGb 761 reduced the tumor size and significantly reduced tumor CYP19 mRNA expression. Taken together, our results indicated that EGb 761 inhibited aromatase and exerted antitumor effects on breast cancer cells both in vitro and in vivo. These findings suggest that EGb761 may be a useful aromatase inhibitor for the treatment for estrogen-sensitive breast cancer. PMID:26706698

  10. In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

    DEFF Research Database (Denmark)

    Lykkesfeldt, Anne E; Henriksen, Katrine L; Rasmussen, Birgitte B;

    2009-01-01

    Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. RESULTS: Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from...... TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. CONCLUSION: TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2...... estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. TRIAL REGISTRATION: Sub-study of trial P025 for advanced breast cancer....

  11. Development of a cell-defined siRNA microarray for analysis of gene function in human bone marrow stromal cells.

    Science.gov (United States)

    Kim, Hi Chul; Kim, Gi-Hwan; Cho, Ssang-Goo; Lee, Eun Ju; Kwon, Yong-Jun

    2016-03-01

    Small interfering RNA (siRNA) screening approaches have provided useful tools for the validation of genetic functions; however, image-based siRNA screening using multiwell plates requires large numbers of cells and time, which could be the barrier in application for gene mechanisms study using human adult cells. Therefore, we developed the advanced method with the cell-defined siRNA microarray (CDSM), for functional analysis of genes in small scale within slide glass using human bone marrow stromal cells (hBMSCs). We designed cell spot system with biomaterials (sucrose, gelatin, poly-L-lysine and matrigel) to control the attachment of hBMSCs inside spot area on three-dimensional (3D) hydrogel-coated slides. The p65 expression was used as a validation standard which described our previous report. For the optimization of siRNA mixture, first, we detected five kinds of commercialized reagent (Lipofectamine 2000, RNAi-Max, Metafectine, Metafectine Pro, TurboFectin 8.0) via validation. Then, according to quantification of p65 expression, we selected 2 μl of RNAi-Max as the most effective reagent condition on our system. Using same validation standard, we optimized sucrose and gelatin concentration (80 mM and 0.13%), respectively. Next, we performed titration of siRNA quantity (2.66-5.55 μM) by reverse transfection time (24 h, 48 h, 72 h) and confirmed 3.75 μM siRNA concentration and 48 h as the best condition. To sum up the process for optimized CDSM, 3 μl of 20 μM siRNA (3.75 μM) was transferred to the 384-well V-bottom plate containing 2 μl of dH2O and 2 μl of 0.6M sucrose (80 mM). Then, 2 μl of RNAi-Max was added and incubated for 20 min at room temperature after mixing gently and centrifugation shortly. Five microliters of gelatin (0.26%) and 2 μl of growth factor reduced phenol red-free matrigel (12.5%) were added and mixed by pipetting gently. Finally, optimized siRNA mixture was printed on 3D hydrogel-coated slides and cell-defined attachment and si

  12. Effects of currently used pesticides in assays for estrogenicity, androgenicity, and aromatase activity in vitro

    DEFF Research Database (Denmark)

    Andersen, Helle Raun; Vinggaard, Anne; Rasmussen, Thomas Høj;

    2002-01-01

    Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides ...... to the natural ligands, the integrated response in the organism might be amplified by the ability of the pesticides to act via several mechanism and the frequent simultaneous exposure to several pesticides.......Twenty-four pesticides were tested for interactions with the estrogen receptor (ER) and the androgen receptor (AR) in transactivation assays. Estrogen-like effects on MCF-7 cell proliferation and effects on CYP19 aromatase activity in human placental microsomes were also investigated. Pesticides...... to their frequent use in Danish greenhouses. In addition, the metabolite mercaptodimethur sulfoxide, the herbicide tribenuron-methyl, and the organochlorine dieldrin, were included. Several of the pesticides, dieldrin, endosulfan, methiocarb, and fenarimol, acted both as estrogen agonists and...

  13. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    OpenAIRE

    Wong, Tsz Yan; Li, Fengjuan; Lin, Shu-mei; Franky L Chan; Chen, Shiuan; Leung, Lai K.

    2014-01-01

    Background Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. Methods In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-express...

  14. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

    OpenAIRE

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative...

  15. Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

    Science.gov (United States)

    Lv, Wei; Liu, Jinzhong; Skaar, Todd C; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A; Cushman, Mark

    2016-01-14

    A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor β (ER-β), and antagonize the activity of β-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment. PMID:26704594

  16. Cloning and mutational analysis of the gamma gene from Azotobacter vinelandii defines a new family of proteins capable of metallocluster binding and protein stabilization.

    Science.gov (United States)

    Rubio, Luis M; Rangaraj, Priya; Homer, Mary J; Roberts, Gary P; Ludden, Paul W

    2002-04-19

    Dinitrogenase is a heterotetrameric (alpha(2)beta(2)) enzyme that catalyzes the reduction of dinitrogen to ammonium and contains the iron-molybdenum cofactor (FeMo-co) at its active site. Certain Azotobacter vinelandii mutant strains unable to synthesize FeMo-co accumulate an apo form of dinitrogenase (lacking FeMo-co), with a subunit composition alpha(2)beta(2)gamma(2), which can be activated in vitro by the addition of FeMo-co. The gamma protein is able to bind FeMo-co or apodinitrogenase independently, leading to the suggestion that it facilitates FeMo-co insertion into the apoenzyme. In this work, the non-nif gene encoding the gamma subunit (nafY) has been cloned, sequenced, and found to encode a NifY-like protein. This finding, together with a wealth of knowledge on the biochemistry of proteins involved in FeMo-co and FeV-co biosyntheses, allows us to define a new family of iron and molybdenum (or vanadium) cluster-binding proteins that includes NifY, NifX, VnfX, and now gamma. In vitro FeMo-co insertion experiments presented in this work demonstrate that gamma stabilizes apodinitrogenase in the conformation required to be fully activable by the cofactor. Supporting this conclusion, we show that strains containing mutations in both nafY and nifX are severely affected in diazotrophic growth and extractable dinitrogenase activity when cultured under conditions that are likely to occur in natural environments. This finding reveals the physiological importance of the apodinitrogenase-stabilizing role of which both proteins are capable. The relationship between the metal cluster binding capabilities of this new family of proteins and the ability of some of them to stabilize an apoenzyme is still an open matter. PMID:11823455

  17. Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug

    International Nuclear Information System (INIS)

    Introduction: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (Ki=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Methods: Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [11C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [11C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [11C-cyano]letrozole fraction in arterial plasma were also measured. Results: [11C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16±2.21 Ci/μmol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. Conclusion: [11C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [11C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as

  18. Inhibition of human placental aromatase activity by hydroxylated polybrominated diphenyl ethers (OH-PBDEs)

    International Nuclear Information System (INIS)

    Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in many different polymers, resins and substrates. Due to their widespread production and use, their high binding affinity to particles, and their lipophilic properties, several PBDE congeners can bioaccumulate in the environment. As a result, PBDEs and their hydroxylated metabolites (OH-PBDEs) have been detected in humans and various wildlife samples, such as birds, seals, and whales. Furthermore, certain OH-PBDEs and their methoxylated derivatives (MeO-PBDEs) are natural products in the marine environment. Recently, our laboratory focused on the possible effects on steroidogenesis of PBDEs and OH-PBDEs, e.g. in the human adrenocortical carcinoma (H295R) cell line indicating that some OH-PBDEs can significantly influence steroidogenic enzymes like CYP19 (aromatase) and CYP17. In the present study, human placental microsomes have been used to study the possible interaction of twenty two OH-PBDEs and MeO-PBDEs with aromatase, the enzyme that mediates the conversion of androgens into estrogens. All OH-PBDE derivates showed significant inhibition of placental aromatase activity with IC50 values in the low micromolar range, while the MeO-PBDEs did not have any effect on this enzyme activity. Enzyme kinetics studies indicated that two OH-PBDEs, 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE47) and 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE47), had a mixed-type inhibition of aromatase activity with apparent Ki/Ki' of 7.68/0,02 μM and 5.01/0.04 μM respectively. For comparison, some structurally related compounds, a dihydroxylated polybrominated biphenyl, which is a natural product (2,2'-dihyroxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diOH-BB80)) and its non-bromo derivative were also included in the study. Again inhibition of aromatase activity could be measured, but their potency was significantly less than those observed for the OH-PBDEs. These results show that a wide range of

  19. Neural stem cell sex dimorphism in aromatase (CYP19 expression: a basis for differential neural fate

    Directory of Open Access Journals (Sweden)

    Jay Waldron

    2010-11-01

    Full Text Available Jay Waldron1, Althea McCourty1, Laurent Lecanu1,21The Research Institute of the McGill University Health Centre, Montreal, Canada; 2Department of Medicine, McGill University, Quebec, CanadaPurpose: Neural stem cell (NSC transplantation and pharmacologic activation of endogenous neurogenesis are two approaches that trigger a great deal of interest as brain repair strategies. However, the success rate of clinical attempts using stem cells to restore neurologic functions altered either after traumatic brain injury or as a consequence of neurodegenerative disease remains rather disappointing. This suggests that factors affecting the fate of grafted NSCs are largely understudied and remain to be characterized. We recently reported that aging differentially affects the neurogenic properties of male and female NSCs. Although the sex steroids androgens and estrogens participate in the regulation of neurogenesis, to our knowledge, research on how gender-based differences affect the capacity of NSCs to differentiate and condition their neural fate is lacking. In the present study, we explored further the role of cell sex as a determining factor of the neural fate followed by differentiating NSCs and its relationship with a potential differential expression of aromatase (CYP19, the testosterone-metabolizing enzyme.Results: Using NSCs isolated from the subventricular zone of three-month-old male and female Long-Evans rats and maintained as neurospheres, we showed that differentiation triggered by retinoic acid resulted in a neural phenotype that depends on cell sex. Differentiated male NSCs mainly expressed markers of neuronal fate, including ßIII-tubulin, microtubule associated protein 2, growth-associated protein 43, and doublecortin. In contrast, female NSCs essentially expressed the astrocyte marker glial fibrillary acidic protein. Quantification of the expression of aromatase showed a very low level of expression in undifferentiated female NSCs

  20. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormonesensitive early breast cancer: a case study

    International Nuclear Information System (INIS)

    In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI) is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms. We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+) breast cancer. A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly. The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia. Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication

  1. Defining asthma in genetic studies

    NARCIS (Netherlands)

    Koppelman, GH; Postma, DS; Meijer, G.

    1999-01-01

    Genetic studies have been hampered by the lack of a gold standard to diagnose asthma. The complex nature of asthma makes it more difficult to identify asthma genes. Therefore, approaches to define phenotypes, which have been successful in other genetically complex diseases, may be applied to define

  2. Complementary or alternative medicine as possible determinant of decreased persistence to aromatase inhibitor therapy among older women with non-metastatic breast cancer.

    Directory of Open Access Journals (Sweden)

    Laetitia Huiart

    Full Text Available PURPOSE: Aromatase inhibitor therapy (AI significantly improves survival in breast cancer patients. Little is known about adherence and persistence to aromatase inhibitors and about the causes of treatment discontinuation among older women. METHODS: We constituted a cohort of women over 65 receiving a first AI therapy for breast cancer between 2006 and 2008, and followed them until June 2011. Women were selected in the population-based French National Health Insurance databases, and data was collected on the basis of pharmacy refills, medical records and face-to-face interviews. Non-persistence to treatment was defined as the first treatment discontinuation lasting more than 3 consecutive months. Time to treatment discontinuation was studied using survival analysis techniques. RESULTS: Overall among the 382 selected women, non-persistence to treatment went from 8.7% (95%CI: 6.2-12.1 at 1 year, to 15.6% (95%CI: 12.2-19.8 at 2 years, 20.8% (95%CI: 16.7-25.6 at 3 years, and 24.7% (95%CI: 19.5-31.0 at 4 years. In the multivariate analysis on a sub-sample of 233 women with available data, women using complementary or alternative medicine (CAM (HR = 3.2; 95%CI: 1.5-6.9 or suffering from comorbidities (HR = 2.2; 95%CI: 1.0-4.8 were more likely to discontinue their treatment, whereas women with polypharmacy (HR = 0.4; 95%CI: 0.2-0.91 were less likely to discontinue. In addition, 13% of the women with positive hormonal receptor status did not fill any prescription for anti-hormonal therapy. CONCLUSION: AI therapy is discontinued prematurely in a substantial portion of older patients. Some patients may use CAM not as a complementary treatment, but as an alternative to conventional medicine. Improving patient-physician communication on the use of CAM may improve hormonal therapy adherence.

  3. Brain aromatase (Cyp19A2) and estrogen receptors, in larvae and adult pejerrey fish Odontesthes bonariensis: Neuroanatomical and functional relations

    Science.gov (United States)

    Strobl-Mazzulla, P. H.; Lethimonier, C.; Gueguen, M.M.; Karube, M.; Fernandino, J.I.; Yoshizaki, G.; Patino, R.; Strussmann, C.A.; Kah, O.; Somoza, G.M.

    2008-01-01

    Although estrogens exert many functions on vertebrate brains, there is little information on the relationship between brain aromatase and estrogen receptors. Here, we report the cloning and characterization of two estrogen receptors, ?? and ??, in pejerrey. Both receptors' mRNAs largely overlap and were predominantly expressed in the brain, pituitary, liver, and gonads. Also brain aromatase and estrogen receptors were up-regulated in the brain of estradiol-treated males. In situ hybridization was performed to study in more detail, the distribution of the two receptors in comparison with brain aromatase mRNA in the brain of adult pejerrey. The estrogen receptors' mRNAs exhibited distinct but partially overlapping patterns of expression in the preoptic area and the mediobasal hypothalamus, as well as in the pituitary gland. Moreover, the estrogen receptor ??, but not ??, were found to be expressed in cells lining the preoptic recess, similarly as observed for brain aromatase. Finally, it was shown that the onset expression of brain aromatase and both estrogen receptors in the head of larvae preceded the morphological differentiation of the gonads. Because pejerrey sex differentiation is strongly influenced by temperature, brain aromatase expression was measured during the temperature-sensitive window and was found to be significantly higher at male-promoting temperature. Taken together these results suggest close neuroanatomical and functional relationships between brain aromatase and estrogen receptors, probably involved in the sexual differentiation of the brain and raising interesting questions on the origin (central or peripheral) of the brain aromatase substrate. ?? 2008 Elsevier Inc.

  4. Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assay

    DEFF Research Database (Denmark)

    Jacobsen, Naja Wessel; Hansen, Cecilie Hurup; Nellemann, Christine;

    2015-01-01

    shown to inhibit the aromatase enzyme in both types of aromatase assays. The IC50 values ranged from 3 to 600μM. All five SSRIs, were further investigated in the H295R cell line. All compounds altered the steroid secretion from the cells, the lowest observed effect levels were 0.9μM and 3.1μ...

  5. Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain.

    Science.gov (United States)

    Cisternas, Carla D; Tome, Karina; Caeiro, Ximena E; Dadam, Florencia M; Garcia-Segura, Luis M; Cambiasso, María J

    2015-10-15

    Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-α and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain. PMID:26231585

  6. Managing arthralgia in a postmenopausal woman taking an aromatase inhibitor for hormone-sensitive early breast cancer: a case study

    Directory of Open Access Journals (Sweden)

    Bryce J

    2012-03-01

    Full Text Available Jane Bryce1, Martina Bauer2, Peyman Hadji21National Cancer Institute, Naples, Italy; 2Philipps University of Marburg, Marburg, GermanyBackground: In order to reduce the risk of recurrence, adjuvant treatment with an aromatase inhibitor (AI is recommended for postmenopausal women following surgery for hormone receptor-positive breast cancer. AIs are associated with improved disease-free survival compared with tamoxifen. The adverse events associated with AIs resemble those of menopause, such as bone density loss and musculoskeletal symptoms.Purpose: We examine the case of a postmenopausal woman who was prescribed anastrozole, a nonsteroidal AI, as adjuvant therapy following surgery for estrogen and progesterone receptor-positive (ER and PgR+ breast cancer.Methods and sample: A 58-year-old postmenopausal woman diagnosed with ER and PgR+ breast cancer was prescribed anastrozole as adjuvant therapy following a right-inferior quadrantectomy. After experiencing joint pain and stiffness, she was prescribed paracetamol and a topical nonsteroidal anti-inflammatory drug. She was also counseled on nonpharmacological interventions. However, she continued to experience symptoms, and reported that she was not taking anastrozole regularly.Results: The case study patient ultimately found relief by switching to letrozole, another aromatase inhibitor. This approach is supported by recent studies examining the benefits of switching strategies between aromatase inhibitors in order to relieve symptoms of arthralgia/myalgia.Conclusions: Both adherence and strategies for managing aromatase inhibitor-associated arthralgia are key to deriving maximal clinical benefit from AI therapy. Switching from one aromatase inhibitor to another may provide a viable option in managing adverse events and enhancing adherence to medication.Keywords: adherence, anastrozole, aromatase inhibitor, arthralgia, breast cancer, letrozole

  7. Organizing effects of sex steroids on brain aromatase activity in quail.

    Directory of Open Access Journals (Sweden)

    Charlotte A Cornil

    Full Text Available Preoptic/hypothalamic aromatase activity (AA is sexually differentiated in birds and mammals but the mechanisms controlling this sex difference remain unclear. We determined here (1 brain sites where AA is sexually differentiated and (2 whether this sex difference results from organizing effects of estrogens during ontogeny or activating effects of testosterone in adulthood. In the first experiment we measured AA in brain regions micropunched in adult male and female Japanese quail utilizing the novel strategy of basing the microdissections on the distribution of aromatase-immunoreactive cells. The largest sex difference was found in the medial bed nucleus of the stria terminalis (mBST followed by the medial preoptic nucleus (POM and the tuberal hypothalamic region. A second experiment tested the effect of embryonic treatments known to sex-reverse male copulatory behavior (i.e., estradiol benzoate [EB] or the aromatase inhibitor, Vorozole on brain AA in gonadectomized adult males and females chronically treated as adults with testosterone. Embryonic EB demasculinized male copulatory behavior, while vorozole blocked demasculinization of behavior in females as previously demonstrated in birds. Interestingly, these treatments did not affect a measure of appetitive sexual behavior. In parallel, embryonic vorozole increased, while EB decreased AA in pooled POM and mBST, but the same effect was observed in both sexes. Together, these data indicate that the early action of estrogens demasculinizes AA. However, this organizational action of estrogens on AA does not explain the behavioral sex difference in copulatory behavior since AA is similar in testosterone-treated males and females that were or were not exposed to embryonic treatments with estrogens.

  8. Effects of Nutrition Relevant Mixtures of Phytoestrogens on Steroidogenesis, Aromatase, Estrogen, and Androgen Activity

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Engell-Kofoed, Anders Elleby; Sonne-Hansen, Katrine;

    2010-01-01

    Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on...... steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced...

  9. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells

    OpenAIRE

    Lui, Asona; New, Jacob; Ogony, Joshua; Thomas, Sufi; Lewis-Wambi, Joan

    2016-01-01

    Background mTOR inhibition of aromatase inhibitor (AI)-resistant breast cancer is currently under evaluation in the clinic. Everolimus/RAD001 (Afinitor®) has had limited efficacy as a solo agent but is projected to become part of combination therapy for AI-resistant breast cancer. This study was conducted to investigate the anti-proliferative and resistance mechanisms of everolimus in AI-resistant breast cancer cells. Methods In this study we utilized two AI-resistant breast cancer cell lines...

  10. The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes.

    Science.gov (United States)

    Olsson, Linda; Zettermark, Sofia; Biloglav, Andrea; Castor, Anders; Behrendtz, Mikael; Forestier, Erik; Paulsson, Kajsa; Johansson, Bertil

    2016-07-01

    Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFB-MYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed ≥1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML. PMID:27022003

  11. A novel system for simultaneous or sequential integration of multiple gene-loading vectors into a defined site of a human artificial chromosome.

    Directory of Open Access Journals (Sweden)

    Teruhiko Suzuki

    Full Text Available Human artificial chromosomes (HACs are gene-delivery vectors suitable for introducing large DNA fragments into mammalian cells. Although a HAC theoretically incorporates multiple gene expression cassettes of unlimited DNA size, its application has been limited because the conventional gene-loading system accepts only one gene-loading vector (GLV into a HAC. We report a novel method for the simultaneous or sequential integration of multiple GLVs into a HAC vector (designated as the SIM system via combined usage of Cre, FLP, Bxb1, and φC31 recombinase/integrase. As a proof of principle, we first attempted simultaneous integration of three GLVs encoding EGFP, Venus, and TdTomato into a gene-loading site of a HAC in CHO cells. These cells successfully expressed all three fluorescent proteins. Furthermore, microcell-mediated transfer of HACs enabled the expression of those fluorescent proteins in recipient cells. We next demonstrated that GLVs could be introduced into a HAC one-by-one via reciprocal usage of recombinase/integrase. Lastly, we introduced a fourth GLV into a HAC after simultaneous integration of three GLVs by FLP-mediated DNA recombination. The SIM system expands the applicability of HAC vectors and is useful for various biomedical studies, including cell reprogramming.

  12. Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics

    International Nuclear Information System (INIS)

    There is concern widely on the increase in human exposure to exogenous (anti)estrogenic compounds. Typical are certain ingredients in cosmetic consumer products such as musks, phthalates and parabens. Monitoring a variety of human samples revealed that these ingredients, including the ones that generally are considered to undergo rapid metabolism, are present at low levels. In this in vitro research individual compounds and combinations of parabens and endogenous estradiol (E2) were investigated in the MCF-7 cell proliferation assay. The experimental design applied a concentration addition model (CA). Data were analyzed with the estrogen equivalency (EEQ) and method of isoboles approach. In addition, the catalytic inhibitory properties of parabens on an enzyme involved in a rate limiting step in steroid genesis (aromatase) were studied in human placental microsomes. Our results point to an additive estrogenic effect in a CA model for parabens. In addition, it was found that parabens inhibit aromatase. Noticeably, the effective levels in both our in vitro systems were far higher than the levels detected in human samples. However, estrogenic compounds may contribute in a cumulative way to the circulating estrogen burden. Our calculation for the extra estrogen burden due to exposure to parabens, phthalates and polycyclic musks indicates an insignificant estrogenic load relative to the endogenous or therapeutic estrogen burden

  13. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.

    Science.gov (United States)

    Cohen, P G

    2001-06-01

    In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time. PMID:11399122

  14. The functional interaction on in vitro gene expression of APOA5 SNPs, defining haplotype APOA5*2, and their paradoxical association with plasma triglyceride but not plasma apoAV levels

    OpenAIRE

    2008-01-01

    The functional interaction on in vitro gene expression of APOA5 SNPs, defining haplotype APOA5*2, and their paradoxical association with plasma triglyceride but not plasma apoAV levels correspondance: Corresponding author. Division of Cardiovascular Genetics, Department of Medicine, Rayne Building, University College London, 5 University Street, London WC1E 6JF, United Kingdom. Tel.: +44 20 7679 6968; fax: +44 20 7679 6212. (Talmud, Philippa J.) p....

  15. Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia.

    Science.gov (United States)

    Bajpai, Anurag; Simm, Peter J; McPherson, Stephen J; Russo, Vincenzo C; Azar, Walid J; Wark, John D; Risbridger, Gail P; Werther, George A

    2010-10-01

    Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved. PMID:20675302

  16. Defining the Metabolic Functions and Roles in Virulence of the rpoN1 and rpoN2 Genes in Ralstonia solanacearum GMI1000.

    Directory of Open Access Journals (Sweden)

    Benjamin R Lundgren

    Full Text Available The alternative sigma factor RpoN is a unique regulator found among bacteria. It controls numerous processes that range from basic metabolism to more complex functions such as motility and nitrogen fixation. Our current understanding of RpoN function is largely derived from studies on prototypical bacteria such as Escherichia coli. Bacillus subtilis and Pseudomonas putida. Although the extent and necessity of RpoN-dependent functions differ radically between these model organisms, each bacterium depends on a single chromosomal rpoN gene to meet the cellular demands of RpoN regulation. The bacterium Ralstonia solanacearum is often recognized for being the causative agent of wilt disease in crops, including banana, peanut and potato. However, this plant pathogen is also one of the few bacterial species whose genome possesses dual rpoN genes. To determine if the rpoN genes in this bacterium are genetically redundant and interchangeable, we constructed and characterized ΔrpoN1, ΔrpoN2 and ΔrpoN1 ΔrpoN2 mutants of R. solanacearum GMI1000. It was found that growth on a small range of metabolites, including dicarboxylates, ethanol, nitrate, ornithine, proline and xanthine, were dependent on only the rpoN1 gene. Furthermore, the rpoN1 gene was required for wilt disease on tomato whereas rpoN2 had no observable role in virulence or metabolism in R. solanacearum GMI1000. Interestingly, plasmid-based expression of rpoN2 did not fully rescue the metabolic deficiencies of the ΔrpoN1 mutants; full recovery was specific to rpoN1. In comparison, only rpoN2 was able to genetically complement a ΔrpoN E. coli mutant. These results demonstrate that the RpoN1 and RpoN2 proteins are not functionally equivalent or interchangeable in R. solanacearum GMI1000.

  17. Defining the Metabolic Functions and Roles in Virulence of the rpoN1 and rpoN2 Genes in Ralstonia solanacearum GMI1000.

    Science.gov (United States)

    Lundgren, Benjamin R; Connolly, Morgan P; Choudhary, Pratibha; Brookins-Little, Tiffany S; Chatterjee, Snigdha; Raina, Ramesh; Nomura, Christopher T

    2015-01-01

    The alternative sigma factor RpoN is a unique regulator found among bacteria. It controls numerous processes that range from basic metabolism to more complex functions such as motility and nitrogen fixation. Our current understanding of RpoN function is largely derived from studies on prototypical bacteria such as Escherichia coli. Bacillus subtilis and Pseudomonas putida. Although the extent and necessity of RpoN-dependent functions differ radically between these model organisms, each bacterium depends on a single chromosomal rpoN gene to meet the cellular demands of RpoN regulation. The bacterium Ralstonia solanacearum is often recognized for being the causative agent of wilt disease in crops, including banana, peanut and potato. However, this plant pathogen is also one of the few bacterial species whose genome possesses dual rpoN genes. To determine if the rpoN genes in this bacterium are genetically redundant and interchangeable, we constructed and characterized ΔrpoN1, ΔrpoN2 and ΔrpoN1 ΔrpoN2 mutants of R. solanacearum GMI1000. It was found that growth on a small range of metabolites, including dicarboxylates, ethanol, nitrate, ornithine, proline and xanthine, were dependent on only the rpoN1 gene. Furthermore, the rpoN1 gene was required for wilt disease on tomato whereas rpoN2 had no observable role in virulence or metabolism in R. solanacearum GMI1000. Interestingly, plasmid-based expression of rpoN2 did not fully rescue the metabolic deficiencies of the ΔrpoN1 mutants; full recovery was specific to rpoN1. In comparison, only rpoN2 was able to genetically complement a ΔrpoN E. coli mutant. These results demonstrate that the RpoN1 and RpoN2 proteins are not functionally equivalent or interchangeable in R. solanacearum GMI1000. PMID:26659655

  18. Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure-Function Perspective.

    Science.gov (United States)

    Ghosh, Debashis; Lo, Jessica; Egbuta, Chinaza

    2016-06-01

    Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme's structure-function relationships. PMID:26689671

  19. Management of adenomyosis in infertile women: comparison between laparotomic resection and administration of aromatase inhibitor (Experience in 55 cases

    Directory of Open Access Journals (Sweden)

    Rajuddin Rajuddin

    2006-03-01

    Full Text Available The objective of this study was to observe the results of adenomyosis mangement with resection and administration of aromatase inhibitor. Cases of ademyosis in infertile women were collected for three years (January 1999 to December 2001 and the diagnoses were confirmed using transvaginal USG. Cases were grouped into two groups, i.e. group 1 (undergoing laparotomic resection and group 2 (receiving treatment with aromatase inhibitor of anastrozole. Both groups were evaluated for changes in clinical symptoms, rate of successful pregnancy, and postoperative recurrency rate. During three years as many as 1619 infertility cases were managed, and among which 66 (4.07% cases of adenomyosis were diagnosed with transvaginal USG. As many as 55 cases were analyzed, i.e., 32 cases underwent resection and 23 cases received aromatase inhibitor. Of 32 cases of surgical resection, the histopathological results showed 30 (93.75% cases of adenomyosis and 2 (6.25% cases of uterus myoma. In the group undergoing resection three cases (9.4% were successfully pregnant, i.e., two cases had live birth, one case ended up with 6-week abortion. Moreover, 25 (78.1% cases were not pregnant and 4 (12.5% cases had recurrency, while 24 (75.35% cases experienced disappearance of symptoms yet not pregnant. On the other hand, of 23 cases in the group receiving aromatase inhibitor 2 (8.6% cases were able to be pregnant, one case had live birth and another case ended up with abortion, while 14 (59.1% cases had disappearance of symptoms yet not pregnant. During three months of treatment with aromatase inhibitor, a reduction in the lesion size between 7.31 mm3 and 25.90 mm3 were observed with CI 95% (p < 0.001. In conclusion, treatment with aromatase inihibitor did not heal lesions, but only reduced the size of adenomyosis lesions. On the other hand, resection could heal lesions, yet recurrency of disease may occur (12.5% after one postoperative year. (Med J Indones 2006; 15

  20. Modulation of Δ9-tetrahydrocannabinol-induced MCF-7 breast cancer cell growth by cyclooxygenase and aromatase

    International Nuclear Information System (INIS)

    Δ9-Tetrahydrocannabinol (Δ9-THC), a major constituent of marijuana, has been shown to stimulate the growth of MCF-7 breast cancer cells through cannabinoid receptor-independent signaling [Takeda, S., Yamaori, S., Motoya, E., Matsunaga, T., Kimura, T., Yamamoto, I., Watanabe, K., 2008. Δ9-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. Toxicology 245, 141-146]. Although the growth of MCF-7 cells is known to be stimulated by 17β-estradiol (E2), the interaction of Δ9-THC and E2 in MCF-7 cell growth is not fully clarified so far. In the present study, by using E2-sensitive MCF-7 cells that have expressed cyclooxygenase-2 (COX-2) and cytochrome P450 19 (aromatase), we studied whether or not COX-2 and aromatase are involved in Δ9-THC-mediated MCF-7 cell proliferation. It was shown that Δ9-THC-induced MCF-7 cell growth was inhibited by COX-2 inhibitors and was stimulated by arachidonic acid (a COX substrate). However, the growth of MCF-7 cells induced by Δ9-THC was not stimulated by PGE2, and the expression of aromatase was not affected by COX-2 inhibitors, arachidonic acid, and PGE2, suggesting that there is a disconnection between COX-2 (PGE2) and aromatase in Δ9-THC-mediated MCF-7 cell proliferation. On the other hand, Δ9-THC-induced MCF-7 cell growth was elevated by two kinds of aromatase inhibitors. Taken together with the evidence that Δ9-THC-induced MCF-7 cell proliferation was interfered with testosterone (an aromatase substrate) and exogenously provided E2, it is suggested that (1) the growth stimulatory effects of Δ9-THC are mediated by the product(s) of COX-2 except for PGE2, (2) the action of Δ9-THC is modulated by E2, and (3) COX-2 and aromatase are individually engaged in the proliferation of MCF-7 cells induced by Δ9-THC.

  1. Paternal Retrieval Behavior Regulated by Brain Estrogen Synthetase (Aromatase) in Mouse Sires that Engage in Communicative Interactions with Pairmates

    Science.gov (United States)

    Akther, Shirin; Huang, Zhiqi; Liang, Mingkun; Zhong, Jing; Fakhrul, Azam A. K. M.; Yuhi, Teruko; Lopatina, Olga; Salmina, Alla B.; Yokoyama, Shigeru; Higashida, Chiharu; Tsuji, Takahiro; Matsuo, Mie; Higashida, Haruhiro

    2015-01-01

    Parental behaviors involve complex social recognition and memory processes and interactive behavior with children that can greatly facilitate healthy human family life. Fathers play a substantial role in child care in a small but significant number of mammals, including humans. However, the brain mechanism that controls male parental behavior is much less understood than that controlling female parental behavior. Fathers of non-monogamous laboratory ICR mice are an interesting model for examining the factors that influence paternal responsiveness because sires can exhibit maternal-like parental care (retrieval of pups) when separated from their pups along with their pairmates because of olfactory and auditory signals from the dams. Here we tested whether paternal behavior is related to femininity by the aromatization of testosterone. For this purpose, we measured the immunoreactivity of aromatase [cytochrome P450 family 19 (CYP19)], which synthesizes estrogen from androgen, in nine brain regions of the sire. We observed higher levels of aromatase expression in these areas of the sire brain when they engaged in communicative interactions with dams in separate cages. Interestingly, the number of nuclei with aromatase immunoreactivity in sires left together with maternal mates in the home cage after pup-removing was significantly larger than that in sires housed with a whole family. The capacity of sires to retrieve pups was increased following a period of 5 days spent with the pups as a whole family after parturition, whereas the acquisition of this ability was suppressed in sires treated daily with an aromatase inhibitor. The results demonstrate that the dam significantly stimulates aromatase in the male brain and that the presence of the pups has an inhibitory effect on this increase. These results also suggest that brain aromatization regulates the initiation, development, and maintenance of paternal behavior in the ICR male mice. PMID:26696812

  2. Gene transcript analysis blood values correlate with {sup 68}Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Kidd, M.; Modlin, I.M.; Drozdov, I. [Wren Laboratories, Branford, CT (United States); Prasad, V. [Charite University Hospital, Department of Nuclear Medicine, Berlin (Germany); Severi, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Ambrosini, V. [S. Orsola-Malpighi University Hospital, Nuclear Medicine, Bologna (Italy); Kwekkeboom, D.J.; Krenning, E.P. [Erasmus Medical Center Rotterdam, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [Zentralklinik Bad Berka, THERANOSTICS Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)

    2015-08-15

    Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between {sup 68}Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive {sup 68}Ga-SSA PET: data set 1 ({sup 68}Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ({sup 68}Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUV{sub max}), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUV{sub max} measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ{sup 2} = 20.1, p < 2.5 x 10{sup -6}). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUV{sub max} (R {sup 2} = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUV{sub max}. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUV{sub max} [ROC-derived AUC (R {sup 2} = 0.7, p < 0.05)]. No statistical relationship was identified

  3. Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

    International Nuclear Information System (INIS)

    Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between 68Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive 68Ga-SSA PET: data set 1 (68Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 (68Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ2 = 20.1, p < 2.5 x 10-6). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUVmax (R 2 = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R 2 = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident. 68Ga

  4. The interaction between aromatase, metalloproteinase 2,9 and cd44 in breast cancer A interação entre aromatase, metalloproteinase 2, 9 e cd44 no câncer de mama

    Directory of Open Access Journals (Sweden)

    Fábio Bagnoli

    2010-01-01

    Full Text Available OBJECTIVE: This study intends to verify the expression levels and correlation of aromatase, matrix metalloproteinase 2 (MMP-2, matrix metalloproteinase 9 (MMP-9 and CD44 in ductal carcinoma in situ (DCIS and infiltrating ductal carcinoma (IDC when both are found in the same breast. METHODS: One hundred and ten cases were evaluated by tissue microarray (TMA and immunohistochemically screened with anti-aromatase polyclonal antibodies, anti-MMP-2 monoclonal antibodies, anti-MMP-9 policlonal antibodies and anti-CD44 monoclonal antibodies. RESULTS: Aromatase was expressed in IDC and DCIS in 63 (57.3% and 60 (67% of the cases respectively; MMP-2 was similarly expressed in IDC and DCIS in 15 (13.60% cases; MMP-9 was positively expressed in IDC and DCIS in 83 (75.50% and 82 (74.50% cases, respectively; CD44 was positively expressed in IDC and DCIS in 49 (44.50% and 48 (42.60% of the cases, respectively; all of them were highly correlated (pOBJETIVO: O objetivo desse estudo é verificar as expressões e correlações da aromatase, metalloproteinase 2 da matriz (MMP2, metalloproteinase 9 da matriz (MMP-9 e CD44 no carcinoma ductal in situ (CDIS e carcinoma ductal infiltrativo (CDI quando ambos estão presentes simultaneamente na mesma mama. MÉTODOS: Foram avaliados 110 casos pelo método de tissue microarray (TMA e através da utilização de anticorpos policlonais antiaromatase, anticorpos monoclonais anti-MMP-2, anticorpos policlonais anti-MMP-9 e anticorpos monoclonais anti-CD44. RESULTADOS: A aromatase estava expressa de forma positiva no CDI e CDIS em 63 (57,3% e 60 (67% casos, respectivamente. A expressão de MMP-2 estava expressa de forma positiva em 15 (13,6% casos tanto no CDI, quanto no CDIS. A expressão da MMP-9 estava expressa de forma positiva em 83 (75,5% e 82 (74,5% casos de CDI e CDIS, respectivamente. A expressão de CD44 estava expressa de forma positiva em 49 (44,5% e 48 (42,6% casos de CDI e CDIS, respectivamente. Todos eles

  5. Aromatase inhibitors - a viable option for recurrent granulosa cell tumour of ovary: overview and case report

    International Nuclear Information System (INIS)

    Granulosa cell tumour of the ovary in adults is a rare tumour of low malignant potential affecting middle aged peri or post menopausal patients. These tumours are often diagnosed at an early stage, due to their hormonally active nature. They, however, have unique distinguishing histologic features and behaviour of frequent and late local or systemic relapses. The diagnosis can be challenging with unusual presentations. There is high association of endometrial carcinoma. Surgery is the mainstay of management in early low risk disease, while radiotherapy and systemic platinum based chemotherapy are employed in higher stage with poor prognostic indices. Survival is good in early stage disease. Recurrent, progressive, and treatment refractory disease is not infrequent and poses management challenge. Endocrine manipulation and hormone treatment are employed in few cases with equivocal results, as reported in literature. We present a case of recurrent and treatment refractory GCT in a postmenopausal patient, managed by aromatase inhibitor Anastrozole with reasonable efficacy. (author)

  6. Induction of Female-to-Male Sex Change in Adult Zebrafish by Aromatase Inhibitor Treatment

    Science.gov (United States)

    Takatsu, Kanae; Miyaoku, Kaori; Roy, Shimi Rani; Murono, Yuki; Sago, Tomohiro; Itagaki, Hideyuki; Nakamura, Masaru; Tokumoto, Toshinobu

    2013-12-01

    This study investigated whether undifferentiated germ and/or somatic stem cells remain in the differentiated ovary of a species that does not undergo sex changes under natural conditions and retain their sexual plasticity. The effect of aromatase inhibitor (AI)-treatment on sexually mature female zebrafish was examined. A 5-month AI treatment caused retraction of the ovaries after which testes-like organs appeared, and cyst structures filled with spermatozoa-like cells were observed in sections of these tissues. Electron microscopic observations revealed that these cells appeared as large sperm heads without tails. Sperm formation was re-examined after changing the diet to an AI-free food. A large number of normal sperm were obtained after eight weeks, and no formation of ovarian tissue was observed. Artificial fertilization using sperm from the sex-changed females was successful. These results demonstrated that sex plasticity remains in the mature ovaries of this species.

  7. Exon Array Analysis using re-defined probe sets results in reliable identification of alternatively spliced genes in non-small cell lung cancer

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    Gröne Jörn

    2010-11-01

    Full Text Available Abstract Background Treatment of non-small cell lung cancer with novel targeted therapies is a major unmet clinical need. Alternative splicing is a mechanism which generates diverse protein products and is of functional relevance in cancer. Results In this study, a genome-wide analysis of the alteration of splicing patterns between lung cancer and normal lung tissue was performed. We generated an exon array data set derived from matched pairs of lung cancer and normal lung tissue including both the adenocarcinoma and the squamous cell carcinoma subtypes. An enhanced workflow was developed to reliably detect differential splicing in an exon array data set. In total, 330 genes were found to be differentially spliced in non-small cell lung cancer compared to normal lung tissue. Microarray findings were validated with independent laboratory methods for CLSTN1, FN1, KIAA1217, MYO18A, NCOR2, NUMB, SLK, SYNE2, TPM1, (in total, 10 events and ADD3, which was analysed in depth. We achieved a high validation rate of 69%. Evidence was found that the activity of FOX2, the splicing factor shown to cause cancer-specific splicing patterns in breast and ovarian cancer, is not altered at the transcript level in several cancer types including lung cancer. Conclusions This study demonstrates how alternatively spliced genes can reliably be identified in a cancer data set. Our findings underline that key processes of cancer progression in NSCLC are affected by alternative splicing, which can be exploited in the search for novel targeted therapies.

  8. Sex Differences in Brain Aromatase Activity: Genomic and Non-Genomic Controls

    Science.gov (United States)

    Balthazart, Jacques; Charlier, Thierry D.; Cornil, Charlotte A.; Dickens, Molly J.; Harada, Nobuhiro; Konkle, Anne T. M.; Voigt, Cornelia; Ball, Gregory F.

    2011-01-01

    Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months), brain aromatase activity (AA), and transcription are markedly (four- to sixfold) increased by genomic actions of sex steroids. Initial work indicated that the preoptic AA is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of AA, immunoreactivity, and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. AA in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in AA have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral significance. PMID:22645508

  9. Aromatase inhibitors, efficacy and metabolic risk in the treatment of postmenopausal women with early breast cancer

    Directory of Open Access Journals (Sweden)

    Stefano Gonnelli

    2008-11-01

    Full Text Available Stefano Gonnelli1, Roberto Petrioli21Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy (Dir. R. Nuti.; 2Department of Human Pathology and Oncology, Medical Oncology Section, University of Siena, Italy (Dir. G. FranciniAbstract: The third-generation aromatase inhibitors (AIs, letrozole, anastrozole and exemestane, are becoming the first choice endocrine drugs for post-menopausal women with breast cancer, since they present greater efficacy when compared with tamoxifen in both adjuvant and metastatic setting. In particular, several large and well designed trials have suggested an important role for AIs in the adjuvant treatment of postmenopausal women with estrogen-receptor positive breast cancer either in the upfront, sequential or extended adjuvant mode. Overall, AIs are associated with a small but significant improvement in disease free survival. The expanding use of AIs in the treatment of early breast cancer means that individual patients will be exposed to the agents for longer durations, making it increasingly important to establish their long-term safety. This review focused on the effects of AIs on bone metabolism, serum lipids and cardiovascular risk. AIs have adverse effects on bone turnover with a reduction of bone mineral density and an increase in the rate of fragility fractures. With respect to tamoxifen AIs present lower thrombotic risk and a less favorable impact on lipid profile, whereas the true effects on cardiovascular risk still remain to be clarified. An adequate monitoring of bone mineral density (BMD and lipid profile could be recommended for post-menopausal women candidate to AIs.Keywords: breast cancer, aromatase inhibitors, bone loss, lipids, cardiovascular risk

  10. Unique Distribution of Aromatase in the Human Brain: In Vivo Studies With PET and [N-Methyl-11C]Vorozole

    Energy Technology Data Exchange (ETDEWEB)

    Biegon, A.; Biegon, A.; Kim, S.W.; Alexoff, D.; Millard, J.; Carter, P.; Hubbard, B.; King, P.; Logan, J.; Muench, L.; Pareto, D.; Schlyer, D.; Shea, C.; Telang, F.; Wang, G.-J.; Xu, Y.; Fowler, J.

    2010-10-01

    Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl-{sup 11}C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V{sub T}) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced VT in all regions, though the size of the reduction was region-dependent, ranging from {approx}70% blocking in thalamus andpreoptic area to {approx}10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain.

  11. Gene expression profiling defines a high-risk entity of multiple myeloma%基因表达谱鉴定高危多发性骨髓瘤

    Institute of Scientific and Technical Information of China (English)

    Feng-huang Zhan; Bart Barlogie; John Shaughnessy Jr

    2007-01-01

    Multiple myeloma (MM) is the second most common hematological malignancy and remains incurable. The marked variation in survival of patients with symptomatic myeloma ranging from few months to more than 15 years can be explained by differences in tumor mass, proliferative activity and, more recently, by cytogenetic and molecular genetic characteristics of the myeloma clone. Oligonucleotide microarray-based gene expression analysis was applied to CD138-enriched plasma cells from newly diagnosed patients with symptomatic or progressive multiple myeloma treated with melphalan-based high-dose therapy. Here we discuss recent progress made in the development of molecular-based diagnostics and prognostics for MM from Myeloma Institute for Research and Therapy of University Arkansas for Medical Sciences, where we treat more patients with myeloma than anywhere else in the world. Seven distinct entities of myeloma were elucidated by genomic profiling. Expression extremes of 70 genes from a high-risk signature profile,30% of which were derived from chromosome 1, were strongly linked to disease-related survival. CKS1B located on chromosome 1q21, responsible for promoting cell cycle progression by inducing the degradation of p27Kip1, represented a strong candidate gene related to rapid patient death and was studied in detail. The data suggest that CKS1B influences myeloma cell growth and survival through SKP2- and P27(Kip1)-dependent and independent mechanisms and that therapeutic strategies aimed at abolishing CKS1B function may hold promise for the treatment of high-risk disease for which effective therapies are currently lacking.%多发性骨髓瘤是一种常见的血液系统恶性肿瘤,其发病率在血液系统恶性肿瘤中居第二位,目前仍不可治愈.且多发性骨髓瘤患者生存时间跨度大,短至数月,长达15年以上,这说明骨髓瘤患者间存在遗传异质性,表现为分化程度不一及细胞和分子遗传特征的差异.阿肯色州立

  12. SOXC and MiR17-92 gene expression profiling defines two subgroups with different clinical outcome in mantle cell lymphoma.

    Science.gov (United States)

    Roisman, Alejandro; Huamán Garaicoa, Fuad; Metrebian, Fernanda; Narbaitz, Marina; Kohan, Dana; García Rivello, Hernán; Fernandez, Isolda; Pavlovsky, Astrid; Pavlovsky, Miguel; Hernández, Luis; Slavutsky, Irma

    2016-06-01

    Mantle cell lymphoma (MCL) is a heterogeneous B-cell lymphoid malignancy where most patients follow an aggressive clinical course whereas others are associated with an indolent performance. SOX4, SOX11, and SOX12 belong to SOXC family of transcription factors involved in embryonic neurogenesis and tissue remodeling. Among them, SOX11 has been found aberrantly expressed in most aggressive MCL patients, being considered a reliable biomarker in the pathology. Several studies have revealed that microRNAs (miRs) from the miR-17-92 cluster are among the most deregulated miRNAs in human cancers, still little is known about this cluster in MCL. In this study we screened the transcriptional profiles of 70 MCL patients for SOXC cluster and miR17, miR18a, miR19b and miR92a, from the miR-17-92 cluster. Gene expression analysis showed higher SOX11 and SOX12 levels compared to SOX4 (P ≤ 0.0026). Moreover we found a negative correlation between the expression of SOX11 and SOX4 (P < 0.0001). miR17-92 cluster analysis showed that miR19b and miR92a exhibited higher levels than miR17 and miR18a (P < 0.0001). Unsupervised hierarchical clustering revealed two subgroups with significant differences in relation to aggressive MCL features, such as blastoid morphological variant (P = 0.0412), nodal presentation (P = 0.0492), CD5(+) (P = 0.0004) and shorter overall survival (P < 0.0001). Together, our findings show for the first time an association between the differential expression profiles of SOXC and miR17-92 clusters in MCL and also relate them to different clinical subtypes of the disease adding new biological information that may contribute to a better understanding of this pathology. © 2016 Wiley Periodicals, Inc. PMID:26998831

  13. Farnesoid X Receptor, through the Binding with Steroidogenic Factor 1-responsive Element, Inhibits Aromatase Expression in Tumor Leydig Cells*

    OpenAIRE

    Catalano, Stefania; Malivindi, Rocco; Giordano, Cinzia; Gu, Guowei; Panza, Salvatore; Bonofiglio, Daniela; Lanzino, Marilena; Sisci, Diego; Panno, Maria Luisa; Andò, Sebastiano

    2009-01-01

    The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. It is expressed in the liver and the gastrointestinal tract, but also in several non-enterohepatic tissues including testis. Recently, FXR was identified as a negative modulator of the androgen-estrogen-converting aromatase enzyme in human breast cancer cells. In the present study we detected the expression of FXR in Leydig normal and tumor cell lines and in rat testes tissue. ...

  14. Dietary Polyphenols Suppress Elevated Levels of Proinflammatory Mediators and Aromatase in the Mammary Gland of Obese Mice

    OpenAIRE

    Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya; Du, Baoheng; Hudis, Clifford A.; Giri, Dilip; Kopelovich, Levy; Zhou, Xi Kathy; Dannenberg, Andrew J.

    2013-01-01

    In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose...

  15. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    OpenAIRE

    Schiff, Rachel; Chamness, Gary C.; Brown, Powel H.

    2003-01-01

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new s...

  16. Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

    OpenAIRE

    Takagi, K.; Ishida, T; Miki, Y; Hirakawa, H; Kakugawa, Y; Amano, G.; Ebata, A.; Mori, N; Nakamura, Y.; Watanabe, M.; Amari, M; Ohuchi, N.; Sasano, H; Suzuki, T

    2013-01-01

    Background: Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment. Methods: Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by...

  17. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner

    OpenAIRE

    Dickens, M.J.; Balthazart, J.; Cornil, C. A.

    2012-01-01

    Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with s...

  18. The effect of oral contraceptives on aromatase and Cox-2 expression in the endometrium of patients with idiopathic menorrhagia or adenomyosis

    Directory of Open Access Journals (Sweden)

    Maia H Jr

    2013-06-01

    Full Text Available Hugo Maia Jr,1–3 Clarice Haddad,3 Nathaniel Pinheiro,4 Julio Casoy31School of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil; 2Itaigara Memorial Day Hospital, Salvador, Bahia, Brazil; 3CEPARH (Centro de Pesquisas e Assistência em Reprodução Humana, Salvador, Bahia, Brazil; 4Imagepat Pathology Laboratory, Federal University of Bahia, Salvador, Bahia, BrazilBackground: The presence of aromatase and cyclooxygenase-2 (Cox-2 expression was investigated in the endometrium of patients with idiopathic menorrhagia or adenomyosis. The effect of oral contraceptives administered in extended regimens on the endometrial expression of these enzymes was also investigated.Methods and results: Aromatase expression was detected by immunohistochemistry in the endometrial glands and stroma of patients with idiopathic menorrhagia or adenomyosis. There was no difference in the percentage of aromatase expression in the endometria between the two groups. The mean intensity of Cox-2 expression in the glandular epithelium also did not differ significantly between the groups. Among the patients using oral contraceptives in extended regimens, the relative decrease in both aromatase and Cox-2 expression was significantly greater in amenorrheic patients compared with those who were experiencing breakthrough bleeding.Conclusion: The presence of aromatase expression in the endometrium is associated with the occurrence of menorrhagia, irrespective of the presence of adenomyosis. Continuous expression of these enzymes in the endometrium of users of oral contraceptives in extended regimens is positively associated with the presence of breakthrough bleeding. This suggests a role for both aromatase and Cox-2 in the etiology of abnormal uterine bleeding.Keywords: menorrhagia, aromatase, endometrium, Cox-2, adenomyosis

  19. Use of aromatase inhibitors to treat endometriosis-related pain symptoms: a systematic review

    Directory of Open Access Journals (Sweden)

    Venturini Pier L

    2011-06-01

    Full Text Available Abstract This systematic review aims to assess the efficacy of aromatase inhibitors (AIs in treating pain symptoms caused by endometriosis. A comprehensive literature search was conducted to identify all the published studies evaluating the efficacy of type II nonsteroidal aromatase inhibitors (anastrozole and letrozole in treating endometriosis-related pain symptoms. The MEDLINE, EMBASE, PubMed, and SCOPUS databases and the Cochrane System Reviews were searched up to October 2010. This review comprises of the results of 10 publications fitting the inclusion criteria; these studies included a total of 251 women. Five studies were prospective non-comparative, four were randomized controlled trials (RCTs and one was a prospective patient preference trial. Seven studies examined the efficacy of AIs in improving endometriosis-related pain symptoms, whilst three RCTs investigated the use of AIs as post-operative therapy in preventing the recurrence of pain symptoms after surgery for endometriosis. All the observational studies demonstrated that AIs combined with either progestogens or oral contraceptive pill reduce the severity of pain symptoms and improve quality of life. One patient preference study demonstrated that letrozole combined with norethisterone acetate is more effective in reducing pain and deep dyspareunia than norethisterone acetate alone. However, letrozole causes a higher incidence of adverse effects and does not improve patients' satisfaction or influence recurrence of symptoms after discontinuation of treatment. A RCT showed that combining letrozole with norethisterone acetate causes a lower incidence of adverse effects and lower discontinuation rate than combining letrozole with triptorelin. Two RCTs demonstrated that, after surgical treatment of endometriosis, the administration of AIs combined with gonadotropin releasing hormone analogue for 6 months reduces the risk of endometriosis recurrence when compared with gonadotropin

  20. Definable deduction relation

    Institute of Scientific and Technical Information of China (English)

    张玉平

    1999-01-01

    The nonmonotonic deduction relation in default reasoning is defined with fixed point style, which has the many-extension property that classical logic is not possessed of. These two kinds of deductions both have boolean definability property, that is, their extensions or deductive closures can be defined by boolean formulas. A generalized form of fixed point method is employed to define a class of deduction relations, which all have the above property. Theorems on definability and atomless boolean algebras in model theory are essential in dealing with this assertion.

  1. Locally produced estrogen through aromatization might enhance tissue expression of pituitary tumor transforming gene and fibroblast growth factor 2 in growth hormone-secreting adenomas.

    Science.gov (United States)

    Ozkaya, Hande Mefkure; Comunoglu, Nil; Keskin, Fatma Ela; Oz, Buge; Haliloglu, Ozlem Asmaz; Tanriover, Necmettin; Gazioglu, Nurperi; Kadioglu, Pinar

    2016-06-01

    Aromatase, a key enzyme in local estrogen synthesis, is expressed in different pituitary tumors including growth hormone (GH)-secreting adenomas. We aimed to evaluate aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) expressions in GH-secreting adenomas, and investigate their correlation with clinical, pathologic, and radiologic parameters. This cross-sectional study was conducted in a tertiary center in Turkey. Protein expressions were determined via immunohistochemical staining in ex vivo tumor samples of 62 patients with acromegaly and ten normal pituitary tissues. Concordantly increased aromatase, PTTG, and FGF2 expressions were detected in the tumor samples as compared with controls (p tumors expressed ERα while ERβ was detected only in mixed somatotroph adenomas. Aromatase, ERβ, PTTG expressions were not significantly different between patients with and without remission (p > 0.05 for all). FGF2 expression was significantly higher in patients without postoperative and late remission (p = 0.002 and p = 0.012, respectively), with sphenoid bone invasion, optic chiasm compression, and somatostatin analog resistance (p = 0.005, p = 0.033, and p = 0.013, respectively). Aromatase, PTTG and FGF2 expressions were positively correlated with each other (r = 0,311, p = 0.008 for aromatase, FGF2; r = 0.380, p = 0.001 for aromatase, PTTG; r = 0.400, p = 0.001 for FGF2, PTTG). PTTG-mediated FGF2 upregulation is associated with more aggressive tumor features in patients with acromegaly. Also, locally produced estrogen through aromatization might have a role in this phenomenon. PMID:26578364

  2. Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice

    International Nuclear Information System (INIS)

    Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk. In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. The animals were given celecoxib at 1500 ppm or aspirin at 200 ppm by oral administration with androstenedione injection. Our results showed that both COX inhibitors could suppress the cancer xenograft growth without changing the plasma estrogen level. Protein expression of ERα, COX-2, Cyclin A, and Bcl-xL were reduced in celecoxib-treated tumor samples, whereas only Bcl-xL expression was suppressed in those treated with aspirin. Among the breast cancer-related miRNAs, miR-222 expression was elevated in samples treated with celecoxib. Further studies in culture cells verified that the increase in miR-222 expression might contribute to ERα downregulation but not the growth deterrence of cells. Overall, this study suggested that both celecoxib and aspirin could prevent breast cancer growth by regulating proteins in the cell cycle and apoptosis without blocking estrogen synthesis. Besides, celecoxib might affect miR expression in an undesirable fashion

  3. Postmenopausal Breast Cancer, Aromatase Inhibitors, and Bone Health: What the Surgeon Should Know.

    Science.gov (United States)

    Baatjes, K J; Apffelstaedt, J P; Kotze, M J; Conradie, M

    2016-09-01

    Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important. PMID:27189076

  4. A Case of Erythrocytosis in a Patient Treated with an Aromatase Inhibitor for Breast Cancer

    Directory of Open Access Journals (Sweden)

    Abhinav Iyengar

    2013-01-01

    Full Text Available A previously healthy 79-year-old female was referred to hematology for further evaluation of erythrocytosis. Two years earlier she had been diagnosed with ER/PR-positive ductal carcinoma of the breast and was receiving hormonal therapy with exemestane. No secondary cause of erythrocytosis was identified. Serum erythropoietin (EPO level was normal, and molecular testing for the JAK2 V617F and exon 12 mutations was negative. A bone marrow biopsy showed a mild increase in erythropoiesis, and no spontaneous erythroid colonies were demonstrated. Erythrocytosis is common reason for referral to a hematologist. The myeloproliferative disorder, polycythemia vera, and the rare congenital polycythemias represent primary erythrocytosis. Common secondary causes include smoking, obstructive sleep apnea, and other pulmonary diseases. Erythrocytosis is well described with certain classes of drugs, including androgens. We hypothesize that exemestane contributed to the development of erythrocytosis in our patient. To our knowledge, erythrocytosis has not been previously described in association with aromatase inhibitors. These drugs prevent the conversion of androstenedione and testosterone to estrogen; thus the physiologic mechanisms may be similar to those responsible for erythrocytosis seen with exogenous androgens. These mechanisms are not well understood, but may include altered iron metabolism by a reduction in hepcidin levels.

  5. Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update.

    Science.gov (United States)

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

    There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2-3 years followed by exemestane or anastrozole for 2-3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2-3 years of tamoxifen. The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures. PMID:16981992

  6. Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1.

    Science.gov (United States)

    McBryan, Jean; Theissen, Sarah M; Byrne, Christopher; Hughes, Eamon; Cocchiglia, Sinead; Sande, Stephen; O'Hara, Jane; Tibbitts, Paul; Hill, Arnold D K; Young, Leonie S

    2012-01-15

    Aromatase inhibitors (AI) are a standard-of-care treatment for postmenopausal, estrogen receptor-positive breast cancers. Although tumor recurrence on AI therapy occurs, the mechanisms underlying acquired resistance to AIs remain unknown. In this study, we examined a cohort of endocrine-treated breast cancer patients and used a cell line model of resistance to the AI letrozole. In patients treated with a first-line AI, hormone receptor switching between primary and resistant tumors was a common feature of disease recurrence. Resistant cells exhibited a switch from steroid-responsive growth to growth factor-responsive and endocrine-independent growth, which was accompanied by the development of a more migratory and disorganized phenotype. Both the resistant cells and tumors from AI-resistant patients showed high expression of the steroid receptor coactivator SRC-1. Direct interactions between SRC-1 and the transcription factor Ets2 regulated Myc and MMP9. SRC-1 was required for the aggressive and motile phenotype of AI-resistant cells. Interestingly, SRC-1 expression in primary and/or recurrent tumors was associated with a reduction in disease-free survival in treated patients. Moreover, there was a significant association between SRC-1 and Ets2 in the recurrent tissue compared with the matched primary tumor. Together, our findings elucidate a mechanism of AI-specific metastatic progression in which interactions between SRC-1 and Ets2 promote dedifferentiation and migration in hormone-dependent breast cancer. PMID:22108824

  7. Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.

    Science.gov (United States)

    Sulaica, Elisabeth; Han, Tiffany; Wang, Weiqun; Bhat, Raksha; Trivedi, Meghana V; Niravath, Polly

    2016-06-01

    Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients. PMID:27178335

  8. Defining Quantum Control Flow

    OpenAIRE

    Ying, Mingsheng; Yu, Nengkun; Feng, Yuan

    2012-01-01

    A remarkable difference between quantum and classical programs is that the control flow of the former can be either classical or quantum. One of the key issues in the theory of quantum programming languages is defining and understanding quantum control flow. A functional language with quantum control flow was defined by Altenkirch and Grattage [\\textit{Proc. LICS'05}, pp. 249-258]. This paper extends their work, and we introduce a general quantum control structure by defining three new quantu...

  9. Historically defined autobiographical periods

    DEFF Research Database (Denmark)

    Brown, Norman R.; Hansen, Tia G. B.; Lee, Peter J.;

    2012-01-01

    The chapter reviews a research programme that has demonstrated the existence of historically defined autobiographical periods and identified the conditions that bring them about. Data from four samples of World War II-generation adults show that historically defined autobiographical periods endure...

  10. The relationship of bone-tumor-induced spinal cord astrocyte activation and aromatase expression to mechanical hyperalgesia and cold hypersensitivity in intact female and ovariectomized mice.

    Science.gov (United States)

    Smeester, B A; O'Brien, E E; Michlitsch, K S; Lee, J-H; Beitz, A J

    2016-06-01

    Recently, our group established a relationship between tumor-induced spinal cord astrocyte activation and aromatase expression and the development of bone tumor nociception in male mice. As an extension of this work, we now report on the association of tumor-induced mechanical hyperalgesia and cold hypersensitivity to changes in spinal cord dorsal horn GFAP and aromatase expression in intact (INT) female mice and the effect of ovariectomy on these parameters. Implantation of fibrosarcoma cells produced robust mechanical hyperalgesia in INT animals, while ovariectomized (OVX) females had significantly less mechanical hyperalgesia. Cold hypersensitivity was apparent by post-implantation day 7 in INT and OVX females compared to their saline-injected controls and increased throughout the experiment. The decrease in mechanical hyperalgesia in OVX females was mirrored by significant decreases in spinal astrocyte activity in laminae I-II, III-IV, V-VI and X and aromatase expression in laminae V-VI and X in the dorsal horn of tumor-bearing animals. Administration of the aromatase inhibitor letrozole reduced tumor-induced hyperalgesia in INT females only suggesting that the tumor-induced increase in aromatase expression and its associated increase in spinal estrogen play a role in the development of bone tumor-induced hyperalgesia. Finally, intrathecal (i.t.) administration of 17β-estradiol caused a significant increase in tumor-induced hyperalgesia in INT tumor-bearing females. Since i.t. 17β-estradiol increases tumor pain and ovariectomy significantly decreases tumor pain, as well as spinal aromatase, estrogen may play a critical role in the spinal cord response to the changing tumor environment and the development of tumor-induced nociception. PMID:26995084

  11. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    Energy Technology Data Exchange (ETDEWEB)

    Gorrochategui, Eva; Pérez-Albaladejo, Elisabet [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Casas, Josefina [Department of Biomedicinal Chemistry, IQAC–CSIC, 08034 Barcelona, Catalonia (Spain); Lacorte, Sílvia, E-mail: slbqam@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain); Porte, Cinta, E-mail: cinta.porte@cid.csic.es [Department of Environmental Chemistry, IDAEA–CSIC, 08034 Barcelona, Catalonia (Spain)

    2014-06-01

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  12. Perfluorinated chemicals: Differential toxicity, inhibition of aromatase activity and alteration of cellular lipids in human placental cells

    International Nuclear Information System (INIS)

    The cytotoxicity of eight perfluorinated chemicals (PFCs), namely, perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoA), perfluorobutanesulfonate (PFBS), perfluorohexanesulfonate (PFHxS) and perfluorooctanesulfonate (PFOS) was assessed in the human placental choriocarcinoma cell line JEG-3. Only the long chain PFCs – PFOS, PFDoA, PFNA, PFOA – showed significant cytotoxicity in JEG-3 cells with EC50 values in the range of 107 to 647 μM. The observed cytotoxicity was to some extent related to a higher uptake of the longer chain PFCs by cells (PFDoA > PFOS ≫ PFNA > PFOA > PFHxA). Moreover, this work evidences a high potential of PFOS, PFOA and PFBS to act as aromatase inhibitors in placental cells with IC50s in the range of 57–80 μM, the inhibitory effect of PFBS being particularly important despite the rather low uptake of the compound by cells. Finally, exposure of JEG-3 cells to a mixture of the eight PFCs (0.6 μM each) led to a relative increase (up to 3.4-fold) of several lipid classes, including phosphatidylcholines (PCs), plasmalogen PC and lyso plasmalogen PC, which suggests an interference of PFCs with membrane lipids. Overall, this work highlights the ability of the PFC mixture to alter cellular lipid pattern at concentrations well below those that generate toxicity, and the potential of the short chain PFBS, often considered a safe substitute of PFOS, to significantly inhibit aromatase activity in placental cells. - Highlights: • Eight perfluorinated chemicals of different chain lengths have been selected. • Long chain ones – PFOS, PFDoA, PFNA, PFOA – were cytotoxic in placenta cells. • The uptake of long chain perfluorinated chemicals by cells was comparatively higher. • PFOS, PFOA and the short chain PFBS significantly inhibited aromatase activity. • A mixture of perfluorinated chemicals significantly altered placenta cell

  13. Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli

    OpenAIRE

    Black, Michael P; Balthazart, Jacques; Baillien, Michelle; Grober, Matthew S.

    2010-01-01

    In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the...

  14. Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Michelle L Van Sinderen

    Full Text Available The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2 treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα and interleukin 6 (IL6. Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.

  15. Evaluation of the quality and accuracy of information regarding aromatase inhibitors available on the internet.

    Science.gov (United States)

    Beaton, Ceri; Codd, Rhodri J; Holland, Phillip A; Gateley, Christopher A

    2008-01-01

    The internet is commonly used by patients to access medical information, particularly where new treatments become available and are highlighted in the press. There is however, no regulation of the quality or accuracy of the information presented on web sites. The aim of this study was to evaluate the quality and accuracy of the information concerning the aromatase inhibitors (AIs). The three most popular search engines: Google, Yahoo, and MSN were utilized. The top ten "hits" for the generic and proprietary names of each AIs: anastrozole (Arimidex), exemestane (Aromasin), and letrozole (Femara) were evaluated using a 12-point score by a single assessor. The accuracy of the information provided was compared with the National Institute for Health and Clinical Excellence guidelines. The mean score for the 180 web sites was only 6.13 out of 12 (0-11). If we consider a score of 9 or more out of 12 (> or =75%) for a web site to represent good quality information, then 51 (28%) of pages scored well. Google was slightly better than Yahoo and MSN; with the highest percentage of web sites scoring well. In evaluating hits according to type of web sites, 50 (28%) were charity web sites and 30 (17%) were drug company web sites and both groups scored significantly higher than the overall mean (charity p = 0.014, drug company p = 0.001). Only 2 of 180 hits gave accurate statistical evidence regarding the benefits of AIs over tamoxifen. We have found that the quality and accuracy of information concerning AIs provided on the Internet is poor and patients using it are unlikely to find accurate information. It is therefore our duty as healthcare providers to guide patients, so as to avoid them from being overwhelmed by irrelevant and conflicting information. PMID:18537915

  16. Defining origins of malignant B cells: a new circulating normal human IgM(+)D(+) B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population.

    Science.gov (United States)

    Weston-Bell, N; Townsend, M; Di Genova, G; Forconi, F; Sahota, S S

    2009-11-01

    In probing the cell of origin in malignant B cells, an imprint of somatic hypermutation (SHM) in immunoglobulin (Ig) variable (V) region genes delineates antigen encounter, and identifying the precise pathway generating SHM in the normal B-cell counterpart becomes relevant. SHM remains the definitive memory imprint in normal human B cells, but CD27 expression also delineates memory. Recently, dye extrusion adenosine triphosphate-binding transporter assays identified circulating isotype-switched memory B cells that lacked CD27, yet exhibited low levels of SHM. To extend findings, we report a pre-switched CD27(-ve) circulating memory B-cell population in normal blood using comparable assays, and isolated CD19(+)IgM(+)D(+)CD27(-ve) cells (>99% purity) for the analysis of IGHV5/IGHV3-IGHM transcripts. Of these (n=334), approximately 78% were germ line and naive B cell derived. Strikingly, 21.9% of the transcripts were mutated. They showed 3-5 mutations (13.5% of sequences) and >5 mutations (8.4% of sequences) per transcript. Accrual of mutations in a subset of CD19(+)IgM(+)D(+)CD27(-ve) cells define a new circulating pre-switched memory B-cell pool, present in substantial numbers in the population harboring naive B cells. These CD19(+)IgM(+)D(+)CD27(-ve) memory B cells may have a distinct lineage and function, and seem relevant to understanding origins of malignant B cells, in particular those of hairy cell leukemia cells, which display mutated V genes yet lack CD27 expression. PMID:19776762

  17. Between-female variation in house sparrow yolk testosterone concentration is negatively associated with CYP19A1 (aromatase) mRNA expression in ovarian follicles.

    Science.gov (United States)

    Egbert, Jeremy R; Jackson, Melissa F; Rodgers, Buel D; Schwabl, Hubert

    2013-03-01

    Maternally-derived yolk androgens influence the development and long-term phenotype of offspring in oviparous species. Between-female variation in the amounts of these yolk androgens has been associated with a number of social and environmental factors, suggesting that the variation is adaptive, but the mechanisms behind it are unknown. Using two different approaches, we tested the hypothesis that variation in yolk androgen levels across individuals is associated with variation in their capacity to synthesize androgens. First, we injected female house sparrows with exogenous gonadotropin-releasing hormone (GnRH) to maximally stimulate ovarian steroidogenesis. Second, we collected pre-ovulatory follicle tissue and quantified the mRNA expression of four key enzymes of the steroid synthesis pathway: steroidogenic acute regulatory protein (StAR), cytochrome P450-side chain cleavage enzyme (CYP11A1), 17β-hydroxysteroid dehydrogenase (HSD17B1), and aromatase (CYP19A1). Thirty minutes after GnRH injection, androgen concentrations in both the plasma and in the yolks of pre-ovulatory follicles were significantly elevated compared to controls. However, this measure of steroidogenic capacity did not explain variation in yolk testosterone levels, although physiological differences between house sparrows and more widely studied poultry models were revealed by this approach. Steroidogenic enzyme mRNA levels were detectable in all samples and were significantly lower in the most mature pre-ovulatory follicles. Of the four measured genes, CYP19A1 expression exhibited a significant negative relationship with yolk testosterone concentrations in laid eggs, revealing a key mechanism for between-female variation in yolk testosterone. Furthermore, this suggests that any factors which alter the expression of CYP19A1 within an individual female could have dramatic effects on offspring phenotype. PMID:23247271

  18. How to define surveillance?

    Directory of Open Access Journals (Sweden)

    Christian Fuchs

    2011-12-01

    Full Text Available The task of this paper is to explore and compare ways of defining surveillance. In order to give meaning to concepts that describe the realities of society, social theory is needed. Therefore social theory is employed in this paper for discussing ways of defining surveillance. “Living in ‘surveillance societies’ may throw up challenges of a fundamental – ontological – kind” (Lyon, 1994, p.19. Social theory is a way of clarifying such ontological questions that concern the basic nature and reality of surveillance. A distinction between neutral and negative concepts of surveillance is drawn. Some potential disadvantages of neutral concepts of surveillance are outlined. This paper wants to contribute to the discussion of how to best define surveillance and wants to show that one of the main theoretical differences and questions in surveillance theory is if surveillance should be defined as a negative or a neutral concept.

  19. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    International Nuclear Information System (INIS)

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC50: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They inhibited

  20. Two natural products, trans-phytol and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol, inhibit the biosynthesis of estrogen in human ovarian granulosa cells by aromatase (CYP19)

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Jiajia [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Yuan, Yun [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Lu, Danfeng; Du, Baowen [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Xiong, Liang; Shi, Jiangong [State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Yang, Lijuan [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Liu, Wanli [MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Yuan, Xiaohong [School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang (China); Zhang, Guolin, E-mail: zhanggl@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China); Wang, Fei, E-mail: wangfei@cib.ac.cn [Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu (China); Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu (China)

    2014-08-15

    Aromatase is the only enzyme in vertebrates to catalyze the biosynthesis of estrogens. Although inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer, the whole-body inhibition of aromatase causes severe adverse effects. Thus, tissue-selective aromatase inhibitors are important for the treatment of estrogen-dependent cancers. In this study, 63 natural products with diverse structures were examined for their effects on estrogen biosynthesis in human ovarian granulosa-like KGN cells. Two compounds—trans-phytol (SA-20) and (22E)-ergosta-6,9,22-triene-3β,5α,8α-triol (SA-48)—were found to potently inhibit estrogen biosynthesis (IC{sub 50}: 1 μM and 0.5 μM, respectively). Both compounds decreased aromatase mRNA and protein expression levels in KGN cells, but had no effect on the aromatase catalytic activity in aromatase-overexpressing HEK293A cells and recombinant expressed aromatase. The two compounds decreased the expression of aromatase promoter I.3/II. Neither compound affected intracellular cyclic AMP (cAMP) levels, but they inhibited the phosphorylation or protein expression of cAMP response element-binding protein (CREB). The effects of these two compounds on extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs), and AKT/phosphoinositide 3-kinase (PI3K) pathway were examined. Inhibition of p38 MAPK could be the mechanism underpinning the actions of these compounds. Our results suggests that natural products structurally similar to SA-20 and SA-48 may be a new source of tissue-selective aromatase modulators, and that p38 MAPK is important in the basal control of aromatase in ovarian granulosa cells. SA-20 and SA-48 warrant further investigation as new pharmaceutical tools for the prevention and treatment of estrogen-dependent cancers. - Highlights: • Two natural products inhibited estrogen biosynthesis in human ovarian granulosa cells. • They

  1. Defining Documentary Film

    DEFF Research Database (Denmark)

    Juel, Henrik

    2006-01-01

    A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film......A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film...

  2. Interpolation and Definability

    Science.gov (United States)

    Gabbay, Dov M.; Maksimova, Larisa L.

    This chapter is on interpolation and definability. This notion is not only central in pure logic, but has significant meaning and applicability in all areas where logic itself is applied, especially in computer science, artificial intelligence, logic programming, philosophy of science and natural language. The notion may sometimes appear to the reader as too technical/mathematical but it does also have a general meaning in terms of expressibility and definability.

  3. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  4. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Directory of Open Access Journals (Sweden)

    Nicolas Defarge

    2016-02-01

    Full Text Available Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH, the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations, and not the declared active ingredient glyphosate (G alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone.

  5. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels

    Science.gov (United States)

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18–2000 times for co-formulants, 8–141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine—POEA and alkyl polyglucoside—APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  6. Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels.

    Science.gov (United States)

    Defarge, Nicolas; Takács, Eszter; Lozano, Verónica Laura; Mesnage, Robin; Spiroux de Vendômois, Joël; Séralini, Gilles-Eric; Székács, András

    2016-01-01

    Pesticide formulations contain declared active ingredients and co-formulants presented as inert and confidential compounds. We tested the endocrine disruption of co-formulants in six glyphosate-based herbicides (GBH), the most used pesticides worldwide. All co-formulants and formulations were comparably cytotoxic well below the agricultural dilution of 1% (18-2000 times for co-formulants, 8-141 times for formulations), and not the declared active ingredient glyphosate (G) alone. The endocrine-disrupting effects of all these compounds were measured on aromatase activity, a key enzyme in the balance of sex hormones, below the toxicity threshold. Aromatase activity was decreased both by the co-formulants alone (polyethoxylated tallow amine-POEA and alkyl polyglucoside-APG) and by the formulations, from concentrations 800 times lower than the agricultural dilutions; while G exerted an effect only at 1/3 of the agricultural dilution. It was demonstrated for the first time that endocrine disruption by GBH could not only be due to the declared active ingredient but also to co-formulants. These results could explain numerous in vivo results with GBHs not seen with G alone; moreover, they challenge the relevance of the acceptable daily intake (ADI) value for GBHs exposures, currently calculated from toxicity tests of the declared active ingredient alone. PMID:26927151

  7. Brain cytochrome P450 aromatase activity in roach (Rutilus rutilus): seasonal variations and impact of environmental contaminants.

    Science.gov (United States)

    Geraudie, Perrine; Hinfray, Nathalie; Gerbron, Marie; Porcher, Jean-Marc; Brion, François; Minier, Christophe

    2011-10-01

    P450 aromatase catalyses the conversion of C19 androgens to C18 estrogens which is thought to be essential for the regulation of the reproductive function. In this study, brain aromatase activity (AA) was measured monthly over a reproductive cycle in wild roach (Rutilus rutilus) sampled in a reference site in Normandy. AA peaked during the breeding season, reaching 35 fmol mg(-1)min(-1) in both male and female fish, and was low during the rest of the year except for a significant rise in October. AA was correlated with ovary maturation (measured either as gonado-somatic index or by histological analysis of the gonads) and plasma sex-steroid levels (11-ketotestosterone in males and 17-β-estradiol in females). Measurements of AA in polluted sites showed that activity was significantly upregulated in sites with fish showing high levels of plasma vitellogenin and large proportion of intersexuality (20-50%) thus suggesting the occurrence of estrogenic compounds and their involvement in AA modulation. PMID:21820384

  8. Effects of the aromatase inhibitor Letrozole on serum immunoglobulin and lysozyme levels in immunized rainbow trout (Oncorhynchus mykiss Walbaum females

    Directory of Open Access Journals (Sweden)

    Paria Akbary

    2013-12-01

    Full Text Available Letrozole is a synthetic aromatase inhibitor and interfere in the committed step in the synthesis of endogenous estrogens from androgens. Also estrogens regulate the immune system in teleost. Changes of 17- β- esrtradiol (E2, serum immunoglobulin and lysozyme levels were measured using a method based on the ability of lysozyme to lyse the bacterium Micrococcus lysodeikticus, enzyme-linked immunosorbent assay (ELISA and ELISA respectively. Twelve broodstocks were injected weekly with 2.5 mg kg-1 letrozole (an endocrine disrupter component two months before spawning season and vaccinated intraperitoneally (i.p with a bacterin (inactivated L. garviae one month before spawning. Twelve broodstocks for vaccination and twelve female rainbow trout as control group were also immiunised (i.p with the bacterin and injected (i.p with PBS, respectively. In the group received 2.5 mg AI kg-1 per week, serum E2 levels were significantly lower than that of other groups. Total immunoglobulin level and lysozyme activity were significantly higher in the parents received 2.5 mg kg-1 per week and were immunized with 10-9 cells ml-1 Lactococcus garvieae  compared to the group which immunized with L. garvieae and the control (non- immunized. The present study, suggests that aromatase inhibitors such as letrozole may be a potential tool to regulate the synthesis of E2, is involved in the hormone- immune system interaction in rainbow trout.

  9. Can play be defined?

    DEFF Research Database (Denmark)

    Eichberg, Henning

    2015-01-01

    Can play be defined? There is reason to raise critical questions about the established academic demand that at phenomenon – also in humanist studies – should first of all be defined, i.e. de-lineated and by neat lines limited to a “little box” that can be handled. The following chapter develops the...... critical argument against this academic technique by going back to the history of cultural anthropology of play. This history did not develop in a linear way, but by shifts between different periods of colonial and anticolonial positions, as well as between more positivistic and more relativist approaches...... construction. Human beings can very well understand play – or whatever phenomenon in human life – without defining it....

  10. Androgen priming using aromatase inhibitor and hCG during early-follicular-phase GnRH antagonist down-regulation in modified antagonist protocols

    DEFF Research Database (Denmark)

    Løssl, Kristine; Andersen, A N; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, C Yding

    2006-01-01

    Temporary exposure of follicles to increased levels of androgens may enhance their sensitivity to FSH. The aim of this study was to increase the intraovarian androgen level using aromatase inhibitors and hCG before controlled ovarian stimulation (COH) and to test this concept clinically....

  11. Short-term androgen priming by use of aromatase inhibitor and hCG before controlled ovarian stimulation for IVF. A randomized controlled trial

    DEFF Research Database (Denmark)

    Lossl, K; Andersen, C Yding; Loft, A; Freiesleben, N L C; Bangsbøll, S; Andersen, A Nyboe; Løssl, Kristine

    2008-01-01

    Temporary exposure of follicles to increased levels of androgens may augment follicular responsiveness. The present study tested whether short-term androgen priming by aromatase inhibitor and human chorionic gonadotrophin (hCG) before controlled ovarian stimulation (COS) increases the number of top...

  12. Differential responsiveness of luteinized human granulosa cells to gonadotropins and insulin-like growth factor I for induction of aromatase activity

    International Nuclear Information System (INIS)

    The objective of this study was to examine the in vitro responsiveness of cultured luteinized human granulosa cells over time to insulin-like growth factor 1 (IGF-1), human follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) for the induction of aromatase activity. Granulosa cells were retrieved from preovulatory follicles in patients undergoing in vitro fertilization. Cells were cultured for a period of 72 hours or 10 days. The ability of hCG, human FSH, and/or IGF-I to induce aromatase activity was assayed by the stereospecific release of tritium from [1B-3H]androstenedione. Short-term cultures (72 hours) demonstrated a marked rise in aromatase activity in response to human FSH and IGF-I, whereas a smaller response to hCG was observed. In contrast, 10-day cultures demonstrated responsiveness predominantly to hCG rather than human FSH for the induction of aromatase activity with no remarkable effect of IGF-I. Luteinized human granulosa cells undergo a transformation from an initial human FSH and IGF-I responsive state to an hCG responsive state in long-term cultures

  13. Defining Data Science

    OpenAIRE

    Zhu, Yangyong; Xiong, Yun

    2015-01-01

    Data science is gaining more and more and widespread attention, but no consensus viewpoint on what data science is has emerged. As a new science, its objects of study and scientific issues should not be covered by established sciences. Data in cyberspace have formed what we call datanature. In the present paper, data science is defined as the science of exploring datanature.

  14. Defining Game Mechanics

    DEFF Research Database (Denmark)

    Sicart (Vila), Miguel Angel

    2008-01-01

    This article defins game mechanics in relation to rules and challenges. Game mechanics are methods invoked by agents for interacting with the game world. I apply this definition to a comparative analysis of the games Rez, Every Extend Extra and Shadow of the Colossus that will show the relevance...... of a formal definition of game mechanics. Udgivelsesdato: Dec 2008...

  15. On Defining Mass

    Science.gov (United States)

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement…

  16. Integrative STEM Education Defined

    OpenAIRE

    Sanders, Mark E.

    2013-01-01

    "In operationally defining integrative STEM education, we hope to avoid the gross confusion/ambiguity associated with STEM education. Those who wish to use integrative STEM education to describe instruction must be certain that instruction is grounded in the context of technological/engineering design activity.

  17. Effect of a hormone-releasing intrauterine system (Mirena® on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection

    Directory of Open Access Journals (Sweden)

    Maia R

    2012-04-01

    Full Text Available Hugo Maia Jr1,2, Clarice Haddad1, Julio Casoy1, Rebeca Maia1, Nathanael Pinheiro3, Elsimar M Coutinho11Centro de Pesquisa e Assistência em Reprodução Humana (CEPARH, 2Itaigara Memorial Day Hospital, 3IMAGEPAT, Salvador, Bahia, BrazilObjective: To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena® on aromatase and cyclooxygenase-2 (Cox-2 expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment.Patients and methods: Patients with adenomyosis (n = 89 were included in this study. Twenty-two patients had been using Mirena® for 5 years but had not been submitted to endometrial resection prior to insertion of the device. Twenty-four patients were submitted to endometrial resection at the time of Mirena® insertion. The remaining 43 patients with adenomyosis had undergone no previous hormonal treatment and served as a control group. Cox-2 and aromatase expression were determined in the endometrium by immunohistochemistry.Results: Use of Mirena® for 5 years reduced aromatase expression in the endometrium; however, this reduction was significantly greater in the uteri previously submitted to endometrial resection. The reduction in Cox-2 expression was significant only in the uteri submitted to endometrial resection followed by the insertion of Mirena®.Conclusion: Endometrial resection followed by the insertion of Mirena® was associated with greater rates of amenorrhea in patients with adenomyosis, which in turn were associated with a more effective inhibition of aromatase and Cox-2 expression in the endometrium.Keywords: aromatase, Mirena®, adenomyosis, Cox-2, endometrium, levonorgestrel

  18. Reinvestigation of the synthesis and evaluation of [N-methyl-{sup 11}C]vorozole, a radiotracer targeting cytochrome P450 aromatase

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Won [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States)], E-mail: swkim@bnl.gov; Biegon, Anat; Katsamanis, Zachary E. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Ehrlich, Carolin W. [Johannes-Gutenberg Universitaet Mainz, Institut fuer Organische Chemie, Duesbergweg 10-14, Mainz (Germany); Hooker, Jacob M.; Shea, Colleen [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Muench, Lisa [National Institute on Alcoholism and Alcohol Abuse, Bethesda, MD (United States); Xu Youwen; King, Payton; Carter, Pauline; Alexoff, David L. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Fowler, Joanna S. [Medical Department, Brookhaven National Laboratory, Upton, NY 11973 (United States); Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (United States); Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY (United States)

    2009-04-15

    Introduction: We reinvestigated the synthesis of [N-methyl-{sup 11}C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-{sup 11}C]vorozole. Methods: Norvorozole was alkylated with [{sup 11}C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ({sup 13}C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-{sup 11}C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-{sup 11}C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-{sup 11}C]vorozole binds to aromatase. [N-methyl-{sup 11}C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-{sup 11}C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

  19. Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Meijer Danielle

    2011-07-01

    Full Text Available Abstract Background Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas in vitro and in vivo. Methods We investigated the protein expression of estrogen receptor alpha (ESR1, androgen receptor (AR, and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4 or exemestane (n = 2 treatment in 6 chondrosarcoma patients with progressive disease was explored. Results We showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma in vitro. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients. Conclusions The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth.

  20. Reinvestigation of the synthesis and evaluation of [N-methyl-11C]vorozole, a radiotracer targeting cytochrome P450 aromatase

    International Nuclear Information System (INIS)

    Introduction: We reinvestigated the synthesis of [N-methyl-11C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-11C]vorozole. Methods: Norvorozole was alkylated with [11C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy (13C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-11C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-11C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-11C]vorozole binds to aromatase. [N-methyl-11C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-11C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

  1. DEFINING SUCCESS IN PROJECTS

    Directory of Open Access Journals (Sweden)

    José Rodrigues de Farias Filho

    2011-05-01

    Full Text Available The Project Management Discipline has been widely used in the last years for companies around the world and these companies have been investing large amounts on surveys, training and consulting in order to get benefits for the organizations that need to create competitive advantage in the high competitive Market and to achieve their business strategy goals. Studies from the major world authors show many ways to define success at the organizations. In Brazil, the Benchmarking Study in GP from the PMI Chapters in 2009, show most studied companies don’t have a process do assess whether they are achieving the expected business goals with their investments in Project Management. This article goal is to demonstrate many ways to define success in project, which will facilitate the process to assess whether the companies are achieving these expected goals. The methodology used was a literature review, collecting publications, textbooks and documents from subject-matter-experts.

  2. Defining Legal Moralism

    DEFF Research Database (Denmark)

    Thaysen, Jens Damgaard

    2015-01-01

    This paper discusses how legal moralism should be defined. It is argued that legal moralism should be defined as the position that “For any X, it is always a pro tanto reason for justifiably imposing legal regulation on X that X is morally wrong (where “morally wrong” is not conceptually equivalent...... to “harmful”)”. Furthermore, a distinction between six types of legal moralism is made. The six types are grouped according to whether they are concerned with the enforcement of positive or critical morality, and whether they are concerned with criminalising, legally restricting, or refraining from...... legally protecting morally wrong behaviour. This is interesting because not all types of legal moralism are equally vulnerable to the different critiques of legal moralism that have been put forth. Indeed, I show that some interesting types of legal moralism have not been criticised at all....

  3. Defining talent management components

    OpenAIRE

    Golchin Shafieian

    2014-01-01

    In today's world of global trade, it can guarantee success and excellence of organizations against competitors is talented human resources in an organization, especially at the managerial level. But the challenges that organizations face include: attracting, evaluating, exploring, and developing and keeping talent. The main objective of this study is to define the components of talent management in the University of Chaloos, in order to provide a way to reduce the challenges and short comings...

  4. Defining local food

    DEFF Research Database (Denmark)

    Eriksen, Safania Normann

    2013-01-01

    Despite evolving local food research, there is no consistent definition of “local food.” Various understandings are utilized, which have resulted in a diverse landscape of meaning. The main purpose of this paper is to examine how researchers within the local food systems literature define local...... food, and how these definitions can be used as a starting point to identify a new taxonomy of local food based on three domains of proximity....

  5. Software Defined Networking

    OpenAIRE

    Roncero Hervás, Óscar

    2014-01-01

    Software Defined Networks (SDN) is a paradigm in which routing decisions are taken by a control layer. In contrast to conventional network structures, the control plane and forwarding plane are separated and communicate through standard protocols like OpenFlow. Historically, network management was based on a layered approach, each one isolated from the others. SDN proposes a radically different approach by bringing together the management of all these layers into a single controller. It is th...

  6. SDN : Software defined networks

    OpenAIRE

    Wiklund, Petter

    2014-01-01

    This report is a specialization in Software defined networking. SDN really comes to revolutionize the industry and it’s under constant development. But is the technology ready to be launched into operation yet? The report would initially involve a number of problems that today's network technology is facing. It then follows a deeper description of what this software-based networking technology really is and how it works. Further, the technique is being tested in a lab assignment, using a prog...

  7. Defining biodiversity resources

    OpenAIRE

    Gadgil, Madhav

    2000-01-01

    The scope of the Biological Diversity Bill, tabled in the monsoon 2000 session of the Indian Parliament is excessively wide covering all biological resources. Instead it should focus on diversity related end-uses such as drugs, industrial enzymes, cosmetics, dyestuffs, plant growth regulators, emulsifiers, oleoresins and genes used for improving crops and livestock through breeding and genetic intervention. It should seek to regulate collection and movement of such biodiversity resources and ...

  8. Defining Business Network

    Directory of Open Access Journals (Sweden)

    Raffaele Trequattrini

    2012-02-01

    Full Text Available The purpose of the present scientific contribution is to investigate from the business economics standpoing the emerging phenomenon of company networks. In particular, through the analysis of the theory of networks will be proposed the principal categories of business networks, and even before this the concept of the network will be defined. The proposed research, qualitatively, represents the point of departure for the study of the network phenomenon in light of the current economic phase termed “economy of knowledge”. Moreover, the research questions are the following: From where does the theory of networks arise? Do company networks consider themselves equal to knowledge networks?

  9. Defining Business Network

    Directory of Open Access Journals (Sweden)

    Raffaele Trequattrini

    2012-02-01

    Full Text Available The purpose of the present scientific contribution is to investigate from the businesseconomics standpoing the emerging phenomenon of company networks. In particular,through the analysis of the theory of networks will be proposed the principal categories ofbusiness networks, and even before this the concept of the network will be defined. Theproposed research, qualitatively, represents the point of departure for the study of thenetwork phenomenon in light of the current economic phase termed “economy of knowledge”.Moreover, the research questions are the following: From where does the theory of networksarise? Do company networks consider themselves equal to knowledge networks?

  10. Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs)

    International Nuclear Information System (INIS)

    Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

  11. [Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

    Science.gov (United States)

    Sakurai, Kenichi; Fujisaki, Shigeru; Suzuki, Shuhei; Adachi, Keita; Nagashima, Saki; Masuo, Yuki; Tomita, Ryouichi; Gonda, Kenji; Enomoto, Katsuhisa; Amano, Sadao; Matsuo, Sadanori; Umeda, Nao

    2015-10-01

    We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy. PMID:26489554

  12. Defining talent management components

    Directory of Open Access Journals (Sweden)

    Golchin Shafieian

    2014-07-01

    Full Text Available In today's world of global trade, it can guarantee success and excellence of organizations against competitors is talented human resources in an organization, especially at the managerial level. But the challenges that organizations face include: attracting, evaluating, exploring, and developing and keeping talent. The main objective of this study is to define the components of talent management in the University of Chaloos, in order to provide a way to reduce the challenges and short comings and also to look for ways to improve employee performance is discussed. This study is based on data collected from all employees of the University of Chaloos in August 2013; through two questionnaires have been developed. The statistical population has been considered 407 persons in these universities and according the Morgan Table, 198 persons were selected as sample of among research society. More over, 28 questions are used for determining components of talent management. Finally, we concluded that the component of talent management have been properly defined in the Universities of Chaloos.

  13. Software-Defined Cluster

    Institute of Scientific and Technical Information of China (English)

    聂华; 杨晓君; 刘淘英

    2015-01-01

    The cluster architecture has played an important role in high-end computing for the past 20 years. With the advent of Internet services, big data, and cloud computing, traditional clusters face three challenges: 1) providing flexible system balance among computing, memory, and I/O capabilities;2) reducing resource pooling overheads;and 3) addressing low performance-power efficiency. This position paper proposes a software-defined cluster (SDC) architecture to deal with these challenges. The SDC architecture inherits two features of traditional cluster: its architecture is multicomputer and it has loosely-coupled interconnect. SDC provides two new mechanisms: global I/O space (GIO) and hardware-supported native access (HNA) to remote devices. Application software can define a virtual cluster best suited to its needs from resources pools provided by a physical cluster, and traditional cluster ecosystems need no modification. We also discuss a prototype design and implementation of a 32-processor cloud server utilizing the SDC architecture.

  14. Evaluation of a bioluminescent mouse model expressing aromatase PII-promoter-controlled luciferase as a tool for the study of endocrine disrupting chemicals

    International Nuclear Information System (INIS)

    Dysfunction of the enzyme aromatase (CYP19) is associated with endocrine pathologies such as osteoporosis, impaired fertility and development of hormone-dependent cancers. Certain endocrine disrupting chemicals affect aromatase expression and activity in vitro, but little is known about their ability to do so in vivo. We evaluated a bioluminescent mouse model (LPTA (registered) )CD-1-Tg(Cyp19-luc)-Xen) expressing luciferase under control of the gonadal aromatase pII promoter as an in vivo screening tool for chemicals that may affect aromatase expression. We studied the effects of forskolin, pregnant mare serum gonadotropin and atrazine in this model (atrazine was previously shown to induced pII-promoter-driven aromatase expression in H295R human adrenocortical carcinoma cells). About 2-4 out of every group of 10 male or female Cyp19-luc mice injected i.p. with 10 mg/kg forskolin had increased gonadal bioluminescence after 3-5 days compared to controls; the others appeared non-responsive. Similarly, about 4 per group of 9 individual females injected with pregnant mare serum gonadotropin had increased ovarian bioluminescence after 24 h. There was a statistically significant correlation between ovarian bioluminescence and plasma estradiol concentrations (n = 14; p = 0.022). Males exposed to a single dose of 100 mg/kg or males and females exposed to 5 daily injections of 30 mg/kg atrazine showed no change in gonadal bioluminescence over a 7 day period, but a significant interaction was found between atrazine (100 mg/kg) and time in female mice (p < 0.05; two-way ANOVA). Ex vivo luciferase activity in dissected organs was increased by forskolin in testis, epididymis and ovaries. Atrazine (30 mg/kg/day) increased (30%) luciferase activity significantly in epididymis only. In conclusion, certain individual Cyp19-luc mice are highly responsive to aromatase inducers, suggesting this model, with further optimization, may have potential as an in vivo screening tool for

  15. On Defining Mass

    Science.gov (United States)

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement surrounding the Large Hadron Collider at CERN is associated with discovering the mechanism responsible for the masses of the elementary particles. This paper will first briefly examine the leading definitions, pointing out their shortcomings. Then, utilizing relativity theory, it will propose—for consideration by the community of physicists—a conceptual definition of mass predicated on the more fundamental concept of energy, more fundamental in that everything that has mass has energy, yet not everything that has energy has mass.

  16. Implementing Software Defined Radio

    CERN Document Server

    Grayver, Eugene

    2013-01-01

    Software Defined Radio makes wireless communications easier, more efficient, and more reliable. This book bridges the gap between academic research and practical implementation. When beginning a project, practicing engineers, technical managers, and graduate students can save countless hours by considering the concepts presented in these pages. The author covers the myriad options and trade-offs available when selecting an appropriate hardware architecture. As demonstrated here, the choice between hardware- and software-centric architecture can mean the difference between meeting an aggressive schedule and bogging down in endless design iterations. Because of the author’s experience overseeing dozens of failed and successful developments, he is able to present many real-life examples. Some of the key concepts covered are: Choosing the right architecture for the market – laboratory, military, or commercial Hardware platforms – FPGAs, GPPs, specialized and hybrid devices Standardization efforts to ens...

  17. Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells.

    Science.gov (United States)

    Chapman-Rothe, N; Curry, E; Zeller, C; Liber, D; Stronach, E; Gabra, H; Ghaem-Maghami, S; Brown, R

    2013-09-19

    In embryonic stem (ES) cells, bivalent chromatin domains containing H3K4me3 and H3K27me3 marks silence developmental genes, while keeping them poised for activation following differentiation. We have identified gene sets associated with H3K27me3 and H3K4me3 marks at transcription start sites in a high-grade ovarian serous tumour and examined their association with epigenetic silencing and malignant progression. This revealed novel silenced bivalent marked genes, not described previously for ES cells, which are significantly enriched for the PI3K (P<10(-7)) and TGF-β signalling pathways (P<10(-5)). We matched histone marked gene sets to gene expression sets of eight normal fallopian tubes and 499 high-grade serous malignant ovarian samples. This revealed a significant decrease in gene expression for the H3K27me3 and bivalent gene sets in malignant tissue. We then correlated H3K27me3 and bivalent gene sets to gene expression data of ovarian tumour 'stem cell-like' sustaining cells versus non-sustaining cells. This showed a significantly lower expression for the H3K27me3 and bivalent gene sets in the tumour-sustaining cells. Similarly, comparison of matched chemo-sensitive and chemo-resistant ovarian cell lines showed a significantly lower expression of H3K27me3/bivalent marked genes in the chemo-resistant compared with the chemo-sensitive cell line. Our analysis supports the hypothesis that bivalent marks are associated with epigenetic silencing in ovarian cancer. However it also suggests that additional tumour specific bivalent marks, to those known in ES cells, are present in tumours and may potentially influence the subsequent development of drug resistance and tumour progression. PMID:23128397

  18. Defining the Anthropocene

    Science.gov (United States)

    Lewis, Simon; Maslin, Mark

    2016-04-01

    Time is divided by geologists according to marked shifts in Earth's state. Recent global environmental changes suggest that Earth may have entered a new human-dominated geological epoch, the Anthropocene. Should the Anthropocene - the idea that human activity is a force acting upon the Earth system in ways that mean that Earth will be altered for millions of years - be defined as a geological time-unit at the level of an Epoch? Here we appraise the data to assess such claims, first in terms of changes to the Earth system, with particular focus on very long-lived impacts, as Epochs typically last millions of years. Can Earth really be said to be in transition from one state to another? Secondly, we then consider the formal criteria used to define geological time-units and move forward through time examining whether currently available evidence passes typical geological time-unit evidence thresholds. We suggest two time periods likely fit the criteria (1) the aftermath of the interlinking of the Old and New Worlds, which moved species across continents and ocean basins worldwide, a geologically unprecedented and permanent change, which is also the globally synchronous coolest part of the Little Ice Age (in Earth system terms), and the beginning of global trade and a new socio-economic "world system" (in historical terms), marked as a golden spike by a temporary drop in atmospheric CO2, centred on 1610 CE; and (2) the aftermath of the Second World War, when many global environmental changes accelerated and novel long-lived materials were increasingly manufactured, known as the Great Acceleration (in Earth system terms) and the beginning of the Cold War (in historical terms), marked as a golden spike by the peak in radionuclide fallout in 1964. We finish by noting that the Anthropocene debate is politically loaded, thus transparency in the presentation of evidence is essential if a formal definition of the Anthropocene is to avoid becoming a debate about bias. The

  19. Defining the genetic blueprint of kidney development.

    Science.gov (United States)

    Potter, S Steven; Brunskill, Eric W; Patterson, Larry T

    2011-09-01

    Thousands of genes show differential expression patterns during kidney development, suggesting that the genetic program driving this process is complex. While great progress has been made in defining the outline of the genetic basis of nephrogenesis, it is clear that much remains to be learned. A global atlas of the gene expression profiles of the multiple elements of the developing kidney would allow the identification of novel growth factor-receptor interactions, identify additional molecular markers of distinct components, facilitate the generation of compartment specific GFP-CRE transgenic mouse tools, lend insights into the genetic regulatory circuits governing nephron formation, and fully characterize the waves of gene expression that impel nephrogenesis. Both microarrays and next generation deep sequencing of cDNA libraries can be used to define comprehensive, sensitive, and quantitative gene expression profiles. In addition, laser capture microdissection and transgenic GFP mice can be used to isolate specific compartments and pure cell types from the developing kidney. Advancing technologies are even allowing robust gene expression profiling of single cells. The final goal is the production of an exquisitely detailed atlas of the gene expression program that drives kidney development. PMID:21336810

  20. Immunolocalization of aromatase, estrogen and estrogen receptor α and β in the epithelium of digestive tract and enteric neurons of amphioxus (Branchiostoma belcheri )

    Institute of Scientific and Technical Information of China (English)

    FANG Yongqiang; WENG Youzhu; YE Rongzhong; LIU Lili

    2005-01-01

    Immunohistochemical localization of aromatase, estrogen and estrogen receptor in the digestive tract and enteric neurons of amphioxus is investigated. It was found that immunoreactive proteins of aromatase, estrogen and ER-α and β are expressed in hepatic diverticulum, epithelial cells of anterior and posterior region of midgut, as well as in enteric neurons, while hindgut showed immunonegative. The results suggest that digestive tract of amphioxus may be able to synthesize estrogen and possess endocrine function, like rat gastric epithelium and enteric neurons in mammals. The present study provides authentic morphological evidence for explaining the action mechanism of estrogen in regulating the digestive function of gut and the functional evolution of estrogen, which has important theoretical significance in amphioxus.

  1. Aromatase enzyme (P450arom mRNA expression in mouse gonads and the effect of intra-peritoneal amino acid injection

    Directory of Open Access Journals (Sweden)

    Hüseyin Baki Çiftci

    2011-07-01

    Full Text Available The aim of this study was show the presence of (P450arom mRNA expressions in mouse gonads and to measure the effect of intra-peritoneal serine/threonine or glycine injections on the expression of aromatase enzyme P450arommRNA. Three different (1.4, 2.4 and 4.4kb P450arom mRNA species were indentified in mouse testis and the ovary. Relative to saline injected group (S, all the species of P450arom enzyme mRNA decreased in serine/threonine (A or glycine (G injected female mice, while all of them were increased in male. Aromatase enzyme mRNA expression is differently regulated in male and female mice.

  2. Hanford Defined Wastes model

    International Nuclear Information System (INIS)

    This paper describes the methodology behind the Hanford Defined Wastes (HDW) model for estimating the contents of Hanford high level waste (HLW) tanks. The HDW model is based on historical process and transaction histories for each tank and has four major components: Waste Status and Transaction Record Summary (WSTRS), Tank Layer Model (TLM), Supernatant Mixing Model (SMM), and HDW Compositions. Three examples of the application of HDW model estimates are described, including comparisons with global site inventories, comparisons with per tank assays, and comparisons of HDW TOC (Total Organic Carbon) estimates with existing hydrogen watch list tanks. The HDW model provides a cross check on existing assumptions for the global site inventory of wastes. Note that existing inventories for Hanford are based on much the same source information as the HDW model, chemicals used and process flowsheet data. Despite that, the HDW model predicts that the sodium inventory for Hanford tanks is 40,300 MT (metric tonnes), which is only 58% of the previous baseline estimate of 69,000 MT. There are other significant differences for inventories of chromium, iron, and nitrate as well. There are two causes for these differences; (1) previous neglect of chemical inventory placed into the ground at Hanford; (2) double counting attributed to tank inventory that was retrieved, reprocessed, and returned to the tanks. This double-counted inventory was counted once when it first went into the tanks and then again after it was reprocessed. The HDW model estimates also can provide a basis for targeting tanks for organic safety issues. In particular, the HDW model has shown that 88% of flammable gas watch list tanks have HDW estimated organic concentrations in excess of 0.64 wt% TOC. Derivation of variabilities for the HDW model estimates and other potential uses will also be outlined

  3. Defining an emerging disease.

    Science.gov (United States)

    Moutou, F; Pastoret, P-P

    2015-04-01

    Defining an emerging disease is not straightforward, as there are several different types of disease emergence. For example, there can be a 'real' emergence of a brand new disease, such as the emergence of bovine spongiform encephalopathy in the 1980s, or a geographic emergence in an area not previously affected, such as the emergence of bluetongue in northern Europe in 2006. In addition, disease can emerge in species formerly not considered affected, e.g. the emergence of bovine tuberculosis in wildlife species since 2000 in France. There can also be an unexpected increase of disease incidence in a known area and a known species, or there may simply be an increase in our knowledge or awareness of a particular disease. What all these emerging diseases have in common is that human activity frequently has a role to play in their emergence. For example, bovine spongiform encephalopathy very probably emerged as a result of changes in the manufacturing of meat-and-bone meal, bluetongue was able to spread to cooler climes as a result of uncontrolled trade in animals, and a relaxation of screening and surveillance for bovine tuberculosis enabled the disease to re-emerge in areas that had been able to drastically reduce the number of cases. Globalisation and population growth will continue to affect the epidemiology of diseases in years to come and ecosystems will continue to evolve. Furthermore, new technologies such as metagenomics and high-throughput sequencing are identifying new microorganisms all the time. Change is the one constant, and diseases will continue to emerge, and we must consider the causes and different types of emergence as we deal with these diseases in the future. PMID:26470448

  4. Effect of a hormone-releasing intrauterine system (Mirena®) on aromatase and Cox-2 expression in patients with adenomyosis submitted or not, to endometrial resection

    OpenAIRE

    Maia, Hugo; Haddad, Clarice; Casoy, Julio; Maia, Rebeca; Pinheiro, Nathanael; Coutinho, Elsimar M.

    2012-01-01

    Objective To investigate the effect of a levonorgestrel-releasing intrauterine system (Mirena®) on aromatase and cyclooxygenase-2 (Cox-2) expression in the endometrium of patients with adenomyosis who were submitted to endometrial resection at the time of insertion, compared to a group not submitted to endometrial resection and a group of controls with adenomyosis not submitted to any previous hormonal treatment. Patients and methods Patients with adenomyosis (n = 89) were included in this st...

  5. Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium

    OpenAIRE

    Lagergren, K; Ek, WE; D Levine; Chow, W-H; Bernstein, L; Casson, AG; Risch, HA; Shaheen, NJ; Bird, NC; Reid, BJ; Corley, DA; Hardie, LJ; Wu, AH; Fitzgerald, RC; Pharoah, P

    2015-01-01

    Background: The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute. Methods: This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the o...

  6. Kinetic analysis of the three-step steroid aromatase reaction of human cytochrome P450 19A1.

    Science.gov (United States)

    Sohl, Christal D; Guengerich, F Peter

    2010-06-01

    Cytochrome P450 19A1 (P450 19A1), the aromatase, catalyzes the conversion of androgens to estrogens through a sequential three-step reaction, generating 19-hydroxy and 19-aldehyde intermediates en route to the product estrogen. A procedure for the heterologous expression and purification of P450 19A1 in Escherichia coli was developed (k(cat) of 0.06 s(-1) for the conversion of androstenedione to estrone). Binding of the substrate and intermediates show low micromolar dissociation constants and are at least two-step processes. Rates of reduction of the iron were fast in the presence of substrate, either intermediate, or product. P450 19A1 is a distributive rather than a processive enzyme, with the sequential reaction allowing free dissociation of the intermediates as revealed by pulse-chase experiments. Conversion of androstenedione to estrone (under single turnover conditions) generated a progress curve showing changes in the concentrations of the substrate, intermediates, and product. A minimal kinetic model containing the individual rate constants for the steps in P450 19A1 catalysis was developed to globally fit the time course of the overall reaction, the dissociation constants, the two-step ligand binding, the distributive character, the iron-reduction rates, and the steady-state conversion of the 19-hydroxy androstenedione and 19-aldehyde androstenedione intermediates to estrone. PMID:20385561

  7. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    Science.gov (United States)

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors. PMID:26899138

  8. A Novel Mathematical Approach to Define the Genes/SNPs Conferring Risk or Protection in Sporadic Amyotrophic Lateral Sclerosis Based on Auto Contractive Map Neural Networks and Graph Theory.

    Science.gov (United States)

    Buscema, Massimo; Penco, Silvana; Grossi, Enzo

    2012-01-01

    Background. Complex diseases like amyotrophic lateral sclerosis (ALS) implicate phenotypic and genetic heterogeneity. Therefore, multiple genetic traits may show differential association with the disease. The Auto Contractive Map (AutoCM), belonging to the Artificial Neural Network (ANN) architecture, "spatializes" the correlation among variables by constructing a suitable embedding space where a visually transparent and cognitively natural notion such as "closeness" among variables reflects accurately their associations. Results. In this pilot case-control study single nucleotide polymorphism (SNP) in several genes has been evaluated with a novel data mining approach based on an AutoCM. We have divided the ALS dataset into two dataset: Cases and Control dataset; we have applied to each one, independently, the AutoCM algorithm. Six genetic variants were identified which differently contributed to the complexity of the system: three of the above genes/SNPs represent protective factors, APOA4, NOS3, and LPL, since their contribution to the whole complexity resulted to be as high as 0.17. On the other hand ADRB3, LIPC, and MMP3, whose hub relevancies contribution resulted to be as high as 0.13, seem to represent susceptibility factors. Conclusion. The biological information available on these six polymorphisms is consistent with possible pathogenetic pathways related to ALS. PMID:22934166

  9. A Novel Mathematical Approach to Define the Genes/SNPs Conferring Risk or Protection in Sporadic Amyotrophic Lateral Sclerosis Based on Auto Contractive Map Neural Networks and Graph Theory

    Directory of Open Access Journals (Sweden)

    Massimo Buscema

    2012-01-01

    Full Text Available Background. Complex diseases like amyotrophic lateral sclerosis (ALS implicate phenotypic and genetic heterogeneity. Therefore, multiple genetic traits may show differential association with the disease. The Auto Contractive Map (AutoCM, belonging to the Artificial Neural Network (ANN architecture, “spatializes” the correlation among variables by constructing a suitable embedding space where a visually transparent and cognitively natural notion such as “closeness” among variables reflects accurately their associations. Results. In this pilot case-control study single nucleotide polymorphism (SNP in several genes has been evaluated with a novel data mining approach based on an AutoCM. We have divided the ALS dataset into two dataset: Cases and Control dataset; we have applied to each one, independently, the AutoCM algorithm. Six genetic variants were identified which differently contributed to the complexity of the system: three of the above genes/SNPs represent protective factors, APOA4, NOS3, and LPL, since their contribution to the whole complexity resulted to be as high as 0.17. On the other hand ADRB3, LIPC, and MMP3, whose hub relevancies contribution resulted to be as high as 0.13, seem to represent susceptibility factors. Conclusion. The biological information available on these six polymorphisms is consistent with possible pathogenetic pathways related to ALS.

  10. Cyclin A1 and P450 Aromatase Promote Metastatic Homing and Growth of Stem-like Prostate Cancer Cells in the Bone Marrow.

    Science.gov (United States)

    Miftakhova, Regina; Hedblom, Andreas; Semenas, Julius; Robinson, Brian; Simoulis, Athanasios; Malm, Johan; Rizvanov, Albert; Heery, David M; Mongan, Nigel P; Maitland, Norman J; Allegrucci, Cinzia; Persson, Jenny L

    2016-04-15

    Bone metastasis is a leading cause of morbidity and mortality in prostate cancer. While cancer stem-like cells have been implicated as a cell of origin for prostate cancer metastasis, the pathways that enable metastatic development at distal sites remain largely unknown. In this study, we illuminate pathways relevant to bone metastasis in this disease. We observed that cyclin A1 (CCNA1) protein expression was relatively higher in prostate cancer metastatic lesions in lymph node, lung, and bone/bone marrow. In both primary and metastatic tissues, cyclin A1 expression was also correlated with aromatase (CYP19A1), a key enzyme that directly regulates the local balance of androgens to estrogens. Cyclin A1 overexpression in the stem-like ALDH(high) subpopulation of PC3M cells, one model of prostate cancer, enabled bone marrow integration and metastatic growth. Further, cells obtained from bone marrow metastatic lesions displayed self-renewal capability in colony-forming assays. In the bone marrow, cyclin A1 and aromatase enhanced local bone marrow-releasing factors, including androgen receptor, estrogen and matrix metalloproteinase MMP9 and promoted the metastatic growth of prostate cancer cells. Moreover, ALDH(high) tumor cells expressing elevated levels of aromatase stimulated tumor/host estrogen production and acquired a growth advantage in the presence of host bone marrow cells. Overall, these findings suggest that local production of steroids and MMPs in the bone marrow may provide a suitable microenvironment for ALDH(high) prostate cancer cells to establish metastatic growths, offering new approaches to therapeutically target bone metastases. Cancer Res; 76(8); 2453-64. ©2016 AACR. PMID:26921336

  11. Aromatase enzyme (P450arom) mRNA expression in mouse gonads and the effect of intra-peritoneal amino acid injection

    OpenAIRE

    Hüseyin Baki Çiftci

    2011-01-01

    The aim of this study was show the presence of (P450arom) mRNA expressions in mouse gonads and to measure the effect of intra-peritoneal serine/threonine or glycine injections on the expression of aromatase enzyme P450arommRNA. Three different (1.4, 2.4 and 4.4kb) P450arom mRNA species were indentified in mouse testis and the ovary. Relative to saline injected group (S), all the species of P450arom enzyme mRNA decreased in serine/threonine (A) or glycine (G) injected female mice, while all o...

  12. Comparison of the effect of cortisol on aromatase activity and androgen metabolism in two human fibroblast cell lines derived from the same individual

    DEFF Research Database (Denmark)

    Svenstrup, B; Brünner, N; Dombernowsky, P;

    1990-01-01

    The effect of preincubation with cortisol on estrogen and androgen metabolism was investigated in human fibroblast monolayers grown from biopsies of genital and non-genital skin of the same person. The activity in the cells of aromatase, 5 alpha-reductase, 17 beta-hydroxysteroid oxidoreductase and...... 3 alpha-hydroxysteroid oxidoreductase was investigated by isolating estrone, estradiol, estriol, dihydrotestosterone, androstanedione, androsterone, 3 alpha-androstanediol, testosterone and androstenedione after incubation of the cells with [14C]testosterone or [14C]androstenedione. For experiments...

  13. Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.

    Science.gov (United States)

    Ekpo, Ernest U; Brennan, Patrick C; Mello-Thoms, Claudia; McEntee, Mark F

    2016-06-01

    Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women. PMID:27130722

  14. Comparative study on individual aromatase inhibitors on cardiovascular safety profile: a network meta-analysis

    Directory of Open Access Journals (Sweden)

    Zhao XH

    2015-09-01

    Full Text Available Xihe Zhao,1 Lei Liu,2 Kai Li,1 Wusheng Li,1 Li Zhao,1 Huawei Zou1 1Department of Oncology, 2Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: The third-generation aromatase inhibitors (AIs: anastrozole, letrozole, and exemestane have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancer complementing chemotherapy and surgery. Because of the absence of direct head-to-head comparisons of these AIs, an indirect comparison is needed for individual treatment choice. In this network systemic assessment, the cardiovascular (CV side effects in using anastrozole, letrozole, and exemestane based on original studies on AIs vs placebo or tamoxifen were compared. We integrated all available direct and indirect evidences. The odds ratio (OR of severe CV events for indirect comparisons between exemestane and anastrozole was 1.41 (95% confidence interval [CI] =0.49–2.78, letrozole and anastrozole was 1.80 (95% CI =0.40–3.92, and letrozole and exemestane was 1.46 (95% CI =0.34–3.4. OR of subgroup risk for AIs and tamoxifen were all >1 except for thrombolism risk subgroup. The results showed that the total and severe CV risk ranking is letrozole, exemestane, and anastrozole in descending order. None of the AIs showed advantages in CV events than tamoxifen except for thromboembolism event incidence. Keywords: CV risk, breast cancer, AI, network meta-analysis

  15. Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort

    Science.gov (United States)

    Castel, Liana D.; Hartmann, Katherine E.; Mayer, Ingrid A.; Saville, Benjamin R.; Alvarez, JoAnn; Boomershine, Chad S.; Abramson, Vandana G.; Chakravarthy, A. Bapsi; Friedman, Debra L.; Cella, David F.

    2013-01-01

    BACKGROUND More than 80,000 postmenopausal breast cancer patients in the US each year are estimated to begin a five-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. OBJECTIVES To describe one-year arthralgia trajectories and baseline covariates among AI patients and a postmenopausal comparison group. METHODS Patients initiating AIs (n=91) were surveyed at the time of AI initiation and at six repeated assessments over one year. A comparison group of postmenopausal women without breast cancer (n=177) completed concomitantly-timed surveys. Numeric rating scales (0–10) were used to measure pain in eight joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS By week six, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means=1.8, (95% CI 1.2–2.7, p=0.002), adjusting for baseline characteristics. Arthralgia then worsened further over a year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe longitudinal arthralgia. CONCLUSIONS Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia. PMID:23575918

  16. Defined Contribution vs Defined Pension: Reforming the Legal Retirement Age

    OpenAIRE

    Lacomba, Juan Antonio; Lagos, Francisco Miguel

    2008-01-01

    In this paper we analyze the effects of changing Social Security parameters on the optimal legal retirement age. Two Social Security Systems are studied, with opposite results. When the pension scheme has a defined contribution, a more redistributive system will delay the preferred legal retirement age. On the other hand, when the pension benefit is the defined parameter, the increase in the redistribution level will lower this preferred age.

  17. The neurovirulence and neuroinvasiveness of chimeric tick-borne encephalitis/dengue virus can be attenuated by introducing defined mutations into the envelope and NS5 protein genes and the 3' non-coding region of the genome

    International Nuclear Information System (INIS)

    Tick-borne encephalitis (TBE) is a severe disease affecting thousands of people throughout Eurasia. Despite the use of formalin-inactivated vaccines in endemic areas, an increasing incidence of TBE emphasizes the need for an alternative vaccine that will induce a more durable immunity against TBE virus (TBEV). The chimeric attenuated virus vaccine candidate containing the structural protein genes of TBEV on a dengue virus genetic background (TBEV/DEN4) retains a high level of neurovirulence in both mice and monkeys. Therefore, attenuating mutations were introduced into the envelope (E315) and NS5 (NS5654,655) proteins, and into the 3' non-coding region (Δ30) of TBEV/DEN4. The variant that contained all three mutations (vΔ30/E315/NS5654,655) was significantly attenuated for neuroinvasiveness and neurovirulence and displayed a reduced level of replication and virus-induced histopathology in the brains of mice. The high level of safety in the central nervous system indicates that vΔ30/E315/NS5654,655 should be further evaluated as a TBEV vaccine.

  18. Defining Modules, Modularity and Modularization

    DEFF Research Database (Denmark)

    Miller, Thomas Dedenroth; Pedersen, Per Erik Elgård

    The paper describes the evolution of the concept of modularity in a historical perspective. The main reasons for modularity are: create variety, utilize similarities, and reduce complexity. The paper defines the terms: Module, modularity, and modularization....

  19. Theoretical approaches to elections defining

    OpenAIRE

    Natalya V. Lebedeva

    2011-01-01

    Theoretical approaches to elections defining develop the nature, essence and content of elections, help to determine their place and a role as one of the major national law institutions in democratic system.

  20. QUALITY OF LIFE OF WOMEN RECIEVING ADJUVANT HORMONAL TREATMENT FOR BREAST CANCER – A RANDOMIZED TRIAL COMPARING TAMOXIFEN WITH AROMATASE INHIBITORS

    Directory of Open Access Journals (Sweden)

    C. Volovat

    2011-05-01

    Full Text Available Purpose: The assessment and comparison of the quality of life in women with early stages breast cancer receiving Tamoxifen versus aromatase inhibitors (AINs. Methods: There were selected 223 patients treated at Center of Medical Oncology Iasi, with early stages breast cancer. The patients were divided in two groups: 115 patients receiving Tamoxifen and 107 patients receiving aromatase inhibitors. From the patients receiving AINs, 33 of patients have received Exemestane, 60 patients Letrozole and 14 patients Anastrazole. The patients have completed an EORTC C30 and EORTC BR23 questionnaire at the beginning of the treatment (after one month and after 2 years of treatment. There was calculated the difference related with global status, functional scales, emotional scales, cognitive scales and symptom scales. Results: Statistic results show a better quality of life for Anastrazole vs. Letrozole and for AINs vs. Tamoxifen group, mainly on physical scales both after 2 months and after 2 years of treatment. In the same time, the physical scales were with better results after 1 month of treatment vs. 2 years of treatment. Conclusions: Following the hormonal treatment period, there is a mild worsening of quality of life for Tamoxifen and AINs too. In the same time, the quality of life is better in the group with AINs treatment comparative with the Tamoxifen treatment.

  1. Effect of Yikun Neiyi Wan on the Expression of Aromatase P450,COX-2, and ER Related Receptor in Endometrial Cells in Vitro from Patients with Endometriosis

    Institute of Scientific and Technical Information of China (English)

    WANG Qing; ZHAO Hong; XIANG Qing; JU Hai; HAN Shu-min; WANG Ling-yan; XU Bo

    2009-01-01

    Objective: To investigate the effect of Yikun Neiyi Wan (益坤内异丸 YKNYW) and gestrinone on the expression of aromatase P450 (P450arom), cyclo-oxygenase-2 (COX-2) and estrogen receptor (ER) in isolated ectopic and normal endometrial stroma cells in vitro. Methods: Digestion and serial filtration were used to isolate and culture the ectopic and eutopic endometrial cells from patients with chocolate cyst in virto. Transformation of the cell morphology was observed in a inverted microscope. The effect of YKNYW on the expression of aromatase P450, cyclo-oxygenase-2, estrogen receptor in cultured endometriosis cells were detected by immunohistochemical method. Results: The expression levels of P450arom, COX-2 in glandular epithelium cells in vitro were decreased significantly by YKNYW compared with gestrinone (P<0.05). ER expression in mesenchymal cells of endometriosis was increased by YKNYW in the large and medium dosage groups compared with gestrinone. Conclusion: The mechanism by which YKNYW alleviates endometriosis pain is possibly related to the decrease in ectopic endometrial P450 arom and COX-2 expression in glandular epithelium, contrary to gestrinone, and the increase in ER expression in mesenchymalis, consistent with gestrione in patients with endometriosis.

  2. Gene expression

    International Nuclear Information System (INIS)

    We prepared probes for isolating functional pieces of the metallothionein locus. The probes enabled a variety of experiments, eventually revealing two mechanisms for metallothionein gene expression, the order of the DNA coding units at the locus, and the location of the gene site in its chromosome. Once the switch regulating metallothionein synthesis was located, it could be joined by recombinant DNA methods to other, unrelated genes, then reintroduced into cells by gene-transfer techniques. The expression of these recombinant genes could then be induced by exposing the cells to Zn2+ or Cd2+. We would thus take advantage of the clearly defined switching properties of the metallothionein gene to manipulate the expression of other, perhaps normally constitutive, genes. Already, despite an incomplete understanding of how the regulatory switch of the metallothionein locus operates, such experiments have been performed successfully

  3. Targeted Metabolomics Approach To Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarker Profiling.

    Science.gov (United States)

    Chan, George Ho Man; Ho, Emmie Ngai Man; Leung, David Kwan Kon; Wong, Kin Sing; Wan, Terence See Ming

    2016-01-01

    The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. The conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas chromatography or liquid chromatography coupled with mass spectrometry. Such an approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times render the direct detection approach ineffective as the detection window is short. A targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Because the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomics approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry for a group of 2 resting and 2 in-training thoroughbred geldings treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups

  4. Defining and Classifying Interest Groups

    DEFF Research Database (Denmark)

    Baroni, Laura; Carroll, Brendan; Chalmers, Adam;

    2014-01-01

    The interest group concept is defined in many different ways in the existing literature and a range of different classification schemes are employed. This complicates comparisons between different studies and their findings. One of the important tasks faced by interest group scholars engaged in...... large-N studies is therefore to define the concept of an interest group and to determine which classification scheme to use for different group types. After reviewing the existing literature, this article sets out to compare different approaches to defining and classifying interest groups with a sample...... cluster actors according to a number of key background characteristics and second assess how the categories of the different interest group typologies relate to these clusters. We demonstrate that background characteristics do align to a certain extent with certain interest group types but also find...

  5. Modular Software-Defined Radio

    Directory of Open Access Journals (Sweden)

    Rhiemeier Arnd-Ragnar

    2005-01-01

    Full Text Available In view of the technical and commercial boundary conditions for software-defined radio (SDR, it is suggestive to reconsider the concept anew from an unconventional point of view. The organizational principles of signal processing (rather than the signal processing algorithms themselves are the main focus of this work on modular software-defined radio. Modularity and flexibility are just two key characteristics of the SDR environment which extend smoothly into the modeling of hardware and software. In particular, the proposed model of signal processing software includes irregular, connected, directed, acyclic graphs with random node weights and random edges. Several approaches for mapping such software to a given hardware are discussed. Taking into account previous findings as well as new results from system simulations presented here, the paper finally concludes with the utility of pipelining as a general design guideline for modular software-defined radio.

  6. Defining and Classifying Interest Groups

    DEFF Research Database (Denmark)

    Baroni, Laura; Carroll, Brendan; Chalmers, Adam; Marquez, Luz Maria Muñoz; Rasmussen, Anne

    2014-01-01

    The interest group concept is defined in many different ways in the existing literature and a range of different classification schemes are employed. This complicates comparisons between different studies and their findings. One of the important tasks faced by interest group scholars engaged in l...

  7. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish.

    Science.gov (United States)

    Di Rosa, Viviana; López-Olmeda, Jose Fernando; Burguillo, Ana; Frigato, Elena; Bertolucci, Cristiano; Piferrer, Francesc; Sánchez-Vázquez, Francisco Javier

    2016-01-01

    Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase) and the antimüllerian hormone (amh, testis) was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase) and ZT 15:39 h (at night), respectively. The expression of foxl2 (forkhead box L2) was also rhythmic in the ovary (acrophase located at ZT 5:02 h) and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1) was rhythmic in testes (acrophase at ZT 18:36 h). In the brain, cyp19a1b (brain aromatase) and cyp11b (11beta-hydroxylase) presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish. PMID:27322588

  8. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish.

    Directory of Open Access Journals (Sweden)

    Viviana Di Rosa

    Full Text Available Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase and the antimüllerian hormone (amh, testis was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase and ZT 15:39 h (at night, respectively. The expression of foxl2 (forkhead box L2 was also rhythmic in the ovary (acrophase located at ZT 5:02 h and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1 was rhythmic in testes (acrophase at ZT 18:36 h. In the brain, cyp19a1b (brain aromatase and cyp11b (11beta-hydroxylase presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish.

  9. Daily Rhythms of the Expression of Key Genes Involved in Steroidogenesis and Gonadal Function in Zebrafish

    Science.gov (United States)

    Di Rosa, Viviana; López-Olmeda, Jose Fernando; Burguillo, Ana; Frigato, Elena; Bertolucci, Cristiano; Piferrer, Francesc; Sánchez-Vázquez, Francisco Javier

    2016-01-01

    Fish present daily and seasonal rhythms in spawning and plasmatic levels of steroids that control reproduction. However, the existence of the rhythms of expression of the genes that underlie the endocrine mechanisms responsible for processes such as steroidogenesis and reproduction in fish have still been poorly explored to date. Here we investigated the daily pattern of the expression of key genes involved in sex steroid production that ultimately set the sex ratio in fish. Adult zebrafish were maintained under a 12:12 h light-dark cycle at a constant temperature of 27°C and were sampled every 4 h during a 24-hour cycle. The expression of key genes in the gonads and brains of female and male individuals were analyzed. In gonads, the expression of aromatase (cyp19a1a, ovarian aromatase) and the antimüllerian hormone (amh, testis) was rhythmic, with almost opposite acrophases: ZT 5:13 h (in the light phase) and ZT 15:39 h (at night), respectively. The expression of foxl2 (forkhead box L2) was also rhythmic in the ovary (acrophase located at ZT 5:02 h) and the expression of dmrt1 (doublesex and mab-3-related transcription factor 1) was rhythmic in testes (acrophase at ZT 18:36 h). In the brain, cyp19a1b (brain aromatase) and cyp11b (11beta-hydroxylase) presented daily differences, especially in males, where the expression peaked at night. These results provide the first evidence for marked time-of-the-day-dependent differences in the expression of the genes involved in sex ratio control, which should be considered when investigating processes such as reproduction, sex differentiation and steroidogenesis in fish. PMID:27322588

  10. Autism and Genes

    Science.gov (United States)

    National Institutes of Health, 2005

    2005-01-01

    This document defines and discusses autism and how genes play a role in the condition. Answers to the following questions are covered: (1) What are genes? (2) What is autism? (3) What causes autism? (4) Why study genes to learn about autism? (5) How do researchers look for the genes involved in autism? (screen the whole genome; conduct cytogenetic…

  11. Defining and managing sustainable yield.

    Science.gov (United States)

    Maimone, Mark

    2004-01-01

    Ground water resource management programs are paying increasing attention to the integration of ground water and surface water in the planning process. Many plans, however, show a sophistication in approach and presentation that masks a fundamental weakness in the overall analysis. The plans usually discuss issues of demand and yield, yet never directly address a fundamental issue behind the plan--how to define sustainable yield of an aquifer system. This paper points out a number of considerations that must be addressed in defining sustainable yield in order to make the definition more useful in practical water resource planning studies. These include consideration for the spatial and temporal aspects of the problem, the development of a conceptual water balance, the influence of boundaries and changes in technology on the definition, the need to examine water demand as well as available supply, the need for stakeholder involvement, and the issue of uncertainty in our understanding of the components of the hydrologic system. PMID:15584295

  12. Defining Clusters of Related Industries

    OpenAIRE

    Mercedes Delgado; Porter, Michael E.; Scott Stern

    2014-01-01

    Clusters are geographic concentrations of industries related by knowledge, skills, inputs, demand, and/or other linkages. A growing body of empirical literature has shown the positive impact of clusters on regional and industry performance, including job creation, patenting, and new business formation. There is an increasing need for cluster-based data to support research, facilitate comparisons of clusters across regions, and support policymakers and practitioners in defining regional strate...

  13. Defining the TECHNOLOGY TRANSFER ALLIANCE

    OpenAIRE

    Ahlbom, Gabriella; Åman, Anna

    2011-01-01

    The aim of this project was to define the Technology Transfer Alliance (TTA), a nonprofit organization for Higher Education Institutions supporting capacity building in ICT and renewable energy through a project-driven learning. TTA is today still only an idea, waiting to be launched, which is why the goals for this bachelor thesis are to establish partnerships with institutions that will support the reaching of the goals of TTA, as well as providing a more solid definition of the functions o...

  14. Network Coded Software Defined Networking

    DEFF Research Database (Denmark)

    Krigslund, Jeppe; Hansen, Jonas; Roetter, Daniel Enrique Lucani;

    2015-01-01

    Software Defined Networking (SDN) and Network Coding (NC) are two key concepts in networking that have garnered a large attention in recent years. On the one hand, SDN's potential to virtualize services in the Internet allows a large flexibility not only for routing data, but also to manage buffe......). Our results on single–hop, multi–hop, and multi–path scenarios show that gains of 3x to 11x are attainable over standard TCP and multi–path TCP....

  15. The definability of physical concepts

    Directory of Open Access Journals (Sweden)

    Adonai S. Sant'Anna

    2005-11-01

    Full Text Available Our main purpose here is to make some specific considerations about the definability of physical concepts like mass, force, time, space, spacetime, and closed systems in the context of physical theories. Our starting motivation is a simple example of a collection of definitions of closed system in the literature of physics and philosophy of physics. Next we discuss the problem of definitions in theoretical physics from the point of view of modern theories of definition.

  16. The definability of physical concepts

    OpenAIRE

    Adonai S. Sant'Anna

    2005-01-01

    Our main purpose here is to make some specific considerations about the definability of physical concepts like mass, force, time, space, spacetime, and closed systems in the context of physical theories. Our starting motivation is a simple example of a collection of definitions of closed system in the literature of physics and philosophy of physics. Next we discuss the problem of definitions in theoretical physics from the point of view of modern theories of definition.

  17. AIDS defining disease: Disseminated cryptococcosis

    Directory of Open Access Journals (Sweden)

    Roshan Anupama

    2006-01-01

    Full Text Available Disseminated cryptococcosis is one of the acquired immune deficiency syndrome defining criteria and the most common cause of life threatening meningitis. Disseminated lesions in the skin manifest as papules or nodules that mimic molluscum contagiosum (MC. We report here a human immunodeficiency virus positive patient who presented with MC like lesions. Disseminated cryptococcosis was confirmed by India ink preparation and histopathology. The condition of the patient improved with amphotercin B.

  18. Software Defined Radio Transceiver Implementation

    OpenAIRE

    Corley, Gerry; Sanchez Mora , Magdalena; Farrell, Ronan

    2008-01-01

    This document presents the design and implementation of a low cost reconfigurable radio transceiver platform. The platform will be used as a research tool in the investigation of software defined radio techniques. The hardware presented is an evolution of work presented at the 2006 RIA colloquium. The platform consists of four hardware elements, namely a radio transmitter, a radio receiver, a baseband interface and a PC to perform signal processing and configuration. Data and control c...

  19. Defining and teaching veterinary professionalism

    OpenAIRE

    Mossop, Liz

    2012-01-01

    Despite extensive research and discussion around the notion of medical professionalism, veterinary professionalism is an understudied area. The aim of this study was to define the concept of veterinary professionalism and analyse the hidden curriculum of a new veterinary school, in order to produce a new curriculum of professionalism. This study used a constructivist grounded theory method to develop the definition. An iterative approach, using interviews and focus groups, collected inform...

  20. Defining and measuring ecological specialization

    OpenAIRE

    Devictor, Vincent; Clavel, Joanne; Julliard, Romain; Lavergne, Sébastien; Mouillot, David; Thuiller, Wilfried; Venail, Patrick; Villéger, Sébastien; Mouquet, Nicolas

    2010-01-01

    1.  Ecological specialization is one of the main concepts in ecology and conservation. However, this concept has become highly context-dependent and is now obscured by the great variability of existing definitions and methods used to characterize ecological specialization. 2.  In this study, we clarify this concept by reviewing the strengths and limitations of different approaches commonly used to define and measure ecological specialization. We first show that ecological specialization can e...

  1. Defining Explanation in Probabilistic Systems

    OpenAIRE

    Chajewska, Urszula; Joseph Y. Halpern

    2013-01-01

    As probabilistic systems gain popularity and are coming into wider use, the need for a mechanism that explains the system's findings and recommendations becomes more critical. The system will also need a mechanism for ordering competing explanations. We examine two representative approaches to explanation in the literature - one due to G\\"ardenfors and one due to Pearl - and show that both suffer from significant problems. We propose an approach to defining a notion of "better explanation" th...

  2. The Interplay of Biology and the Environment Broadly Defined

    OpenAIRE

    Diamond, Adele

    2009-01-01

    This special section of Developmental Psychology contains articles on the interplay of biology and the environment, broadly defined, that have the potential to change or challenge how developmental psychologists think. Topics include how experience affects gene expression; how genes affect how the environment is experienced and what effect the environment has; interactions between the environment and the presence or absence of early brain damage; motor neurons and the understanding of others’...

  3. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular char

  4. Paradoxal metabolic flare detected by 18F-fluorodeoxyglucose positron emission tomography in a patient with metastatic breast cancer treated with aromatase inhibitor and biphosphonate

    International Nuclear Information System (INIS)

    Patients with estrogen-receptor-positive advanced breast cancer are treated with endocrine therapy. The majority of breast cancer localizations show 18F-fluorodeoxyglucose (FDG) uptake at positron emission tomography (PET) examination. In these patients, the metabolic flare after therapy is common and was proposed as an index of therapy efficacy. Nevertheless, prolonged persistence of flare can lead to misinterpretation. We describe a case of a patient with invasive ductal breast cancer with bone metastases at bone scintigraphy and FDG PET scan and with expression of estrogen receptors. Initially, the patient underwent endocrine therapy in addition to a biphosfonate. Owing to progression observed in a bone scan, Tamoxifen was substituted with aromatase inhibitors. Successive bone scan examinations showed stabilization with a marked clinical improvement. A second FDG PET was performed 28 months after the first examination and showed a metabolic flare phenomenon with concomitant partial calcification of osteolitic lesions. This is an unusual case of prolonged metabolic flare

  5. Estrogen biosynthesis: Metabolism of [16, 16, 19-2H3] [19-3H]19-Oxoandrost-4-ene-3, 17-Dione (1) by placental microsomal aromatase

    International Nuclear Information System (INIS)

    Publication of our results showing that 2β-hydroxy-19-oxoandrost-4-ene-3, 17-dione is not an obligatory estrogen precursor, rekindled interest in the late stages of estrogen biosynthesis from (1) and particularly in the utilization of the required third mole of oxygen and of NADPH. To understand the scope of transformations of the 19-oxo (1), and eventually isolate and identify the [oxygenated-(1)] estrogen precursor, we investigated the metabolism of (1) by placental microsomal aromatase. The following new types of metabolites of (1) were discovered: a: [(1)+0]; b: 4,6-dien-3-one analogs of (1) and of 19-norandrogens; c: 19-norandrogens and d: [(19-norandrost-4-ene-3, 17-dione)+0]. Biosynthesis of estrogens will be discussed in the context of the new results

  6. The time since last menstrual period is important as a clinical predictor for non-steroidal aromatase inhibitor-related arthralgia

    International Nuclear Information System (INIS)

    The clinical predictors of aromatase inhibitor-related arthralgia (AIA), a drug-related adverse reaction of aromatase inhibitors (AIs), remain unclear. AIA was prospectively surveyed every 4 months in 328 postmenopausal breast cancer patients administered a non-steroidal AI (anastrozole). Various clinicopathological parameters were recorded and analyzed (chi-square test, Fisher's exact test and logistic regression analysis). The mean observation period was 39.9 months. AIA manifested in 114 patients (34.8%), with peaks of onset at 4 (33.7%) and 8 months (11.4%) after starting AI administration. Some cases manifested even after 13 months. AIA tended to occur in younger patients (incidences of 46.3%, 37.4% and 28.0% for ages of < 55, 55-65 and > 65 years, respectively (p = 0.063)) and decreased significantly with the age at menarche (53.3%, 35.3% and 15.4% for < 12, 12-15 and > 15 years, respectively (p = 0.036)). The incidences were 45.1%, 46.3 and 25.1% for the time since the last menstrual period (LMP) < 5 years, 5-10 years and > 10 years, being significantly lower at > 10 years (p < 0.001). In logistic regression analysis, the AIA incidence was significantly lower in the time since LMP > 10-year group versus the < 5-year group (odds ratio 0.44, p = 0.002), but the age at menarche showed no association. AIA manifested significantly earlier (≤ 6 months) as the time since LMP became shorter (< 5 years). AIA tends to manifest early after starting AI, but some cases show delayed onset. The incidence was significantly lower in patients with a duration of > 10 years since LMP. When the time since LMP was short, the onset of AIA was significantly earlier after starting AI administration

  7. A systematic review and methodological evaluation of published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage breast cancer.

    Directory of Open Access Journals (Sweden)

    Ava A John-Baptiste

    Full Text Available BACKGROUND: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs. For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs of five years of aromatase inhibitors (AI versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS but not overall survival (OS and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions. METHODS: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY. We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty. RESULTS: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities. CONCLUSION: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs

  8. Plasma concentrations of estradiol and testosterone, gonadal aromatase activity and ultrastructure of the testis in Xenopus laevis exposed to estradiol or atrazine

    International Nuclear Information System (INIS)

    The ultrastructure of testicular cells of adult male African clawed frogs (Xenopus laevis) exposed to either estradiol (0.1 μg/L) or 2-chloro-4-ethylamino-6-isopropyl-amino-s-triazine (atrazine; 10 or 100 μg/L) was examined by electron microscopy and compared to plasma concentrations of the steroid hormones, testosterone (T) and estradiol (E2), testicular aromatase activity and gonad growth expressed as the gonado-somatic index (GSI). Exposure to E2 caused significant changes both at the sub-cellular and biochemical levels. Exposure to E2 resulted in significantly fewer sperm cells, inhibition of meiotic division of germ cells, more lipid droplets that are storage compartments for the sex steroid hormone precursor cholesterol, and lesser plasma T concentrations. Although not statistically significant, frogs exposed to E2 had slightly smaller GSI values. These results may be indicative of an inhibition of gonad growth and disrupted germ cell development by E2. Concentrations of E2 in plasma were greater in frogs exposed to E2 in water. Exposure to neither concentration of atrazine caused effects on germ cell development, testicular aromatase activity or plasma hormone concentrations. These results suggest that atrazine does not affect testicular function. In contrast, exposure of male X. laevis to E2 led to sub-cellular events that are indicative of disruption of testicular development, and demasculinization processes (decrease of androgen hormone titers). These results indicate that atrazine does not cause responses that are similar to those caused by exposure to E2

  9. American Society of Gene & Cell Therapy

    Science.gov (United States)

    ... Resources Clinical Trials Information Gene Therapy and Cell Therapy Terminology Gene Therapy & Cell Therapy Breakthroughs FAQs Gene Therapy and Cell Therapy Defined Gene Therapy and Cell Therapy for Diseases Sites of ...

  10. The effect of anastrozole on mRNA expression of oestrogen related gene in MCF-7 breast cancer cells

    Institute of Scientific and Technical Information of China (English)

    SONG Zhang-jun; WU Yi; MA Qing-yong

    2006-01-01

    Objective: To look for additional markers of molecular biology response to anastrozole, a new aromatase inhibitor, on the growth and mRNA expression level of MCF-7 cell. Methods: We investigated the effect of anastrzole on growth and gene expression in the human breast cancer cell line MCF-7and compared with the most widely used antiestrogen tamoxifen. We chose 4 genes to examine regulation of gene expression of estrogen regulated genes: PR A, PR B, ErbB-2 and cyclin D1. Results: Compared with the tamoxifen, a statistically significant growth inhibition was observed with anastrozole. The PRA,PR B and cyclin D1 mRNA level in anastrozole treated cells was sigificantly below the level in tamoxifen treated cells (P<0. 05). They had agonistic effect on ErbB gene (P>0.05). Conclusion: The third generation of aromatase inhibitors anastrozole exert more inhibit function in some expression of estrogen regulated genes than tomoxifen in MCF-7 cell line.

  11. Software Defined DCF77 Receiver

    OpenAIRE

    F. Zaplata; M. Kasal

    2013-01-01

    This paper shows the solution of time stamp software defined receiver integration into low cost com-mercial devices. The receiver is based on a general pur-pose processor and its analog to digital converter. The amplified signal from a narrow-band antenna is connected to the converter and no complicated filtration has to be used. All signal processing is digitally provided by the processor. During signal reception, the processor stays available for its main tasks and signal processing con-sum...

  12. Software Defined DCF77 Receiver

    Directory of Open Access Journals (Sweden)

    F. Zaplata

    2013-12-01

    Full Text Available This paper shows the solution of time stamp software defined receiver integration into low cost com-mercial devices. The receiver is based on a general pur-pose processor and its analog to digital converter. The amplified signal from a narrow-band antenna is connected to the converter and no complicated filtration has to be used. All signal processing is digitally provided by the processor. During signal reception, the processor stays available for its main tasks and signal processing con-sumes only a small part of its computational power.

  13. SMG-ly knocking out gene expression in specific cells: an educational primer for use with "a novel strategy for cell-autonomous gene knockdown in caenorhabditis elegans defines a cell-specific function for the G-protein subunit GOA-1".

    Science.gov (United States)

    Meneely, Philip M; Bloom, Jordana C

    2013-12-01

    A recent article by Maher et al. in GENETICS introduces an alternative approach to cell-type-specific gene knockdown in Caenorhabditis elegans, using nonsense-mediated decay. This strategy has the potential to be applicable to other organisms (this strategy requires that animals can survive without nonsense-mediated decay-not all can). This Primer article provides a guide and resource for educators and students by describing different gene knockdown methodologies, by assisting with the technically difficult portions of the Maher et al. article, and by providing conceptual questions relating to the article. PMID:24302743

  14. Defining Life: Synthesis and Conclusions

    Science.gov (United States)

    Gayon, Jean

    2010-04-01

    The first part of the paper offers philosophical landmarks on the general issue of defining life. §1 defends that the recognition of “life” has always been and remains primarily an intuitive process, for the scientist as for the layperson. However we should not expect, then, to be able to draw a definition from this original experience, because our cognitive apparatus has not been primarily designed for this. §2 is about definitions in general. Two kinds of definition should be carefully distinguished: lexical definitions (based upon current uses of a word), and stipulative or legislative definitions, which deliberately assign a meaning to a word, for the purpose of clarifying scientific or philosophical arguments. The present volume provides examples of these two kinds of definitions. §3 examines three traditional philosophical definitions of life, all of which have been elaborated prior to the emergence of biology as a specific scientific discipline: life as animation (Aristotle), life as mechanism, and life as organization (Kant). All three concepts constitute a common heritage that structures in depth a good deal of our cultural intuitions and vocabulary any time we try to think about “life”. The present volume offers examples of these three concepts in contemporary scientific discourse. The second part of the paper proposes a synthesis of the major debates developed in this volume. Three major questions have been discussed. A first issue (§4) is whether we should define life or not, and why. Most authors are skeptical about the possibility of defining life in a strong way, although all admit that criteria are useful in contexts such as exobiology, artificial life and the origins of life. §5 examines the possible kinds of definitions of life presented in the volume. Those authors who have explicitly defended that a definition of life is needed, can be classified into two categories. The first category (or standard view) refers to two conditions

  15. Defining Usability of PN Services

    DEFF Research Database (Denmark)

    Nicolajsen, Hanne Westh; Ahola, Titta; Fleury, Alexandre;

    In this deliverable usability and user experience are defined in relation to MAGNET Beyond technologies, and it is described how the main MAGNET Beyond concepts can be evaluated through the involvement of users. The concepts include the new "Activity based communication approach" for interacting...... with the MAGNET Beyond system, as well as the core concepts: Personal Network, Personal Network-Federation, Service Discovery, User Profile Management, Personal Network Management, Privacy and Security and Context Awareness. The overall plans for the final usability evaluation are documented based on...... the present status of the pilot services. The evaluation will be conducted on two pilot services, that are being implemented - the Lifestyle companion and the Icebreaker. The plan of the evaluation is to carry out combinations of different types of user evaluation methods. These are user panel...

  16. Inhibition of human CYP19 by azoles used as antifungal agents and aromatase inhibitors, using a new LC-MS/MS method for the analysis of estradiol product formation

    International Nuclear Information System (INIS)

    Azoles are used as fungicides in agriculture or antifungal drugs in medicine. Their therapeutic activity is based on the inhibition of fungal lanosterol-14α-demethylase (CYP51). Azoles are also used for the treatment of estrogen-dependent diseases, e.g. in breast cancer therapy. Inhibition of CYP19 (aromatase) is the working principle for tumor therapy, but is an unwanted side effect of azoles used as fungicides or antifungal drugs. The inhibition of recombinant human CYP19 by 21 azoles in use for the three different purposes was investigated using the natural substrate testosterone. Estradiol product formation was measured by a newly developed and fully validated analytical method based on liquid chromatography-tandem mass spectrometry utilizing photospray ionization (APPI). Potency of enzyme inhibition was expressed in terms of IC5 concentrations. The two cytostatic drugs fadrozole and letrozole were the most potent inhibitors. However, azoles used as fungicides, e.g. prochloraz, or as antifungal drugs, e.g. bifonazole, were almost as potent inhibitors of aromatase as the drugs used in tumor therapy. Comparison of plasma concentrations that may be reached in antifungal therapy do not allow for large safety factors for bifonazole and miconazole. The IC5 values were compared to data obtained with other substrates, such as the pseudo-substrate dibenzylfluorescein (DBF). A high correlation was found, indicating that the fluorescence assay with DBF can well be used for potency ranking and screening of chemicals for aromatase inhibition. The data for antifungal drugs show that side effects on steroid hormone synthesis in humans due to inhibition of aromatase should be considered

  17. Software Defined Common Processing System (SDCPS) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Coherent Logix, Incorporated proposes the Software Defined Common Processing System (SDCPS) program to facilitate the development of a Software Defined Radio...

  18. Defining safety goals. 2. Basic Consideration on Defining Safety Goals

    International Nuclear Information System (INIS)

    severe hereditary effects are 10 x 10-2/Sv and 1.3 x10-2/Sv, respectively. The basic safety goals can be expressed by the complementary accumulative distribution function (CCDF) of dose versus frequencies of events: Pc(C > Cp) 5 (Cp/Co)-α. The aversion factor a is here expressed by the following arbitrary equation, which gives a polynomial curve of the order of m on a logarithmic plane: α = a+b(log(Cp/Co))m, where: Pc = CCDF frequency for Cp (/yr), Cp = dose (mSv), Co = Cp for Pc =1, a, b, m = constants. Figure 1 shows a typical tolerable risk profile (risk limit curve), which is drawn so that all the points obtained in the previous discussions are above the curve (Co=1, a=1, b=0.0772, and m = 2). Safety criteria by ANS (Ref. 2) and SHE (Ref. 3) are shown in Fig. 1 for comparison. An aversion of a factor of 2 is resulted between 1 mSv and 1 Sv. No ALARA is included, which must be considered in defining specific safety goals. The frequency of a single class of events must be lower than the CCDF profile, and a curve lower by a factor of 10 is drawn in Fig. 1. The doses referenced in the current Japanese safety guidelines and site criteria are shown in Fig. 1. The referenced doses seem reasonable, considering the conservatism in the analysis of design-basis accidents. Specific safety goals for each sort of facility can be defined based on the basic safety goals, reflecting the characteristics of the facilities and considering ALARA. The indexes of engineering terms, such as CMF and LERF, are preferable for nuclear power plants, although interpretation from dose to the engineering terms is needed. Other indexes may be used (such as frequency of criticality accidents, etc.) for facilities except for power plants. The applicability of safety goals will thus be improved. Figure 2 shows the relative risk factors (1, 1%, and 0.1%) versus the severity of radiation effects. This might indicate the adequacy of the risk factors. The absolute risk limits, which are derived here from

  19. Estrogen receptor and aromatase expression in gingival carcinoma tissue%雌激素受体及芳香化酶在牙龈癌组织中的表达和意义

    Institute of Scientific and Technical Information of China (English)

    王秋锐; 杨健; 赵华平; 张英怀

    2015-01-01

    AIM:To investigate the expression of estrogen receptor (ER)and aromatase in gingival carcino-ma.METHODS:ER and aromatase were detected by immunohistochemical staining SP method in gingival carcinoma (n=28)and normal gingival tissues(n=15).RESULTS:Positive expression rates of ER and aromatase expression in gingival carcinoma were 50.00% and 42.86% ,in normal gingival tissues were 13.33% and 6.67%,respectively (P<0.05).No significant correlation was found between ER and aromatase in gingival carcinoma.CONCLUSION:Estrogen metablism might be related to gingival carcinoma.Aromatase is not the exclusive reason of the high positive rate of ER.%目的:观察牙龈癌中雌激素受体(ER)与芳香化酶的表达情况,探讨局部雌激素及芳香化酶在牙龈癌中的作用与关系。方法:免疫组化过氧化物酶标记的链酶卵白素法测定雌激素受体及芳香化酶在牙龈癌中的表达。结果:牙龈癌组雌激素受体及芳香化酶的表达阳性率分别为50%和42.86%,正常对照组分别为13.33%和6.67%(P<0.05);牙龈癌中雌激素受体与芳香化酶之间未见明显相关性。结论:牙龈癌有一定的雌激素依赖性;芳香化酶在牙龈癌组织中表达升高,但芳香化酶并不是影响局部雌激素受体升高的唯一因素。

  20. Genes and Gene Therapy

    Science.gov (United States)

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  1. 芳香化酶抑制剂致骨质疏松研究进展%Research of aromatase inhibitor induced osteoporosis

    Institute of Scientific and Technical Information of China (English)

    马翠翠

    2008-01-01

    Breast cancer patients treated by aromatase inhibitor(AI) may cause ovarian failure, resulting in decreased hormone levels. Then bone loss increases, which may result in thinning bone and osteoporosis. In clinic, attention should be given and appropriate means must be chosen to prevent and treat this disease. Calcium + vitamin D, diphosphonate, selective estrogen receptor modulator, Chinese medicine are recommen-ded to reduce the incidence of esteoporosis.%乳腺癌患者服用芳香化酶抑制剂(AI)使得卵巢功能缺失导致体内雌激素水平下降,从而加速骨代谢发生骨质疏松.在临床中应给予重视并根据具体情况选择适当防治手段.推荐使用钙剂+维生素D、双膦酸盐、选择性雌激素受体调节剂、中药等药物治疗,减少骨质疏松的发病率.

  2. Chronic green tea consumption decreases body mass, induces aromatase expression, and changes proliferation and apoptosis in adult male rat adipose tissue.

    Science.gov (United States)

    Monteiro, Rosário; Assunção, Marco; Andrade, José P; Neves, Delminda; Calhau, Conceição; Azevedo, Isabel

    2008-11-01

    Green tea (GT) and its components have been shown to possess antiobesity properties and the corresponding mechanisms of action are being investigated, given the epidemic proportions of obesity incidence. In the current work, we used 12-mo-old male Wistar rats to test the effect of 6 mo of treatment with GT as the sole drinking beverage (52.8 +/- 6.4 mL/d) on adipose tissue (AT). AT aromatase expression was determined by Western blotting, plasma concentrations of 17beta-estradiol and testosterone were determined by RIA, and adipocyte size determined by measuring diameter in tissue sections. Proliferation and apoptosis were also assessed by Ki67 immunostaining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling, respectively. Evaluations were made in subcutaneous (sc) AT and visceral (v) AT. Body weight increased over time in both groups (P rats had a higher percentage of proliferating cells (204.1 +/- 19.5% of control in scAT, P adipocytes (78.3 +/- 1.7% of control in scAT, P < 0.001, and 87.9 +/- 3.2% of control in vAT, P < 0.05). GT also increased the number of apoptotic cells in vAT (320.4 +/- 21.9% of control; P < 0.001). These results suggest new mechanisms for GT on body weight and highlight its potential benefit to prevent or treat obesity and the metabolic syndrome. PMID:18936213

  3. Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.

    Science.gov (United States)

    Lee, Wen-I; Huang, Jing-Long; Chen, Chien-Chang; Lin, Ju-Li; Wu, Ren-Chin; Jaing, Tang-Her; Ou, Liang-Shiou

    2016-03-01

    Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic

  4. On defining semantics of extended attribute grammars

    DEFF Research Database (Denmark)

    Madsen, Ole Lehrmann

    1980-01-01

    Knuth has introduced attribute grammars (AGs) as a tool to define the semanitcs of context-free languages. The use of AGs in connection with programming language definitions has mostly been to define the context-sensitive syntax of the language and to define a translation in code for a hypothetical...

  5. Defining moments in leadership character development.

    Science.gov (United States)

    Bleich, Michael R

    2015-06-01

    Critical moments in life define one's character and clarify true values. Reflective leadership is espoused as an important practice for transformational leaders. Professional development educators can help surface and explore defining moments, strengthen leadership behavior with defining moments as a catalyst for change, and create safe spaces for leaders to expand their leadership capacity. PMID:26057159

  6. Defining the identity of mouse embryonic dermal fibroblasts.

    Science.gov (United States)

    Budnick, Isadore; Hamburg-Shields, Emily; Chen, Demeng; Torre, Eduardo; Jarrell, Andrew; Akhtar-Zaidi, Batool; Cordovan, Olivia; Spitale, Rob C; Scacheri, Peter; Atit, Radhika P

    2016-08-01

    Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. The gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase-seq and histone modification ChiP-seq data on various cell-types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell-types. We found a subset of the signature genes whose expression is dependent on Wnt/β-catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease. genesis 54:415-430, 2016. © 2016 Wiley Periodicals, Inc. PMID:27265328

  7. Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

    Science.gov (United States)

    Shen, Zhi-Gang; Fan, Qi-Xue; Yang, Wei; Zhang, Yun-Long; Wang, Han-Ping

    2015-04-01

    Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17α-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males. PMID:25920714

  8. miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors.

    Science.gov (United States)

    Bacci, Marina; Giannoni, Elisa; Fearns, Antony; Ribas, Ricardo; Gao, Qiong; Taddei, Maria Letizia; Pintus, Gianfranco; Dowsett, Mitch; Isacke, Clare M; Martin, Lesley-Ann; Chiarugi, Paola; Morandi, Andrea

    2016-03-15

    Aromatase inhibitors (AI) have become the first-line endocrine treatment of choice for postmenopausal estrogen receptor-positive (ER(+)) breast cancer patients, but resistance remains a major challenge. Metabolic reprogramming is a hallmark of cancer and may contribute to drug resistance. Here, we investigated the link between altered breast cancer metabolism and AI resistance using AI-resistant and sensitive breast cancer cells, patient tumor samples, and AI-sensitive human xenografts. We found that long-term estrogen deprivation (LTED), a model of AI resistance, was associated with increased glycolysis dependency. Targeting the glycolysis-priming enzyme hexokinase-2 (HK2) in combination with the AI, letrozole, synergistically reduced cell viability in AI-sensitive models. Conversely, MCF7-LTED cells, which displayed a high degree of metabolic plasticity, switched to oxidative phosphorylation when glycolysis was impaired. This effect was ER dependent as breast cancer cells with undetectable levels of ER failed to exhibit metabolic plasticity. MCF7-LTED cells were also more motile than their parental counterparts and assumed amoeboid-like invasive abilities upon glycolysis inhibition with 2-deoxyglucose (2-DG). Mechanistic investigations further revealed an important role for miR-155 in metabolic reprogramming. Suppression of miR-155 resulted in sensitization of MCF7-LTED cells to metformin treatment and impairment of 2-DG-induced motility. Notably, high baseline miR-155 expression correlated with poor response to AI therapy in a cohort of ER(+) breast cancers treated with neoadjuvant anastrozole. These findings suggest that miR-155 represents a biomarker potentially capable of identifying the subset of breast cancers most likely to adapt to and relapse on AI therapy. PMID:26795347

  9. Software Defined Networking (Dagstuhl Seminar 12363)

    OpenAIRE

    Hui, Pan; Koponen, Teemu

    2013-01-01

    This report documents the talks and discussions of Dagstuhl Seminar 12363 "Software Defined Networking". The presented talks represent a spectrum of industrial and academic work as well as both technical and organizational developments surrounding Software Defined Networking (SDN). The topic of SDN has garnered significant attention over the past few years in the networking community and beyond, and indeed the term "Software Defined Networking" itself carries different meani...

  10. Software Defined Common Processing System (SDCPS) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Coherent Logix, Incorporated (CLX) proposes the development of a Software Defined Common Processing System (SDCPS) that leverages the inherent advantages of an...

  11. Reconfigurable, Cognitive Software Defined Radio Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Intelligent Automation Inc, (IAI) is currently developing a software defined radio (SDR) platform that can adaptively switch between different modes of operation...

  12. Defining ovarian reserve to better understand ovarian aging

    Directory of Open Access Journals (Sweden)

    Gleicher Norbert

    2011-02-01

    Full Text Available Abstract Though a widely utilized term and clinical concept, ovarian reserve (OR has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR, a pool of growing (recruited follicles (GFs at different stages of maturation. Functional OR (FOR depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes.

  13. Defining Dynamic Graphics by a Graphical Language

    Institute of Scientific and Technical Information of China (English)

    毛其昌; 戴汝为

    1991-01-01

    A graphical language which can be used for defining dynamic picture and applying control actions to it is defined with an expanded attributed grammar.Based on this a system is built for developing the presentation of application data of user interface.This system provides user interface designers with a friendly and high efficient programming environment.

  14. Cancer gene therapy

    OpenAIRE

    Mitrović Tatjana; Radulović Siniša

    2005-01-01

    Cancer gene therapy can be defined as transfer of nucleic acids into tumor or normal cells with aim to eradicate or reduce tumor mass by direct killing of cells, immunomodulation or correction of genetic errors, and reversion of malignant status. Initially started with lots of optimism and enthusiasm, cancer gene therapy has shown limited success in treatment of patients. This review highlights current limitations and almost endless possibilities of cancer gene therapy. The major difficulty i...

  15. Regulation of gene expression

    International Nuclear Information System (INIS)

    In order to define in molecular terms the mechanisms controlling expression of specific genes in mammalian cells, how gene expression is activated, how tissue-specific expression is effected, how expression is modulated by hormones and other specific effectors, and how genetic control mechanisms are altered in the dysfunction of gene expression in cells transformed to malignancy were studied. Much of this work has focused on expression of the rat liver enzyme tyrosine aminotransferase

  16. DQw3 variants defined by cloned alloreactive T cells.

    Science.gov (United States)

    Mickelson, E M; Nepom, G T; Nisperos, B; Hansen, J A

    1988-01-01

    The polymorphism of HLA class II molecules expressing the serologically defined alloantigen DQw3 was studied using cloned proliferative T lymphocytes. Two clones, IG9 and IC3, were selectively primed against DQw3-associated determinants and tested against a panel of 92 HLA-D homozygous cells. Both clones were specific for DQw3, but each showed a distinct response pattern. Clone IG9 recognized a DQw3-associated determinant expressed on a subset of DR4 and DR5 haplotypes and on all DRw6, 7, w8, and w9 haplotypes tested. In contrast, clone IC3 recognized a distinct DQw3-associated determinant expressed only on a subset of DR4 haplotypes. In monoclonal antibody inhibition experiments, anti-DQ, but not anti-DR or anti-DP antibodies, blocked reactivity of both clones IG9 and IC3, further demonstrating that the determinants defined by these clones are associated with DQ molecules. In DNA hybridization studies using a DQ beta probe, a correlation was observed between restriction site polymorphisms in the DQ beta gene, designated DQw"3.1" and "3.2," and the expression of the T-cell-defined IG9 and IC3 determinants. It is, thus, possible to demonstrate by cloned T-cell reactivity functionally relevant recognition sites on DQw3+ molecules that are associated with structural polymorphisms defined by molecular and genomic analysis. PMID:2452816

  17. Selective constraints in experimentally defined primate regulatory regions.

    Directory of Open Access Journals (Sweden)

    Daniel J Gaffney

    Full Text Available Changes in gene regulation may be important in evolution. However, the evolutionary properties of regulatory mutations are currently poorly understood. This is partly the result of an incomplete annotation of functional regulatory DNA in many species. For example, transcription factor binding sites (TFBSs, a major component of eukaryotic regulatory architecture, are typically short, degenerate, and therefore difficult to differentiate from randomly occurring, nonfunctional sequences. Furthermore, although sites such as TFBSs can be computationally predicted using evolutionary conservation as a criterion, estimates of the true level of selective constraint (defined as the fraction of strongly deleterious mutations occurring at a locus in regulatory regions will, by definition, be upwardly biased in datasets that are a priori evolutionarily conserved. Here we investigate the fitness effects of regulatory mutations using two complementary datasets of human TFBSs that are likely to be relatively free of ascertainment bias with respect to evolutionary conservation but, importantly, are supported by experimental data. The first is a collection of almost >2,100 human TFBSs drawn from the literature in the TRANSFAC database, and the second is derived from several recent high-throughput chromatin immunoprecipitation coupled with genomic microarray (ChIP-chip analyses. We also define a set of putative cis-regulatory modules (pCRMs by spatially clustering multiple TFBSs that regulate the same gene. We find that a relatively high proportion ( approximately 37% of mutations at TFBSs are strongly deleterious, similar to that at a 2-fold degenerate protein-coding site. However, constraint is significantly reduced in human and chimpanzee pCRMS and ChIP-chip sequences, relative to macaques. We estimate that the fraction of regulatory mutations that have been driven to fixation by positive selection in humans is not significantly different from zero. We also find

  18. Chemically defined medium and Caenorhabditis elegans

    Science.gov (United States)

    Szewczyk, Nathaniel J.; Kozak, Elena; Conley, Catharine A.

    2003-01-01

    BACKGROUND: C. elegans has been established as a powerful genetic system. Use of a chemically defined medium (C. elegans Maintenance Medium (CeMM)) now allows standardization and systematic manipulation of the nutrients that animals receive. Liquid cultivation allows automated culturing and experimentation and should be of use in large-scale growth and screening of animals. RESULTS: We find that CeMM is versatile and culturing is simple. CeMM can be used in a solid or liquid state, it can be stored unused for at least a year, unattended actively growing cultures may be maintained longer than with standard techniques, and standard C. elegans protocols work well with animals grown in defined medium. We also find that there are caveats to using defined medium. Animals in defined medium grow more slowly than on standard medium, appear to display adaptation to the defined medium, and display altered growth rates as they change the composition of the defined medium. CONCLUSIONS: As was suggested with the introduction of C. elegans as a potential genetic system, use of defined medium with C. elegans should prove a powerful tool.

  19. Data defining markers of human neural stem cell lineage potential.

    Science.gov (United States)

    Oikari, Lotta E; Okolicsanyi, Rachel K; Griffiths, Lyn R; Haupt, Larisa M

    2016-06-01

    Neural stem cells (NSCs) and neural progenitor cells (NPCs) are self-renewing and multipotent cells, however, NPCs are considered to be more lineage-restricted with a reduced self-renewing capacity. We present data comparing the expression of 21 markers encompassing pluripotency, self-renewal (NSC) as well as neuronal and glial (astrocyte and oligodendrocyte) lineage specification and 28 extracellular proteoglycan (PG) genes and their regulatory enzymes between embryonic stem cell (ESC)-derived human NSCs (hNSC H9 cells, Thermo Fisher) and human cortex-derived normal human NPCs (nhNPCs, Lonza). The data demonstrates expression differences of multiple lineage and proteoglycan-associated genes between hNSC H9 cells and nhNPCs. Data interpretation of markers and proteoglycans defining NSC and neural cell lineage characterisation can be found in "Cell surface heparan sulfate proteoglycans as novel markers of human neural stem cell fate determination" (Oikari et al. 2015) [1]. PMID:26958640

  20. Identification of rare intronic variants defining novel BRCA haplotypes

    Directory of Open Access Journals (Sweden)

    Anca Negura

    2012-10-01

    Full Text Available Sanger DNA sequencing is widely used nowadays to identify germ-line alterations of cancerpredisposition genes. Molecular diagnosis of hereditary risk of breast and ovarian cancer (HBOC is mainly targetingBRCA1 and BRCA2, as carriers of deleterious mutations in any of these genes are at significantly higher risk ofdeveloping cancer than general population. Usual diagnosis performs a pre-screening step, followed by systematicsequencing of exons and exon/intron boundaries. Unfortunately, not all sequence variations found by sequencing arepathogenic. About one half of identified variants are of unclear clinical significance. Common single nucleotidepolymorphisms (SNPs are also usually detected, either heterozygous or homozygous. When systematically detected,SNPs can be used to define haplotypes, which are particularly useful in population disease studies or ethnogenomics.Frequent BRCA1 SNPs are well known, as well as associated haplotypes. Here we present some rare intronic variantsdefining novel BRCA1 haplotypes.

  1. ADSA Foundation Scholar Award: defining dairy flavors.

    Science.gov (United States)

    Drake, MaryAnne

    2004-04-01

    Production and consumption of dairy foods continue to increase annually. Further, new ingredient applications for dairy foods continue to expand. With continued production and consumption, there is also increased competition. Increased competition exists regionally, nationally, and globally. Processors as well as product developers must find ways to maximize existing markets and expand into new markets. A consistent high quality product is necessary to maintain competitiveness. Although microbial safety and stability are key ways to define quality, flavor is one method of defining quality that is often assumed or overlooked. The aggressive and competitive nature of today's market demands more precise and powerful tools for defining flavor and flavor quality. Traditional as well as more recent methods for evaluating dairy flavor are reviewed. The application of defining sensory flavors to fundamental research on flavor chemistry, product understanding, and effective marketing is addressed. PMID:15259211

  2. 29 CFR 779.107 - Goods defined.

    Science.gov (United States)

    2010-07-01

    ... Engaged in Commerce Or in the Production of Goods for Commerce § 779.107 Goods defined. The term goods is...; advertising, motion pictures, newspaper and radio copy; art work and manuscripts for publication; sample...

  3. Software Defined Multiband EVA Radio Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The objective of Phase 2 is to build a reliable, lightweight, programmable, multi-mode, miniaturized EVA Software Defined Radio (SDR) that supports data telemetry,...

  4. Software Defined Multiband EVA Radio Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The objective of this research is to propose a reliable, lightweight, programmable, multi-band, multi-mode, miniaturized frequency-agile EVA software defined radio...

  5. Reconfigurable, Cognitive Software Defined Radio Project

    Data.gov (United States)

    National Aeronautics and Space Administration — IAI is actively developing Software Defined Radio platforms that can adaptively switch between different modes of operation by modifying both transmit waveforms and...

  6. Radiation Tolerant Software Defined Video Processor Project

    Data.gov (United States)

    National Aeronautics and Space Administration — MaXentric's is proposing a radiation tolerant Software Define Video Processor, codenamed SDVP, for the problem of advanced motion imaging in the space environment....

  7. User Defined Spreadsheet Functions in Excel

    OpenAIRE

    Tyszkiewicz, Jerzy; Balson, Dermot

    2012-01-01

    Creating user defined functions (UDFs) is a powerful method to improve the quality of computer applications, in particular spreadsheets. However, the only direct way to use UDFs in spreadsheets is to switch from the functional and declarative style of spreadsheet formulas to the imperative VBA, which creates a high entry barrier even for proficient spreadsheet users. It has been proposed to extend Excel by UDFs declared by a spreadsheet: user defined spreadsheet functions (UDSFs). In this pap...

  8. Optimum Criteria for Developing Defined Structures

    Directory of Open Access Journals (Sweden)

    Ion IVAN

    2008-01-01

    Full Text Available Basic aspects concerning distributed applications are presented: definition, particularities and importance. For distributed applications linear, arborescent, graph structures are defined with different versions and aggregation methods. Distributed applications have associated structures which through their characteristics influence the costs of the stages in the development cycle and the exploitation costs transferred to each user. The complexity of the defined structures is analyzed. The minimum and maximum criteria are enumerated for optimizing distributed application structures.

  9. Defining service innovation: a review and synthesis

    OpenAIRE

    Witell, Lars; Snyder, Hannah; Gustafsson, Anders; Fombelle, Paul; Kristensson, Per

    2016-01-01

    Research on service innovation appears in several research disciplines, with important contributions in marketing, management, and operations research. Although the concept is widely used, few research papers have explicitly defined service innovation. This dearth of research is the motivation for the present study. Through a systematic review of 1301 articles on service innovation appearing in academic journals between 1979 and 2014, this article examines research defining service innovation...

  10. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial.

    Science.gov (United States)

    Rastelli, Antonella L; Taylor, Marie E; Gao, Feng; Armamento-Villareal, Reina; Jamalabadi-Majidi, Shohreh; Napoli, Nicola; Ellis, Matthew J

    2011-08-01

    A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant anastrozole improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain (P = 0.0045), BPI worst-pain (P = 0.04), BPI average-pain (P = 0.0067), BPI pain-severity (P = 0.04), and BPI interference (P = 0.034) scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A (FIQ pain, P = 0.04; BPI average, P = 0.03; BPI severity, P = 0.03; BPI interference, P = 0.04). BMD at the femoral neck decreased in the placebo and did not change in the HDD group (P = 0.06). Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated. PMID:21691817

  11. Software-Defined Cellular Mobile Network Solutions

    Institute of Scientific and Technical Information of China (English)

    Jiandong Li; Peng Liu; Hongyan Li

    2014-01-01

    The emergency relating to software-defined networking (SDN), especially in terms of the prototype associated with OpenFlow, pro-vides new possibilities for innovating on network design. Researchers have started to extend SDN to cellular networks. Such new programmable architecture is beneficial to the evolution of mobile networks and allows operators to provide better services. The typical cellular network comprises radio access network (RAN) and core network (CN); hence, the technique roadmap diverges in two ways. In this paper, we investigate SoftRAN, the latest SDN solution for RAN, and SoftCell and MobileFlow, the latest solu-tions for CN. We also define a series of control functions for CROWD. Unlike in the other literature, we emphasize only software-defined cellular network solutions and specifications in order to provide possible research directions.

  12. Annotating user-defined abstractions for optimization

    Energy Technology Data Exchange (ETDEWEB)

    Quinlan, D; Schordan, M; Vuduc, R; Yi, Q

    2005-12-05

    This paper discusses the features of an annotation language that we believe to be essential for optimizing user-defined abstractions. These features should capture semantics of function, data, and object-oriented abstractions, express abstraction equivalence (e.g., a class represents an array abstraction), and permit extension of traditional compiler optimizations to user-defined abstractions. Our future work will include developing a comprehensive annotation language for describing the semantics of general object-oriented abstractions, as well as automatically verifying and inferring the annotated semantics.

  13. Technical communication: Notes toward defining discipline

    Science.gov (United States)

    Rubens, P. M.

    1981-01-01

    In the field of technical communication, definitions posited in virtually any major text violate every major rule of definitions. The most popular method for defining the field is to state that technical writing is any writing that supports technology or technological activities. There is a need for a nice yardstick for measuring what "technology" is. Some ways in which the field can be defined in a tightly structured empirical way and some implications of technical communication for a humanistic education in a technological age are suggested.

  14. Defining actionable mutations for oncology therapeutic development.

    Science.gov (United States)

    Carr, T Hedley; McEwen, Robert; Dougherty, Brian; Johnson, Justin H; Dry, Jonathan R; Lai, Zhongwu; Ghazoui, Zara; Laing, Naomi M; Hodgson, Darren R; Cruzalegui, Francisco; Hollingsworth, Simon J; Barrett, J Carl

    2016-04-26

    Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials. PMID:27112209

  15. Who defines the need for fishery reform?

    DEFF Research Database (Denmark)

    Jacobsen, Rikke Becker; Raakjær, Jesper

    2014-01-01

    This article investigates recent reforms of the Greenland coastal fisheries in order to contribute to the general lessons on reform and policy networks in the context of a changing Arctic stakeholdership. It analyses participation in fisheries governance decision-making by examining the emergence...... of discourses and policy networks that come to define the very need for reform. A policy network is identified across state ministries, powerful officials, banks and large scale industry that defined the need for fisheries reform within a ‘grand reform’ discourse. But inertia characterised the actual decision...

  16. GNU Based Security in Software Defined Radio

    Directory of Open Access Journals (Sweden)

    H. B. Bhadka

    2012-11-01

    Full Text Available Various new technologies are explored for radio communication toward the 21st century. Among them the technology of "software defined radio" attracts large attention. Software Defined Radio (SDR technology implements some of the functional modules of a radio system in software enabling highly flexible handsets. SDR devices may be reconfigured dynamically via the download of new software modules. Malicious or malfunctioning downloaded software present serious security risks to SDR devices and networks in which they operate. Together with the use of software downloading, future terminals will become a platform to support the deployment of yet unspecified services and applications.

  17. Godel's Second Incompleteness Theorem for Definable Theories

    OpenAIRE

    Seraji, Payam; Chao, Conden

    2016-01-01

    It is proved that if $T$ is a $\\Sigma_{n+1}$ Definable theory which is $\\Sigma_n$-sound and extends $PA$, then $T$ can not prove the sentence $\\Sigma_n-sound(T)$ that expresses the $\\Sigma_n$-soundness of $T$. Optimality of this result is showed by constructing a $\\Sigma_{n+1}$-definable and $\\Sigma_{n-1}$-sound theory extending $PA$ such that $\\Sigma_n-sound(T)$ is $T$-provable. It is also proved that no R.E. arithmetical theory, evevn very weak theories which are not $\\Sigma_1$-complete, ca...

  18. Convergent approaches for defining functional imaging endophenotypes in schizophrenia

    Directory of Open Access Journals (Sweden)

    Godfrey Pearlson

    2009-11-01

    Full Text Available In complex genetic disorders such as schizophrenia, endophenotypes have potential utility both in identifying risk genes and in illuminating pathophysiology. This is due to their presumed status as closer in the etiopathological pathway to the causative genes than is the currently defining clinical phenomenology of the illness and thus their simpler genetic architecture than that of the full syndrome. There, many genes conferring slight individual risk are additive or epistatic (interactive with regard to cumulative schizophrenia risk. In addition the use of endophenotypes has encouraged a conceptual shift away from the exclusive study of categorical diagnoses in manifestly ill patients, towards the study of quantitative traits in patients, unaffected relatives and healthy controls. A more recently employed strategy is thus to study unaffected first degree relatives of schizophrenia patients, who share some of the genetic diathesis without illness-related confounds that may themselves impact fMRI task performance. Consistent with the multiple biological abnormalities associated with the disorder, many candidate endophenotypes have been advanced for schizophrenia, including measures derived from structural brain imaging, EEG, sensorimotor integration, eye movements and cognitive performance (Allen 2009, but recent data derived from quantitative functional brain imaging measures present additional attractive putative endophenotypes. We will review two major, conceptually different approaches that use fMRI in this context. One, the dominant paradigm, employs defined cognitive tasks on which schizophrenia patients perform poorly as “cognitive stress tests”. The second uses very simple probes or “task-free” approaches where performance in patients and controls is equal. We explore the potential advantages and disadvantages of each method, the associated data analytic approaches and recent studies exploring their interface with the genetic

  19. Doublecortin May Play a Role in Defining Chondrocyte Phenotype

    Directory of Open Access Journals (Sweden)

    Dongxia Ge

    2014-04-01

    Full Text Available Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.

  20. Paleontological evidence for defining the Anthropocene

    Science.gov (United States)

    Barnosky, A. D.

    2012-12-01

    Paleontological criteria formed the basis for defining most of the geological eras, periods, epochs, and ages that are commonly recognized. By the same token, the Anthropocene can be defined by paleontological distinctiveness in accordance with commonly accepted biostratigraphic and biochronologic practice. Here I focus on the utility of defining the Anthropocene by the distinctive fossils (or potential fossils of the future) that have accumulated and are accumulating in the sedimentary record. I discuss what kinds of biostratrigraphic criteria would be of most use in recognizing the Anthropocene's base and temporal extent, including pros and cons of definitions based on range zones, interval zones, lineage zones, assemblage zones, and abundance zones, as well as implications for potential reference sections. Key paleontological criteria useful in formally defining the Anthropocene as a geological epoch include (1) anthropogenic trace fossils such as buildings, roads, plastics, etc; (2) abundance zones based on remains of domesticated species and humans; and (3) assemblage zones based on species transported around the globe by people. The magnitude of paleontologically-recognizable changes that have occurred since humans became the dominant species on Earth is at least as great as the paleontological differences that distinguish other Cenozoic epochs, and supports recognition of the Anthropocene as a formal stratigraphic unit.

  1. Precise Interval Timer for Software Defined Radio

    Science.gov (United States)

    Pozhidaev, Aleksey (Inventor)

    2014-01-01

    A precise digital fractional interval timer for software defined radios which vary their waveform on a packet-by-packet basis. The timer allows for variable length in the preamble of the RF packet and allows to adjust boundaries of the TDMA (Time Division Multiple Access) Slots of the receiver of an SDR based on the reception of the RF packet of interest.

  2. Defining enthesitis in spondyloarthritis by ultrasound

    DEFF Research Database (Denmark)

    Terslev, Lene; Naredo, E; Iagnocco, A;

    2014-01-01

    Objective: To standardize ultrasound (US) in enthesitis. Methods: An Initial Delphi exercise was undertaken to define US detected enthesitis and its core components. These definitions were subsequently tested on static images taken from Spondyloarthritis (SpA) patients in order to evaluate their ...

  3. Defining, constructing and assessing learning outcomes.

    Science.gov (United States)

    Taylor, R M

    2009-08-01

    Learning outcomes define the veterinary curriculum and inform students about what they must be able to demonstrate to succeed. Stakeholder consultation during their development ensures that programme learning outcomes equip graduates to contribute to the veterinary profession. Effective learning outcomes form a hierarchy linking the programme, its courses and tasks. Clear outcomes direct students towards higher quality learning by indicating the achievements intended, but leave scope for emergent learning outcomes. Defined technical competencies fit within this overarching framework, complementing higher order learning. Mapping is used to align learning outcomes horizontally and vertically so students are systematically guided towards entry-level competence and professional independence. Constructively aligned learning and assessment tasks ensure learners spend the focused time required to sequentially develop programme outcomes. Assessment by staff, peers and other stakeholders certifies achievement of intended outcomes. Effective assessment also empowers students to define and achieve their own learning outcomes, so they develop the habits of autonomous life-long learning. Evaluation of the quality and consistency of achieved outcomes informs ongoing programme improvement. If we are going to achieve the objectives of this set of papers, i.e. to improve public health education globally (Rev. sci. tech. Off. int. Epiz. 28 [2] 2009), then it is essential that they be well defined in the learning outcomes statement of all veterinary schools. PMID:20128490

  4. Defining International Human Resource Development: A Proposal

    Science.gov (United States)

    McLean, Gary N.; Wang, Xiaohui

    2007-01-01

    From the beginning of the use of the term, there have been struggles over the meaning of human resource development (HRD). In recent years, there has been increased attention to the field's definition. This paper moves this exploration one more step to an exploration of the dilemma of defining international and cross-national HRD. A beginning…

  5. Defining and Operationalising L2 Complexity

    Science.gov (United States)

    Bulte, Bram; Housen, Alex

    2012-01-01

    This chapter takes a critical look at complexity in L2 research. We demonstrate several problems in the L2 literature in terms of how complexity has been defined and operationalised as a construct. In the first part of the chapter we try to unravel its highly complex, multidimensional nature by presenting a taxonomic model that identifies major…

  6. 7 CFR 1210.500 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1210.500 Section 1210.500 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND...

  7. 7 CFR 1280.601 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1280.601 Section 1280.601 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE LAMB PROMOTION, RESEARCH,...

  8. 7 CFR 1260.301 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1260.301 Section 1260.301 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE BEEF PROMOTION AND RESEARCH...

  9. 7 CFR 1215.100 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1215.100 Section 1215.100 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE POPCORN PROMOTION, RESEARCH,...

  10. 7 CFR 1210.400 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1210.400 Section 1210.400 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE WATERMELON RESEARCH AND...

  11. 7 CFR 29.9201 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Terms defined. 29.9201 Section 29.9201 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS...

  12. 7 CFR 1280.401 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1280.401 Section 1280.401 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE LAMB PROMOTION, RESEARCH,...

  13. 7 CFR 1219.200 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1219.200 Section 1219.200 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE HASS AVOCADO PROMOTION,...

  14. 7 CFR 1220.301 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1220.301 Section 1220.301 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE SOYBEAN PROMOTION, RESEARCH,...

  15. 7 CFR 29.12 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 2 2010-01-01 2010-01-01 false Terms defined. 29.12 Section 29.12 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE COMMODITY STANDARDS AND STANDARD CONTAINER REGULATIONS...

  16. 7 CFR 1206.200 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1206.200 Section 1206.200 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE MANGO PROMOTION, RESEARCH,...

  17. 7 CFR 1230.100 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1230.100 Section 1230.100 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE PORK PROMOTION, RESEARCH,...

  18. 7 CFR 1209.200 - Terms defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 10 2010-01-01 2010-01-01 false Terms defined. 1209.200 Section 1209.200 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; MISCELLANEOUS COMMODITIES), DEPARTMENT OF AGRICULTURE MUSHROOM PROMOTION, RESEARCH,...

  19. 7 CFR 160.3 - Rosin defined.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Rosin defined. 160.3 Section 160.3 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) NAVAL STORES REGULATIONS...

  20. Deciding the weak definability of Büchi definable tree languages

    OpenAIRE

    Colcombet, Thomas; Kuperberg, Denis; Löding, Christof; Vanden Boom, Michael

    2013-01-01

    Weakly definable languages of infinite trees are an expressive subclass of regular tree languages definable in terms of weak monadic second-order logic, or equivalently weak alternating automata. Our main result is that given a Büchi automaton, it is decidable whether the language is weakly definable. We also show that given a parity automaton, it is decidable whether the language is recognizable by a nondeterministic co-Büchi automaton. The decidability proofs build on recent results abou...

  1. FINANCIAL ACCOUNTING QUALITY AND ITS DEFINING CHARACTERISTICS

    Directory of Open Access Journals (Sweden)

    Andra M. ACHIM

    2014-11-01

    Full Text Available The importance ofhigh-quality financial statements is highlighted by the main standard-setting institutions activating in the field of accounting and reporting. These have issued Conceptual Frameworks which state and describe the qualitative characteristics of accounting information. In this qualitative study, the research methodology consists of reviewing the literature related to the definition of accounting quality and striving for understanding how it can be explained. The main objective of the study is to identify the characteristics information should possess in order to be of high quality. These characteristics also contribute to the way of defining financial accounting quality. The main conclusions that arise from this research are represented by the facts that indeed financial accounting quality cannot be uniquely defined and that financial information is of good quality when it enhances the characteristics incorporated in the conceptual frameworks issued by both International Accounting Standards Board and Financial Accounting Standards Board.

  2. Control of System with Defined Risk Level

    Directory of Open Access Journals (Sweden)

    Pavol Tomasov

    2002-01-01

    Full Text Available In the following paper the basic requirements for system control with defined risk level is presented. The paper should be an introduction to describe of theoretical apparatus, which was created during some years of research work in the Department of information and safety systems in this area. It a modification or creation of new parts of Information theory, System theory, and Control theory means. This parts are necessary for the analysis and synthesis tasks in the systems where dominant attribute of control is defined risk level. The basic problem is the creation of protect mechanism again the threats from inside and from controlled system environs. For each risk reduction mechanism is needed some redundancy which should be into control algorithm to put by exactly determined way.

  3. Defining Tiger Parenting in Chinese Americans

    Science.gov (United States)

    Kim, Su Yeong

    2016-01-01

    “Tiger” parenting, as described by Amy Chua [2011], has instigated scholarly discourse on this phenomenon and its possible effects on families. Our eight-year longitudinal study, published in the Asian American Journal of Psychology [Kim, Wang, Orozco-Lapray, Shen, & Murtuza, 2013b], demonstrates that tiger parenting is not a common parenting profile in a sample of 444 Chinese American families. Tiger parenting also does not relate to superior academic performance in children. In fact, the best developmental outcomes were found among children of supportive parents. We examine the complexities around defining tiger parenting by reviewing classical literature on parenting styles and scholarship on Asian American parenting, along with Amy Chua’s own description of her parenting method, to develop, define, and categorize variability in parenting in a sample of Chinese American families. We also provide evidence that supportive parenting is important for the optimal development of Chinese American adolescents.

  4. Defining Product Customization as Form Postponement

    OpenAIRE

    Katsuyoshi Takashima

    2010-01-01

    Form postponement is one of the theoretical frameworks used in recent years to explain the development of supply chain management through product customization in various industries, along with the creation of competitive advantage based on it. This study seeks to apply a modified version of Bucklin' s postponement-speculation model to the phenomenon of customization, defining customization as a form of postponement. This model demonstrates that production costs and uncertainty costs determin...

  5. Defining the space in a general spacetime

    Science.gov (United States)

    Arminjon, Mayeul

    2016-01-01

    A global vector field v on a “spacetime” differentiable manifold V, of dimension N + 1, defines a congruence of world lines: the maximal integral curves of v, or orbits. The associated global space Nv is the set of these orbits. A “v-adapted” chart on V is one for which the ℝN vector x ≡ (xj) (j = 1,…,N) of the “spatial” coordinates remains constant on any orbit l. We consider non-vanishing vector fields v that have non-periodic orbits, each of which is a closed set. We prove transversality theorems relevant to such vector fields. Due to these results, it can be considered plausible that, for such a vector field, there exists in the neighborhood of any point X ∈V a chart χ that is v-adapted and “nice”, i.e. such that the mapping χ¯ : l↦x is injective — unless v has some “pathological” character. This leads us to define a notion of “normal” vector field. For any such vector field, the mappings χ¯ build an atlas of charts, thus providing Nv with a canonical structure of differentiable manifold (when the topology defined on Nv is Hausdorff, for which we give a sufficient condition met in important physical situations). Previously, a local space manifold MF had been associated with any “reference frame” F, defined as an equivalence class of charts. We show that, if F is made of nice v-adapted charts, MF is naturally identified with an open subset of the global space manifold Nv.

  6. Defining invasiveness and invasibility in ecological networks

    OpenAIRE

    C. Hui; Richardson, D. M.; Landi, P; H.O. Minoarivelo; Garnas, J.; Roy, H.E.

    2016-01-01

    The success of a biological invasion is context dependent, and yet two key concepts—the invasiveness of species and the invasibility of recipient ecosystems—are often defined and considered separately. We propose a framework that can elucidate the complex relationship between invasibility and invasiveness. It is based on trait-mediated interactions between species and depicts the response of an ecological network to the intrusion of an alien species, drawing on the concept of community satura...

  7. Software-defined universal microwave photonics processor

    OpenAIRE

    Pérez, Daniel; Gasulla Mestre, Ivana; Capmany Francoy, José

    2015-01-01

    We propose, for the first time to our knowledge, a software-defined reconfigurable microwave photonics signal processor architecture that can be integrated on a chip and is capable of performing all the main functionalities by suitable programming of its control signals. The basic configuration is presented and a thorough end-to-end design model derived that accounts for the performance of the overall processor taking into consideration the impact and interdependencies of both its photonic an...

  8. Defining and Distinguishing Secular and Religious Terrorism

    OpenAIRE

    Gregg, Heather S.

    2014-01-01

    Religious terrorism is typically characterised as acts of unrestrained, irrational and indiscriminant violence, thus offering few if any policy options for counterterrorism measures. This assumption about religious terrorism stems from two challenges in the literature: disproportionate attention to apocalyptic terrorism, and a lack of distinction between religious terrorism and its secular counterpart. This article, therefore, aims to do four things: define and differentiate religiously motiv...

  9. A software defined radio implementation using MATLAB

    OpenAIRE

    Feng, Ziyi

    2013-01-01

    Software Defined Radio (SDR) is a hot topic of wireless communication research in recent years. The idea of SDR is to use ultra-high speed sampling and ADC/DAC modules directly measure the received radio signal and decode whatever it contains. The aim of this project is to study and understand SDR using MATLAB in audio frequency band. In this project, both analog and digital modulation and demodulation methods are studied. Two Matlab sessions are set for sender and...

  10. Defining microbiota for developing new probiotics

    OpenAIRE

    Collado, Maria Carmen; Bäuerl, Christine; Pérez-Martínez, Gaspar

    2012-01-01

    The human body harbors complex communities of microbes that play a prominent role in human health. Detailed characterization of the microbiota in the target population forms the basis of probiotic use. Probiotics are defined as live bacterial preparations with clinically documented health effects in humans and independently of their genus and species, probiotic strains are unique and their beneficial properties on human health have to be assessed in a case-by-case manner. Understanding the me...

  11. Software-defined Quantum Communication Systems

    OpenAIRE

    Humble, Travis S.; Sadlier, Ronald J.

    2014-01-01

    Quantum communication systems harness modern physics through state-of-the-art optical engineering to provide revolutionary capabilities. An important concern for quantum communication engineering is designing and prototyping these systems to evaluate proposed capabilities. We apply the paradigm of software-defined communication for engineering quantum communication systems to facilitate rapid prototyping and prototype comparisons. We detail how to decompose quantum communication terminals int...

  12. Improving network management with Software Defined Networking

    International Nuclear Information System (INIS)

    Software-defined networking (SDN) is developed as an alternative to closed networks in centers for data processing by providing a means to separate the control layer data layer switches, and routers. SDN introduces new possibilities for network management and configuration methods. In this article, we identify problems with the current state-of-the-art network configuration and management mechanisms and introduce mechanisms to improve various aspects of network management

  13. Software Defined Networking for Heterogeneous Networks

    OpenAIRE

    Mendonca, Marc; Astuto, Bruno Nunes; Obraczka, Katia; Turletti, Thierry

    2013-01-01

    In this paper, motivated by the vision that future internets will comprise infrastructure--based and infrastructure--less networks, we explore the use of the Software-Defined Networking (SDN) paradigm in these so-called ''heterogeneous'' networked environments. To make the case for SDN in heterogeneous networks, we examine an application scenario in which SDN is a key enabling technology. We also identify the additional requirements imposed by the SDN paradigm and discuss the research challen...

  14. Software defined networking: meeting carrier grade requirements

    OpenAIRE

    Staessens, Dimitri; Sharma, Sachin; Colle, Didier; Pickavet, Mario; Demeester, Piet

    2011-01-01

    Software Defined Networking is a networking paradigm which allows network operators to manage networking elements using software running on an external server. This is accomplished by a split in the architecture between the forwarding element and the control element. Two technologies which allow this split for packet networks are ForCES and Openflow. We present energy efficiency and resilience aspects of carrier grade networks which can be met by Openflow. We implement flow restoration and ru...

  15. Software-Defined Networking and its Security

    OpenAIRE

    Taha, Abdalla

    2014-01-01

    Software-Defined Networking (SDN) is a new principle in the networking paradigm, which makes a communication network programmable. With this utility, security properties can be redesigned. SDN provides new axioms for security applications to implement security services. In this thesis, security threats troubling Ethernet technology are interpreted and whether the SDN can provide a solution to overcome these is discussed. Furthermore, existing SDN security applications are presented and compar...

  16. Anomaly Traceback using Software Defined Networking

    OpenAIRE

    François, Jérôme; Festor, Olivier

    2014-01-01

    While the threats in Internet are still increasing and evolving (like intra multi-tenant data center attacks), protection and detection mechanisms are not fully accurate. Therefore, forensics is vital for recovering from an attack but also to identify the responsible entities. Therefore, this paper focuses on tracing back to the sources of an anomaly in the network. In this paper, we propose a method leveraging the Software Defined Networking (SDN) paradigm to passively identify switches comp...

  17. Smooth Pursuit of Flicker-Defined Motion

    Science.gov (United States)

    Mulligan, Jeffrey B.; Stevenson, Scott B.

    2014-01-01

    We examined the pursuit response to stimuli defined by space-variant flicker of a dense random dot carrier pattern. On each frame, every element of the pattern could change polarity, with a probability given by a two-dimensional Gaussian distribution. A normal distribution produces a circular region of twinkle, while inverting the distribution results in a spot of static texture in a twinkling surround. In this latter case, the carrier texture could be stationary, or could move with the twinkle modulator, thereby producing first-order motion in the region of the spot. While the twinkle-defined spot produces a strong sensation of motion, the complementary stimulus defined by the absence of twinkle does not, when viewed peripherally, it appears to move in steps even when the generating distribution moves smoothly. We examined pursuit responses to these stimuli using two techniques: 1) the eye movement correlogram, obtained by cross-correlating eye velocity with the velocity of a randomly-moving stimulus; and 2) delayed visual feedback, where transient stabilization of a target can produce spontaneous oscillations of the eye, with a period empirically observed to vary linearly with the applied delay. Both techniques provide an estimate of the internal processing time, which can be as short as 100 milliseconds for a first-order target. Assessed by the correlogram method, the response to flicker-defined motion is delayed by more than 100 milliseconds, and significantly weaker (especially in the vertical dimension). When initially presented in the delayed feedback condition, purely saccadic oscillation is observed. One subject eventually developed smooth oscillations (albeit with significant saccadic intrusions), showing a period-versus-delay slope similar to that observed for first-order targets. This result is somewhat surprising, given that we interpret the slope of the period-versus-delay-function as reflecting the balance between position- and velocity

  18. Quantum Thought Experiments Can Define Nature

    CERN Document Server

    McCartor, D

    2004-01-01

    One would not think that thought experiments could matter to nature, for they are a humble human device. Yet quantum mechanics very naturally frames thought experiments (as distinct from precisely defining what exists). They exemplify the informing powers of radiation. Though based on wave functions that have time symmetry, these tableaux inevitably tell of irreversible behavior by nature. The paper sketches how John von Neumann's measurement theory fits into this and retells N. David Mermin's baseball story.

  19. A software defined GPS signal simulator design

    OpenAIRE

    Pan, Zhenhe

    2014-01-01

    The Global Positioning System (GPS) signal simulator plays a critical role in developing and testing GPS receivers. Unfortunately, very few commercial GPS signal simulators are user-friendly for security researchers because they fail to generate abnormal GPS signals, which are fundamentally important. In this thesis, we develop a cost efficient software defined GPS signal simulator. To reduce the design complexity, we make some reasonable assumptions about the GPS system. This simulator ...

  20. Thermodynamics. Using Affinities to define reversible processes

    CERN Document Server

    Ritacco, Hernán A

    2016-01-01

    In this article a definition of reversible processes in terms of differences in intensive Thermodynamics properties (Affinities) is proposed. This definition makes it possible to both define reversible processes before introducing the concept of entropy and avoid the circularity problem that follows from the Clausius definition of entropy changes. The convenience of this new definition compared to those commonly found in textbooks is demonstrated with examples.

  1. Sarcopenia: describing rather than defining a condition

    OpenAIRE

    Alchin, David Rhys

    2014-01-01

    Background Traditional definitions of sarcopenia have described an aging-associated disorder roughly defined as muscle mass two standard deviations below the young adult demographic. In an effort to clear the ambiguity pertaining to such descriptions, two international bodies have put forth working definitions of sarcopenia, namely The Society of Sarcopenia, Cachexia and Wasting Disorders in 2011, and The European Working Group on Sarcopenia in Older People in 2009. Review This paper will loo...

  2. Software Defined Radio with Parallelized Software Architecture

    Science.gov (United States)

    Heckler, Greg

    2013-01-01

    This software implements software-defined radio procession over multicore, multi-CPU systems in a way that maximizes the use of CPU resources in the system. The software treats each processing step in either a communications or navigation modulator or demodulator system as an independent, threaded block. Each threaded block is defined with a programmable number of input or output buffers; these buffers are implemented using POSIX pipes. In addition, each threaded block is assigned a unique thread upon block installation. A modulator or demodulator system is built by assembly of the threaded blocks into a flow graph, which assembles the processing blocks to accomplish the desired signal processing. This software architecture allows the software to scale effortlessly between single CPU/single-core computers or multi-CPU/multi-core computers without recompilation. NASA spaceflight and ground communications systems currently rely exclusively on ASICs or FPGAs. This software allows low- and medium-bandwidth (100 bps to approx.50 Mbps) software defined radios to be designed and implemented solely in C/C++ software, while lowering development costs and facilitating reuse and extensibility.

  3. Defining chromosomal translocation risks in cancer

    OpenAIRE

    Marc A Hogenbirk; Heideman, Marinus R.; de Rink, Iris; Velds, Arno; Kerkhoven, Ron M.; Wessels, Lodewyk F. A.; Jacobs, Heinz

    2016-01-01

    Applying innovative integrative analyses of multifactorial genome-wide data, we now demonstrate that an open chromatin configuration, which is generically enriched promoter-proximal but not promoter-specific, is the common denominator and key translocation risk-determinant of active chromatin. The finding that gene size directly correlated with its translocation risk, in both mice and cancer patients, independently emphasized the generic irrelevance of any promoter-specific activity. These da...

  4. Genome assortment, not serogroup, defines Vibrio cholerae pandemic strains

    Energy Technology Data Exchange (ETDEWEB)

    Brettin, Thomas S [Los Alamos National Laboratory; Bruce, David C [Los Alamos National Laboratory; Challacombe, Jean F [Los Alamos National Laboratory; Detter, John C [Los Alamos National Laboratory; Han, Cliff S [Los Alamos National Laboratory; Munik, A C [Los Alamos National Laboratory; Chertkov, Olga [Los Alamos National Laboratory; Meincke, Linda [Los Alamos National Laboratory; Saunders, Elizabeth [Los Alamos National Laboratory; Choi, Seon Y [SEOUL NATL. UNIV.; Haley, Bradd J [U. MARYLAND; Taviani, Elisa [U. MARYLAND; Jeon, Yoon - Seong [INTL. VACCINE INST. SEOUL; Kim, Dong Wook [INTL. VACCINE INST. SEOUL; Lee, Jae - Hak [SEOUL NATL. UNIV.; Walters, Ronald A [PNNL; Hug, Anwar [NATL. INST. CHOLERIC ENTERIC DIS.; Colwell, Rita R [U. MARYLAND

    2009-01-01

    Vibrio cholerae, the causative agent of cholera, is a bacterium autochthonous to the aquatic environment, and a serious public health threat. V. cholerae serogroup O1 is responsible for the previous two cholera pandemics, in which classical and El Tor biotypes were dominant in the 6th and the current 7th pandemics, respectively. Cholera researchers continually face newly emerging and re-emerging pathogenic clones carrying combinations of new serogroups as well as of phenotypic and genotypic properties. These genotype and phenotype changes have hampered control of the disease. Here we compare the complete genome sequences of 23 strains of V. cholerae isolated from a variety of sources and geographical locations over the past 98 years in an effort to elucidate the evolutionary mechanisms governing genetic diversity and genesis of new pathogenic clones. The genome-based phylogeny revealed 12 distinct V. cholerae phyletic lineages, of which one, designated the V. cholerae core genome (CG), comprises both O1 classical and EI Tor biotypes. All 7th pandemic clones share nearly identical gene content, i.e., the same genome backbone. The transition from 6th to 7th pandemic strains is defined here as a 'shift' between pathogenic clones belonging to the same O1 serogroup, but from significantly different phyletic lineages within the CG clade. In contrast, transition among clones during the present 7th pandemic period can be characterized as a 'drift' between clones, differentiated mainly by varying composition of laterally transferred genomic islands, resulting in emergence of variants, exemplified by V.cholerae serogroup O139 and V.cholerae O1 El Tor hybrid clones that produce cholera toxin of classical biotype. Based on the comprehensive comparative genomics presented in this study it is concluded that V. cholerae undergoes extensive genetic recombination via lateral gene transfer, and, therefore, genome assortment, not serogroup, should be used to

  5. Defining behavioral and molecular differences between summer and migratory monarch butterflies

    Directory of Open Access Journals (Sweden)

    Kanginakudru Sriramana

    2009-03-01

    Full Text Available Abstract Background In the fall, Eastern North American monarch butterflies (Danaus plexippus undergo a magnificent long-range migration. In contrast to spring and summer butterflies, fall migrants are juvenile hormone deficient, which leads to reproductive arrest and increased longevity. Migrants also use a time-compensated sun compass to help them navigate in the south/southwesterly direction en route for Mexico. Central issues in this area are defining the relationship between juvenile hormone status and oriented flight, critical features that differentiate summer monarchs from fall migrants, and identifying molecular correlates of behavioral state. Results Here we show that increasing juvenile hormone activity to induce summer-like reproductive development in fall migrants does not alter directional flight behavior or its time-compensated orientation, as monitored in a flight simulator. Reproductive summer butterflies, in contrast, uniformly fail to exhibit directional, oriented flight. To define molecular correlates of behavioral state, we used microarray analysis of 9417 unique cDNA sequences. Gene expression profiles reveal a suite of 40 genes whose differential expression in brain correlates with oriented flight behavior in individual migrants, independent of juvenile hormone activity, thereby molecularly separating fall migrants from summer butterflies. Intriguing genes that are differentially regulated include the clock gene vrille and the locomotion-relevant tyramine beta hydroxylase gene. In addition, several differentially regulated genes (37.5% of total are not annotated. We also identified 23 juvenile hormone-dependent genes in brain, which separate reproductive from non-reproductive monarchs; genes involved in longevity, fatty acid metabolism, and innate immunity are upregulated in non-reproductive (juvenile-hormone deficient migrants. Conclusion The results link key behavioral traits with gene expression profiles in brain that

  6. A simple method for defining malaria seasonality

    Directory of Open Access Journals (Sweden)

    Smith Lucy

    2009-12-01

    Full Text Available Abstract Background There is currently no standard way of defining malaria seasonality, resulting in a wide range of definitions reported in the literature. Malaria cases show seasonal peaks in most endemic settings, and the choice and timing for optimal malaria control may vary by seasonality. A simple approach is presented to describe the seasonality of malaria, to aid localized policymaking and targeting of interventions. Methods A series of systematic literature reviews were undertaken to identify studies reporting on monthly data for full calendar years on clinical malaria, hospital admission with malaria and entomological inoculation rates (EIR. Sites were defined as having 'marked seasonality' if 75% or more of all episodes occurred in six or less months of the year. A 'concentrated period of malaria' was defined as the six consecutive months with the highest cumulative proportion of cases. A sensitivity analysis was performed based on a variety of cut-offs. Results Monthly data for full calendar years on clinical malaria, all hospital admissions with malaria, and entomological inoculation rates were available for 13, 18, and 11 sites respectively. Most sites showed year-round transmission with seasonal peaks for both clinical malaria and hospital admissions with malaria, with a few sites fitting the definition of 'marked seasonality'. For these sites, consistent results were observed when more than one outcome or more than one calendar year was available from the same site. The use of monthly EIR data was found to be of limited value when looking at seasonal variations of malaria transmission, particularly at low and medium intensity levels. Conclusion The proposed definition discriminated well between studies with 'marked seasonality' and those with less seasonality. However, a poor fit was observed in sites with two seasonal peaks. Further work is needed to explore the applicability of this definition on a wide-scale, using routine

  7. Zebrafish sex determination and differentiation: Involvement of FTZ-F1 genes

    Directory of Open Access Journals (Sweden)

    Olsson Per-Erik

    2005-11-01

    Full Text Available Abstract Sex determination is the process deciding the sex of a developing embryo. This is usually determined genetically; however it is a delicate process, which in many cases can be influenced by environmental factors. The mechanisms controlling zebrafish sex determination and differentiation are not known. To date no sex linked genes have been identified in zebrafish and no sex chromosomes have been identified. However, a number of genes, as presented here, have been linked to the process of sex determination or differentiation in zebrafish. The zebrafish FTZ-F1 genes are of central interest as they are involved in regulating interrenal development and thereby steroid biosynthesis, as well as that they show expression patterns congruent with reproductive tissue differentiation and function. Zebrafish can be sex reversed by exposure to estrogens, suggesting that the estrogen levels are crucial during sex differentiation. The Cyp19 gene product aromatase converts testosterone into 17 beta-estradiol, and when inhibited leads to male to female sex reversal. FTZ-F1 genes are strongly linked to steroid biosynthesis and the regulatory region of Cyp19 contains binding sites for FTZ-F1 genes, further linking FTZ-F1 to this process. The role of FTZ-F1 and other candidates for zebrafish sex determination and differentiation is in focus of this review.

  8. Defining Starch Binding by Glucan Phosphatases

    DEFF Research Database (Denmark)

    Auger, Kyle; Raththagala, Madushi; Wilkens, Casper;

    2015-01-01

    Starch is a vital energy molecule in plants that has a wide variety of uses in industry, such as feedstock for biomaterial processing and biofuel production. Plants employ a three enzyme cyclic process utilizing kinases, amylases, and phosphatases to degrade starch in a diurnal manner. Starch is...... comprised of the branched glucan amylopectin and the more linear glucan amylose. Our lab has determined the first structures of these glucan phosphatases and we have defined their enzymatic action. Despite this progress, we lacked a means to quickly and efficiently quantify starch binding to glucan...

  9. Rates of Convergence of Recursively Defined Sequences

    DEFF Research Database (Denmark)

    Lambov, Branimir Zdravkov

    2005-01-01

    This paper gives a generalization of a result by Matiyasevich which gives explicit rates of convergence for monotone recursively defined sequences. The generalization is motivated by recent developments in fixed point theory and the search for applications of proof mining to the field. It relaxes...... the requirement for monotonicity to the form xn+1 ≤ (1+an)xn+bn where the parameter sequences have to be bounded in sum, and also provides means to treat computational errors. The paper also gives an example result, an application of proof mining to fixed point theory, that can be achieved by the...

  10. Defining the Observed World in Quantum Mechanics

    CERN Document Server

    Inamori, Hitoshi

    2015-01-01

    This paper defines what constitutes the Observed World in the Quantum Mechanical framework, based strictly on what is actually observed beyond doubt, instead of building observables on what is inferred from actual observations. Such principle narrows down considerably what can be considered as being part of the Observed World. On the other hand, we argue that some information - that is in general assumed as granted - should actually be considered as being part of the Observed World. We discuss the implications of such assertion, in the way we perceive time evolution, information growth and causality.

  11. Animal bioavailability of defined xenobiotic lignin metabolites

    International Nuclear Information System (INIS)

    Lignin has been recognized as a major component of bound pesticide residues in plants and is thought to be undigestible in animals. Two defined ring-U-14C-labeled chloroaniline/lignin metabolites have now been fed to rats, where a release of ∼66% of the bound xenobiotic occurred in the form of simple chloroaniline derivatives. The observed high degree of bioavailability indicates that bound pesticidal residues may possess ecotoxicological significance. In parallel studies, the white-rot fungus Phanerochaete chrysosporium was more efficient, and a soil system was much less efficient, in the degradation of the [ring-U-14C]chloroaniline/lignin metabolites

  12. Software-defined reconfigurable microwave photonics processor.

    Science.gov (United States)

    Pérez, Daniel; Gasulla, Ivana; Capmany, José

    2015-06-01

    We propose, for the first time to our knowledge, a software-defined reconfigurable microwave photonics signal processor architecture that can be integrated on a chip and is capable of performing all the main functionalities by suitable programming of its control signals. The basic configuration is presented and a thorough end-to-end design model derived that accounts for the performance of the overall processor taking into consideration the impact and interdependencies of both its photonic and RF parts. We demonstrate the model versatility by applying it to several relevant application examples. PMID:26072824

  13. Heisenberg's Uncertainty : an Ill-Defined Notion ?

    OpenAIRE

    Rosinger, Elemer Elad

    2012-01-01

    The often cited book [11] of Asher Peres presents Quantum Mechanics without the use of the Heisenberg Uncertainty Principle, a principle which it calls an "ill-defined notion". There is, however, no argument in this regard in the mentioned book, or comment related to the fact that its use in the realms of quanta is not necessary, let alone, unavoidable. A possible comment in this respect is presented here. And it is related to certain simple, purely logical facts in axiomatic theories, facts ...

  14. Software defined networks a comprehensive approach

    CERN Document Server

    Goransson, Paul

    2014-01-01

    Software Defined Networks discusses the historical networking environment that gave rise to SDN, as well as the latest advances in SDN technology. The book gives you the state of the art knowledge needed for successful deployment of an SDN, including: How to explain to the non-technical business decision makers in your organization the potential benefits, as well as the risks, in shifting parts of a network to the SDN modelHow to make intelligent decisions about when to integrate SDN technologies in a networkHow to decide if your organization should be developing its own SDN applications or

  15. Software defined networking applications in distributed datacenters

    CERN Document Server

    Qi, Heng

    2016-01-01

    This SpringerBrief provides essential insights on the SDN application designing and deployment in distributed datacenters. In this book, three key problems are discussed: SDN application designing, SDN deployment and SDN management. This book demonstrates how to design the SDN-based request allocation application in distributed datacenters. It also presents solutions for SDN controller placement to deploy SDN in distributed datacenters. Finally, an SDN management system is proposed to guarantee the performance of datacenter networks which are covered and controlled by many heterogeneous controllers. Researchers and practitioners alike will find this book a valuable resource for further study on Software Defined Networking. .

  16. Defining Requirements for Improved Photovoltaic System Reliability

    Energy Technology Data Exchange (ETDEWEB)

    Maish, A.B.

    1998-12-21

    Reliable systems are an essential ingredient of any technology progressing toward commercial maturity and large-scale deployment. This paper defines reliability as meeting system fictional requirements, and then develops a framework to understand and quantify photovoltaic system reliability based on initial and ongoing costs and system value. The core elements necessary to achieve reliable PV systems are reviewed. These include appropriate system design, satisfactory component reliability, and proper installation and servicing. Reliability status, key issues, and present needs in system reliability are summarized for four application sectors.

  17. Healthcare Engineering Defined: A White Paper

    Directory of Open Access Journals (Sweden)

    Ming-Chien Chyu

    2015-01-01

    Full Text Available Engineering has been playing an important role in serving and advancing healthcare. The term “Healthcare Engineering” has been used by professional societies, universities, scientific authors, and the healthcare industry for decades. However, the definition of “Healthcare Engineering” remains ambiguous. The purpose of this position paper is to present a definition of Healthcare Engineering as an academic discipline, an area of research, a field of specialty, and a profession. Healthcare Engineering is defined in terms of what it is, who performs it, where it is performed, and how it is performed, including its purpose, scope, topics, synergy, education/training, contributions, and prospects.

  18. Defining 'Indigenous': Between Culture and Biology

    Directory of Open Access Journals (Sweden)

    Stephen Pritchard

    2013-08-01

    Full Text Available This essay considers a range of discourses on identity and the definition of culture. I have little doubt that, generally speaking, Indigenous people are quite capable of defining the meaning of ‘Indigenous person’ or ‘culture’ in a way that satisfies their specific immediate needs and interests. My concern here is with the definition of ‘Aboriginal or Indigenous person’ in Australian law and legislation and with the critical response, by members of the scientific community as well as cultural theorists, to references to a biological basis of identity.

  19. Delta Semantics Defined By Petri Nets

    DEFF Research Database (Denmark)

    Jensen, Kurt; Kyng, Morten; Madsen, Ole Lehrmann

    language designed for general system description. It is partly build upon Simula, but is more than a programming language, since it contains several features, which cannot be implemented on a computer system. E.g. a continuous time concept, concurrency between an unbounded number of components and the...... possibility of using predicates to specify state changes. In this paper a formal semantics for Delta is defined and analysed using Petri nets. Petri nets was chosen because the ideas behind Petri nets and Delta concide on several points. A number of proposals for changes in Delta, which resulted from this...

  20. Defining 'Indigenous': Between Culture and Biology

    OpenAIRE

    Stephen Pritchard

    2013-01-01

    This essay considers a range of discourses on identity and the definition of culture. I have little doubt that, generally speaking, Indigenous people are quite capable of defining the meaning of ‘Indigenous person’ or ‘culture’ in a way that satisfies their specific immediate needs and interests. My concern here is with the definition of ‘Aboriginal or Indigenous person’ in Australian law and legislation and with the critical response, by members of the scientific community as well as cultura...

  1. Maize RNA polymerase IV defines trans-generational epigenetic variation.

    Science.gov (United States)

    Erhard, Karl F; Parkinson, Susan E; Gross, Stephen M; Barbour, Joy-El R; Lim, Jana P; Hollick, Jay B

    2013-03-01

    The maize (Zea mays) RNA Polymerase IV (Pol IV) largest subunit, RNA Polymerase D1 (RPD1 or NRPD1), is required for facilitating paramutations, restricting expression patterns of genes required for normal development, and generating small interfering RNA (siRNAs). Despite this expanded role for maize Pol IV relative to Arabidopsis thaliana, neither the general characteristics of Pol IV-regulated haplotypes, nor their prevalence, are known. Here, we show that specific haplotypes of the purple plant1 locus, encoding an anthocyanin pigment regulator, acquire and retain an expanded expression domain following transmission from siRNA biogenesis mutants. This conditioned expression pattern is progressively enhanced over generations in Pol IV mutants and then remains heritable after restoration of Pol IV function. This unusual genetic behavior is associated with promoter-proximal transposon fragments but is independent of sequences required for paramutation. These results indicate that trans-generational Pol IV action defines the expression patterns of haplotypes using co-opted transposon-derived sequences as regulatory elements. Our results provide a molecular framework for the concept that induced changes to the heterochromatic component of the genome are coincident with heritable changes in gene regulation. Alterations of this Pol IV-based regulatory system can generate potentially desirable and adaptive traits for selection to act upon. PMID:23512852

  2. Defining the biological bases of individual differences in musicality.

    Science.gov (United States)

    Gingras, Bruno; Honing, Henkjan; Peretz, Isabelle; Trainor, Laurel J; Fisher, Simon E

    2015-03-19

    Advances in molecular technologies make it possible to pinpoint genomic factors associated with complex human traits. For cognition and behaviour, identification of underlying genes provides new entry points for deciphering the key neurobiological pathways. In the past decade, the search for genetic correlates of musicality has gained traction. Reports have documented familial clustering for different extremes of ability, including amusia and absolute pitch (AP), with twin studies demonstrating high heritability for some music-related skills, such as pitch perception. Certain chromosomal regions have been linked to AP and musical aptitude, while individual candidate genes have been investigated in relation to aptitude and creativity. Most recently, researchers in this field started performing genome-wide association scans. Thus far, studies have been hampered by relatively small sample sizes and limitations in defining components of musicality, including an emphasis on skills that can only be assessed in trained musicians. With opportunities to administer standardized aptitude tests online, systematic large-scale assessment of musical abilities is now feasible, an important step towards high-powered genome-wide screens. Here, we offer a synthesis of existing literatures and outline concrete suggestions for the development of comprehensive operational tools for the analysis of musical phenotypes. PMID:25646515

  3. COMMENSURABLE ENCRYPTION USING USER- DEFINE KEY TECHNIQUE

    Directory of Open Access Journals (Sweden)

    ripal dilipbhai ranpara

    2012-11-01

    Full Text Available Cryptography is the gold standard for security. It is used to protect the transmission and storage of data between two parties by encrypting it into an unreadable format. Cryptography has enabled the first wave of secure transmissions, which has helped fuel the growth of transactions like shopping, banking, and finance over the world’s biggest public network, the Internet. Many Internet applications such as e-mail, databases, and browsers store a tremendous amount of personal and financial information, but frequently the data is left unprotected. Traditional network security is frequently less effective at preventing hackers from accessing this data. For instance, once-private databases are now completely exposed on the Internet. It turns out that getting to the database that holds millions of credit card numbers—the transmission—is secure through the use of cryptography, but the database itself isn’t, fueling the rise of credit card information theft. A paradigm shift is now under way for cryptography. The only way to make data secure in any application that runs over the Internet is to use secret (also known as private key cryptography. The current security methods focus on securing Internet applications using public keys techniques that are no longer effective.so according to my knowledge no one has addressed on COMMENSURABLE USER-DEFINE KEY TECHNIQUE that is used to encrypt the data as per the user-define key

  4. Defining and measuring vulnerability in young people

    Directory of Open Access Journals (Sweden)

    Shilpa Khanna Arora

    2015-01-01

    Full Text Available Adolescents and youth, together addressed as "young people", form the future building blocks of any society. They being most energetic and dynamic, tend to get involved in high-risk behaviors making themselves susceptible to criminal offences, accidents, physical injuries, emotional trauma, and medical problems - some of them extremely serious like transmission of human immunodeficiency virus (HIV. The concept of vulnerability is applicable to all the people who are more exposed to risks than their peers like the young people. In order to deal with social evils like criminal offences, domestic violence, sexual abuse, HIV, etc. we need to define vulnerability and understand the factors that influence it. This review also attempts to summarize the indicators of vulnerability and the data currently available to estimate its burden in India. Measuring the magnitude of vulnerability by means of certain indicators/variables might help us in devising tools to assess this poorly defined entity. This may also evolve a conceptual framework on which targeted remedial interventions can be devised and implemented.

  5. Defining and Measuring Vulnerability in Young People.

    Science.gov (United States)

    Arora, Shilpa Khanna; Shah, Dheeraj; Chaturvedi, Sanjay; Gupta, Piyush

    2015-01-01

    Adolescents and youth, together addressed as "young people", form the future building blocks of any society. They being most energetic and dynamic, tend to get involved in high-risk behaviors making themselves susceptible to criminal offences, accidents, physical injuries, emotional trauma, and medical problems - some of them extremely serious like transmission of human immunodeficiency virus (HIV). The concept of vulnerability is applicable to all the people who are more exposed to risks than their peers like the young people. In order to deal with social evils like criminal offences, domestic violence, sexual abuse, HIV, etc. we need to define vulnerability and understand the factors that influence it. This review also attempts to summarize the indicators of vulnerability and the data currently available to estimate its burden in India. Measuring the magnitude of vulnerability by means of certain indicators/variables might help us in devising tools to assess this poorly defined entity. This may also evolve a conceptual framework on which targeted remedial interventions can be devised and implemented. PMID:26170545

  6. A review of the risks, costs and benefits of defined contribution and defined benefit pension schemes

    OpenAIRE

    Robert Watson

    2008-01-01

    Purpose – The purpose of this paper is to evaluate the relative risks and benefits associated with defined contribution (DC) and defined benefit (DB) pension schemes. New regulatory and governance requirements and demographic changes have all significantly raised the costs and reduced the expected benefits to employers of operating DB schemes. In response, many employers have either closed down their DB schemes, closed the scheme to new members and/or to capped any further accruing of benefit...

  7. Collaborative Analysis of DRD4 and DAT Genotypes in Population-Defined ADHD Subtypes

    Science.gov (United States)

    Todd, Richard D.; Huang, Hongyan; Smalley, Susan L.; Nelson, Stanley F.; Willcutt, Erik G.; Pennington, Bruce F.; Smith, Shelley D.; Faraone, Stephen V.; Neuman, Rosalind J.

    2005-01-01

    Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by…

  8. Defining and measuring pilot mental workload

    Science.gov (United States)

    Kantowitz, Barry H.

    1988-01-01

    A theory is sought that is general enough to help the researcher deal with a wide range of situations involving pilot mental stress. A limited capacity theory of attention forms the basis for the theory. Mental workload is then defined as an intervening variable, similar to attention, that modulates or indexes the tuning between the demands of the environment and the capacity of the organism. Two methods for measuring pilot mental workload are endorsed: (1) objective measures based on secondary tasks; and (2) psychophysiological measures, which have not yet been perfected but which will become more useful as theoretical models are refined. Secondary-task research is illustrated by simulator studies in which flying performance has been shown not to be adversely affected by adding a complex choice-reaction secondary task.

  9. Nurse leader resilience: career defining moments.

    Science.gov (United States)

    Cline, Susan

    2015-01-01

    Resilience is an essential component of effective nursing leadership. It is defined as the ability to survive and thrive in the face of adversity. Resilience can be developed and internalized as a measure to improve retention and reduce burnout. Nurse leaders at all levels should develop these competencies to survive and thrive in an increasingly complex health care environment. Building positive relationships, maintaining positivity, developing emotional insight, creating work-life balance, and reflecting on successes and challenges are effective strategies for resilience building. Nurse leaders have a professional obligation to develop resilience in themselves, the teams they supervise, and the organization as a whole. Additional benefits include reduced turnover, reduced cost, and improved quality outcomes through organizational mindfulness. PMID:25714948

  10. Can we define climate using information theory?

    International Nuclear Information System (INIS)

    The standard definition of climate is, by convention, based on a thirty-year sample. But why? One way to define the sampling period for constructing climatologies is to ask: What is a sufficient sample to construct probability density functions (PDF) for key meteorological variables? I propose an information-theoretic framework for evaluating climatic sampling periods based on level of detail and associated uncertainties in the estimated PDF, the Shannon entropy growth curve and its discrete derivative, and the Kullback-Leibler divergence. I compute these quantities for 235 years of daily data from the Central UK Temperature record and use these statistics to compare popular sampling periods and discuss the feasibility of determining an optimal sampling period.

  11. Reconfigurable, Cognitive Software-Defined Radio

    Science.gov (United States)

    Bhat, Arvind

    2015-01-01

    Software-defined radio (SDR) technology allows radios to be reconfigured to perform different communication functions without using multiple radios to accomplish each task. Intelligent Automation, Inc., has developed SDR platforms that switch adaptively between different operation modes. The innovation works by modifying both transmit waveforms and receiver signal processing tasks. In Phase I of the project, the company developed SDR cognitive capabilities, including adaptive modulation and coding (AMC), automatic modulation recognition (AMR), and spectrum sensing. In Phase II, these capabilities were integrated into SDR platforms. The reconfigurable transceiver design employs high-speed field-programmable gate arrays, enabling multimode operation and scalable architecture. Designs are based on commercial off-the-shelf (COTS) components and are modular in nature, making it easier to upgrade individual components rather than redesigning the entire SDR platform as technology advances.

  12. Medical abortion. defining success and categorizing failures

    DEFF Research Database (Denmark)

    Rørbye, Christina; Nørgaard, Mogens; Vestermark, Vibeke;

    2003-01-01

    Medical abortion was performed in 461 consecutive women with gestational age LT /= 63 days using a regimen of mifepristone 600 mg followed 2 days later by gemeprost 1 mg vaginally. Success, defined as no surgical intervention, declined from 98.7% after 2 weeks to 94.6% after 15 weeks. The...... difference in short- and long-term success rates increased with increasing gestational age. The majority of failures (76%) were diagnosed more than 2 weeks after initiation of the abortion. At a 2-week follow-up visit, the women who turned out to be failures had a larger endometrial width, higher beta......-hCG values and smaller reductions of beta-hCG than those treated successfully. To optimize comparison of success rates after different medical abortion regimens, we suggest that the criteria for success are stated clearly, that the success rates are stratified according to gestational age and that the...

  13. Environmentally acceptable thread compounds: Requirements defined

    International Nuclear Information System (INIS)

    New environmental regulations on thread compounds are now being enforced in several areas with strong maritime tradition and a sensitive environment. These areas include Indonesia, Alaska and portions of Norway. The industry generally recognizes the environmental concerns but, with wider enforcement of regulations imminent, has not been able to define clearly the requirements for environmental compliance. This paper, written in collaboration with The Netherlands State Supervision of Mines, is based on the National Policy on Thread Compounds of The Netherlands. This national policy is representative of policies being followed by other North Sea governments. Similar policies might well be adopted by other governments worldwide. These policies will affect the operator, drilling contractor, and supplier. This paper provides a specific and detailed definition of thread compound requirements by addressing four relevant categories. The categories of interest are regulatory approval, environmental, health, and performance

  14. Software Defined Networking Demands on Software Technologies

    DEFF Research Database (Denmark)

    Galinac Grbac, T.; Caba, Cosmin Marius; Soler, José

    2015-01-01

    Software Defined Networking (SDN) is a networking approach based on a centralized control plane architecture with standardised interfaces between control and data planes. SDN enables fast configuration and reconfiguration of the network to enhance resource utilization and service performances. This......, we review this new approach to networking from an architectural point of view, and identify and discuss some critical quality issues that require new developments in software technologies. These issues we discuss along with use case scenarios. Here in this paper we aim to identify challenges for...... new approach enables a more dynamic and flexible network, which may adapt to user needs and application requirements. To this end, systemized solutions must be implemented in network software, aiming to provide secure network services that meet the required service performance levels. In this paper...

  15. "Defining Computer 'Speed': An Unsolved Challenge"

    CERN Document Server

    CERN. Geneva

    2012-01-01

    Abstract: The reason we use computers is their speed, and the reason we use parallel computers is that they're faster than single-processor computers. Yet, after 70 years of electronic digital computing, we still do not have a solid definition of what computer 'speed' means, or even what it means to be 'faster'. Unlike measures in physics, where the definition of speed is rigorous and unequivocal, in computing there is no definition of speed that is universally accepted. As a result, computer customers have made purchases misguided by dubious information, computer designers have optimized their designs for the wrong goals, and computer programmers have chosen methods that optimize the wrong things. This talk describes why some of the obvious and historical ways of defining 'speed' haven't served us well, and the things we've learned in the struggle to find a definition that works. Biography: Dr. John Gustafson is a Director ...

  16. Defining and testing a granular continuum element

    Energy Technology Data Exchange (ETDEWEB)

    Rycroft, Chris H.; Kamrin, Ken; Bazant, Martin Z.

    2007-12-03

    Continuum mechanics relies on the fundamental notion of amesoscopic volume "element" in which properties averaged over discreteparticles obey deterministic relationships. Recent work on granularmaterials suggests a continuum law may be inapplicable, revealinginhomogeneities at the particle level, such as force chains and slow cagebreaking. Here, we analyze large-scale Discrete-Element Method (DEM)simulations of different granular flows and show that a "granularelement" can indeed be defined at the scale of dynamical correlations,roughly three to five particle diameters. Its rheology is rather subtle,combining liquid-like dependence on deformation rate and solid-likedependence on strain. Our results confirm some aspects of classicalplasticity theory (e.g., coaxiality of stress and deformation rate),while contradicting others (i.e., incipient yield), and can guide thedevelopment of more realistic continuum models.

  17. Oscillator metrology with software defined radio

    CERN Document Server

    Sherman, Jeff A

    2016-01-01

    Analog electrical elements such as mixers, filters, transfer oscillators, isolating buffers, dividers, and even transmission lines contribute technical noise and unwanted environmental coupling in time and frequency measurements. Software defined radio (SDR) techniques replace many of these analog components with digital signal processing (DSP) on rapidly sampled signals. We demonstrate that, generically, commercially available multi-channel SDRs are capable of time and frequency metrology, outperforming purpose-built devices by as much as an order-of-magnitude. For example, for signals at 10 MHz and 6 GHz, we observe SDR time deviation noise floors of about 20 fs and 1 fs, respectively, in under 10 ms of averaging. Examining the other complex signal component, we find a relative amplitude measurement instability of 3e-7 at 5 MHz. We discuss the scalability of a SDR-based system for simultaneous measurement of many clocks. SDR's frequency agility allows for comparison of oscillators at widely different freque...

  18. Multiphoton microscopy in defining liver function

    Science.gov (United States)

    Thorling, Camilla A.; Crawford, Darrell; Burczynski, Frank J.; Liu, Xin; Liau, Ian; Roberts, Michael S.

    2014-09-01

    Multiphoton microscopy is the preferred method when in vivo deep-tissue imaging is required. This review presents the application of multiphoton microscopy in defining liver function. In particular, multiphoton microscopy is useful in imaging intracellular events, such as mitochondrial depolarization and cellular metabolism in terms of NAD(P)H changes with fluorescence lifetime imaging microscopy. The morphology of hepatocytes can be visualized without exogenously administered fluorescent dyes by utilizing their autofluorescence and second harmonic generation signal of collagen, which is useful in diagnosing liver disease. More specific imaging, such as studying drug transport in normal and diseased livers are achievable, but require exogenously administered fluorescent dyes. If these techniques can be translated into clinical use to assess liver function, it would greatly improve early diagnosis of organ viability, fibrosis, and cancer.

  19. Fluorescence in situ hybridization techniques (FISH) to detect changes in CYP19a gene expression of Japanese medaka (Oryzias latipes)

    International Nuclear Information System (INIS)

    The aim of this study was to develop a sensitive in situ hybridization methodology using fluorescence-labeled riboprobes (FISH) that allows for the evaluation of gene expression profiles simultaneously in multiple target tissues of whole fish sections of Japanese medaka (Oryzias latipes). To date FISH methods have been limited in their application due to autofluorescence of tissues, fixatives or other components of the hybridization procedure. An optimized FISH method, based on confocal fluorescence microscopy was developed to reduce the autofluorescence signal. Because of its tissue- and gender-specific expression and relevance in studies of endocrine disruption, gonadal aromatase (CYP19a) was used as a model gene. The in situ hybridization (ISH) system was validated in a test exposure with the aromatase inhibitor fadrozole. The optimized FISH method revealed tissue-specific expression of the CYP19a gene. Furthermore, the assay could differentiate the abundance of CYP19a mRNA among cell types. Expression of CYP19a was primarily associated with early stage oocytes, and expression gradually decreased with increasing maturation. No expression of CYP19a mRNA was observed in other tissues such as brain, liver, or testes. Fadrozole (100 μg/L) caused up-regulation of CYP19a expression, a trend that was confirmed by RT-PCR analysis on excised tissues. In a combination approach with gonad histology, it could be shown that the increase in CYP19a expression as measured by RT-PCR on a whole tissue basis was due to a combination of both increases in numbers of CYP19a-containing cells and an increase in the amount of CYP19a mRNA present in the cells

  20. Exposing the Myths, Defining the Future

    International Nuclear Information System (INIS)

    With this official statement, the WEC calls for policymakers and industry leaders to ''get real'' as the World Energy Council as a global energy body exposes the myths by informing the energy debate and defines a path to a more sustainable energy future. The World Energy Council urged stakeholders to take urgent and incisive actions, to develop and transform the global energy system. Failure to do so could put aspirations on the triple challenge of WEC Energy Trilemma defined by affordability, accessibility and environmental sustainability at serious risk. Through its multi-year in-depth global studies and issue-mapping the WEC has found that challenges that energy sector is facing today are much more crucial than previously envisaged. The WEC's analysis has exposed a number of myths which influence our understanding of important aspects of the global energy landscape. If not challenged, these misconceptions will lead us down a path of complacency and missed opportunities. Much has, and still is, being done to secure energy future, but the WEC' s studies reveal that current pathways fall short of delivering on global aspirations of energy access, energy security and environmental improvements. If we are to derive the full economic and social benefits from energy resources, then we must take incisive and urgent action to modify our steps to energy solutions. The usual business approaches are not effective, the business as usual is not longer a solution. The focus has moved from large universal solutions to an appreciation of regional and national contexts and sharply differentiated consumer expectations.(author)

  1. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder;

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... high frequency of loss of heterozygosity. The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of CRC....

  2. Association study of the oestrogen signalling pathway genes in relation to age at natural menopause

    Indian Academy of Sciences (India)

    Li-Na He; Dong-Hai Xiong; Yong-Jun Liu; Feng Zhang; Robert R. Recker; Hong-Wen Deng

    2007-12-01

    Genetic factors play a significant role in influencing the variation of age at natural menopause (AANM). Estrogen receptor (ESR2), is an important factor in the mechanism of action of estrogen, while the aromatase gene (CYP19) and the 17-alpha-hydroxylase gene (CYP17) are involved in the biosynthesis of estrogen. We tested whether polymorphisms of ESR2, CYP19 and CYP17 genes are associated with AANM in Caucasian females. A total of 52 SNPs (17 for ESR2, 28 for CYP19, and 7 for CYP17) were successfully genotyped for 229 Caucasian women having experienced natural menopause. Comprehensive statistical analyses focusing on the association of these genes with AANM were conducted. The effects of age, height and age at menarche on AANM were adjusted when conducting association analyses. We found that six SNPs (2, 6-7, 9, 13 and 16) within ESR2 were not significantly associated with AANM after Bonferroni correction. However, two blocks of ESR2 were associated with AANM. For CYP19, two SNPs (24 and 27) were nominally associated with AANM. No significant association was observed between CYP17 and AANM. Our results suggest that genetic variation in the ESR2 and CYP19 genes may influence the variation in AANM in Caucasian women.

  3. Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis.

    Science.gov (United States)

    George, Rajani M; Hahn, Katherine L; Rawls, Alan; Viger, Robert S; Wilson-Rawls, Jeanne

    2015-10-01

    Notch2 and Notch3 and genes of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating steroidogenesis. In this study, we sought to determine if Notch signaling in small follicles regulates the proliferation response of granulosa cells to FSH and represses the up-regulation steroidogenic gene expression that occurs in response to FSH as the follicle grows. Inhibition of Notch signaling in small preantral follicles led to the up-regulation of the expression of genes in the steroid biosynthetic pathway. Similarly, progesterone secretion by MA-10 Leydig cells was significantly inhibited by constitutively active Notch. Together, these data indicated that Notch signaling inhibits steroidogenesis. GATA4 has been shown to be a positive regulator of steroidogenic genes, including STAR protein, P450 aromatase, and 3B-hydroxysteroid dehydrogenase. We observed that Notch downstream effectors HEY1, HEY2, and HEYL are able to differentially regulate these GATA4-dependent promoters. These data are supported by the presence of HEY/HES binding sites in these promoters. These studies indicate that Notch signaling has a role in the complex regulation of the steroidogenic pathway. PMID:26183893

  4. Gene-Gene and Gene-Environment Interactions in Ulcerative Colitis

    OpenAIRE

    Wang, Ming-Hsi; FIOCCHI, CLAUDIO; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M. Ilyas; Rebert, Nancy; Duerr, Richard H.; Achkar, Jean-Paul

    2013-01-01

    Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust...

  5. Defining a Standard Metric for Electricity Savings

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Marilyn; Akbari, Hashem; Blumstein, Carl; Koomey, Jonathan; Brown, Richard; Calwell, Chris; Carter, Sheryl; Cavanagh, Ralph; Chang, Audrey; Claridge, David; Craig, Paul; Diamond, Rick; Eto, Joseph H.; Fulkerson, William; Gadgil, Ashok; Geller, Howard; Goldemberg, Jose; Goldman, Chuck; Goldstein, David B.; Greenberg, Steve; Hafemeister, David; Harris, Jeff; Harvey, Hal; Heitz, Eric; Hirst, Eric; Hummel, Holmes; Kammen, Dan; Kelly, Henry; Laitner, Skip; Levine, Mark; Lovins, Amory; Masters, Gil; McMahon, James E.; Meier, Alan; Messenger, Michael; Millhone, John; Mills, Evan; Nadel, Steve; Nordman, Bruce; Price, Lynn; Romm, Joe; Ross, Marc; Rufo, Michael; Sathaye, Jayant; Schipper, Lee; Schneider, Stephen H; Sweeney, James L; Verdict, Malcolm; Vorsatz, Diana; Wang, Devra; Weinberg, Carl; Wilk, Richard; Wilson, John; Worrell, Ernst

    2009-03-01

    The growing investment by governments and electric utilities in energy efficiency programs highlights the need for simple tools to help assess and explain the size of the potential resource. One technique that is commonly used in this effort is to characterize electricity savings in terms of avoided power plants, because it is easier for people to visualize a power plant than it is to understand an abstraction such as billions of kilowatt-hours. Unfortunately, there is no standardization around the characteristics of such power plants. In this letter we define parameters for a standard avoided power plant that have physical meaning and intuitive plausibility, for use in back-of-the-envelope calculations. For the prototypical plant this article settles on a 500 MW existing coal plant operating at a 70percent capacity factor with 7percent T&D losses. Displacing such a plant for one year would save 3 billion kW h per year at the meter and reduce emissions by 3 million metric tons of CO2 per year. The proposed name for this metric is the Rosenfeld, in keeping with the tradition among scientists of naming units in honor of the person most responsible for the discovery and widespread adoption of the underlying scientific principle in question--Dr. Arthur H. Rosenfeld.

  6. Defining Astrology in Ancient and Classical History

    Science.gov (United States)

    Campion, Nicholas

    2015-05-01

    Astrology in the ancient and classical worlds can be partly defined by its role, and partly by the way in which scholars spoke about it. The problem is complicated by the fact that the word is Greek - it has no Babylonian or Egyptian cognates - and even in Greece it was interchangeable with its cousin, 'astronomy'. Yet if we are to understand the role of the sky, stars and planets in culture, debates about the nature of ancient astrology, by both classical and modern scholars, must be taken into account. This talk will consider modern scholars' typologies of ancient astrology, together with ancient debates from Cicero in the 1st century BC, to Plotinus (204/5-270 AD) and Isidore of Seville (c. 560 - 4 April 636). It will consider the implications for our understanding of astronomy's role in culture, and conclude that in the classical period astrology may be best understood through its diversity and allegiance to competing philosophies, and that its functions were therefore similarly varied.

  7. Radio Astronomy Software Defined Receiver Project

    Energy Technology Data Exchange (ETDEWEB)

    Vacaliuc, Bogdan [ORNL; Leech, Marcus [Shirleys Bay Radio Astronomy Consortium; Oxley, Paul [Retired; Flagg, Richard [Retired; Fields, David [ORNL

    2011-01-01

    The paper describes a Radio Astronomy Software Defined Receiver (RASDR) that is currently under development. RASDR is targeted for use by amateurs and small institutions where cost is a primary consideration. The receiver will operate from HF thru 2.8 GHz. Front-end components such as preamps, block down-converters and pre-select bandpass filters are outside the scope of this development and will be provided by the user. The receiver includes RF amplifiers and attenuators, synthesized LOs, quadrature down converters, dual 8 bit ADCs and a Signal Processor that provides firmware processing of the digital bit stream. RASDR will interface to a user s PC via a USB or higher speed Ethernet LAN connection. The PC will run software that provides processing of the bit stream, a graphical user interface, as well as data analysis and storage. Software should support MAC OS, Windows and Linux platforms and will focus on such radio astronomy applications as total power measurements, pulsar detection, and spectral line studies.

  8. Defining microbiota for developing new probiotics

    Directory of Open Access Journals (Sweden)

    Maria Carmen Collado

    2012-06-01

    Full Text Available The human body harbors complex communities of microbes that play a prominent role in human health. Detailed characterization of the microbiota in the target population forms the basis of probiotic use. Probiotics are defined as live bacterial preparations with clinically documented health effects in humans, and independent of their genus and species, probiotic strains are unique and their beneficial properties on human health have to be assessed in a case-by-case manner. Understanding the mechanisms by which probiotics influence microbiota would facilitate the use of probiotics for both dietary management and reduction in risk of specific diseases. The development of high throughput sequencing methods has allowed metagenomic approaches to study the human microbiome. These efforts are starting to generate an inventory of bacterial taxons and functional features bound to particular health or disease status that allow inferring aspects of the microbiome's function. In the future, this information will allow the rational design of dietary interventions aimed to improve consumer's health via modulation of the microbiota.

  9. Defining 'plain language' in contemporary South Africa

    Directory of Open Access Journals (Sweden)

    Eleanor Cornelius

    2015-12-01

    Full Text Available Defining the concept ‘plain language’ has been hugely problematic since the origins of the so-called Plain Language Movement in the 1970s in the United States and elsewhere in the world. Definitions of ‘plain language’ abound, yet James (2008: 6 warns, in relation to plain language practitioners, that “we can’t yet call ourselves a coherent field, let alone a profession, while we offer such varying definitions of what we do”. Contemporary international definitions of ‘plain language’ are of three types: numerical (or formula-based, elements-focused, or outcomes-focused (Cheek 2010. In South Africa, protective legislation gave rise to a local definition of ‘plain language’ which was widely acclaimed for its comprehensiveness and practicality. From a textlinguistic angle, this article ruminates on the nature of the definition of ‘plain language’ in the National Credit Act (2005 and the Consumer Protection Act (2008, and critically appraises the value of the definition as a sharp and reliable conceptual tool for use by plain language practitioners – as applied linguists – in the absence of norms, standards or guidelines for the use of plain language in the consumer industry in contemporary South Africa.

  10. Methodologies for defining quality of life

    Energy Technology Data Exchange (ETDEWEB)

    Glicken, J. [Ecological Planning and Toxicology, Inc., Albuquerque, NM (United States); Engi, D. [Sandia National Labs., Albuquerque, NM (United States)

    1996-10-10

    Quality of life as a concept has been used in many ways in the public policy arena. It can be used in summative evaluations to assess the impacts of policies or programs. Alternatively, it can be applied to formative evaluations to provide input to the formation of new policies. In short, it provides the context for the understanding needed to evaluate the results of choices that have been made in the public policy arena, or the potential of choices yet to be made. In either case, the public policy question revolves around the positive or negative impact the choice will have on quality of life, and the magnitude of that impact. This discussion will develop a conceptual framework that proposes that an assessment of quality of life is based on a comparison of expectations with experience. The framework defines four basic components from which these expectations arise: natural conditions, social conditions, the body, and the mind. Each one of these components is generally described, and associated with a general policy or rhetorical category which gives it its policy vocabulary--environmental quality, economic well-being, human health, and self-fulfillment.

  11. Defining functional dyspepsia Definiendo la dispepsia funcional

    Directory of Open Access Journals (Sweden)

    Fermín Mearin

    2011-12-01

    Full Text Available Dyspepsia and functional dyspepsia represent a highly significant public health issue. A good definition of dyspepsia is key for helping us to better approach symptoms, decision making, and therapy indications. During the last few years many attempts were made at establishing a definition of dyspepsia. Results were little successful on most occasions, and clear discrepancies arose on whether symptoms should be associated with digestion, which types of symptoms were to be included, which anatomic location should symptoms have, etc. The Rome III Committee defined dyspepsia as "a symptom or set of symptoms that most physicians consider to originate from the gastroduodenal area", including the following: postprandial heaviness, early satiety, and epigastric pain or burning. Two new entities were defined: a food-induced dyspeptic symptoms (postprandial distress syndrome; and b epigastric pain (epigastric pain syndrome. These and other definitions have shown both strengths and weaknesses. At times they have been much too complex, at times much too simple; furthermore, they have commonly erred on the side of being inaccurate and impractical. On the other hand, some (the most recent ones are difficult to translate into the Spanish language. In a meeting of gastroenterologists with a special interest in digestive functional disorders, the various aspects of dyspepsia definition were discussed and put to the vote, and the following conclusions were arrived at: dyspepsia is defined as a set of symptoms, either related or unrelated to food ingestion, localized on the upper half of the abdomen. They include: a epigastric discomfort (as a category of severity or pain; b postprandial heaviness; and c early satiety. Associated complaints include: nausea, belching, bloating, and epigastric burn (heartburn. All these must be scored according to severity and frequency. Furthermore, psychological factors may be involved in the origin of functional dyspepsia. On the

  12. CREATIVITY AND INNOVATION AS DEFINED BY WORKER

    Directory of Open Access Journals (Sweden)

    Sônia Maria Guedes Gondim

    2015-12-01

    Full Text Available ABSTRACT Creativity and innovation are now required given the new configurations in work processes, in organizational formats, in physical and intangible technologies, as well as in products and markets. In parallel with the growing centrality and interest in the phenomena of creativity and innovation, a broadening of its concepts is observed. The inflation and trivialization of uses tend to make them self-explanatory and not very enlightening regarding situations to which they apply and the associated effects. The lack of conceptual clarity thus contributes both to undermining policies to promote creativity and innovation in organizations, as well as to hinder the employees' adherence to such policies. The study aimed to characterize the key elements of workers' informal definitions of creativity and innovation, and identify their alignment with definitions and theoretical perspectives. The study included 231 workers from Portuguese-, Spanish-, and Basque-speaking countries, aged 22-75 years. The qualitative data analysis software ATLAS.ti 7 was used for coding and categorization. One point of convergence with the specialized literature was that creativity and innovation strongly associated with novelty in the development of an idea / product / process / service. Creativity, however, is defined more in terms of dispositional factors rather than contextual and situational factors, diverging from current theoretical perspectives. Planning as a key aspect for organizational innovation development is practically absent from the workers' definitions. It discusses some impacts of these settings for organizational management practices.

  13. Defining and resolving current systems in geospace

    Science.gov (United States)

    Ganushkina, N. Y.; Liemohn, M. W.; Dubyagin, S.; Daglis, I. A.; Dandouras, I.; De Zeeuw, D. L.; Ebihara, Y.; Ilie, R.; Katus, R.; Kubyshkina, M.; Milan, S. E.; Ohtani, S.; Ostgaard, N.; Reistad, J. P.; Tenfjord, P.; Toffoletto, F.; Zaharia, S.; Amariutei, O.

    2015-11-01

    Electric currents flowing through near-Earth space (R ≤ 12 RE) can support a highly distorted magnetic field topology, changing particle drift paths and therefore having a nonlinear feedback on the currents themselves. A number of current systems exist in the magnetosphere, most commonly defined as (1) the dayside magnetopause Chapman-Ferraro currents, (2) the Birkeland field-aligned currents with high-latitude "region 1" and lower-latitude "region 2" currents connected to the partial ring current, (3) the magnetotail currents, and (4) the symmetric ring current. In the near-Earth nightside region, however, several of these current systems flow in close proximity to each other. Moreover, the existence of other temporal current systems, such as the substorm current wedge or "banana" current, has been reported. It is very difficult to identify a local measurement as belonging to a specific system. Such identification is important, however, because how the current closes and how these loops change in space and time governs the magnetic topology of the magnetosphere and therefore controls the physical processes of geospace. Furthermore, many methods exist for identifying the regions of near-Earth space carrying each type of current. This study presents a robust collection of these definitions of current systems in geospace, particularly in the near-Earth nightside magnetosphere, as viewed from a variety of observational and computational analysis techniques. The influence of definitional choice on the resulting interpretation of physical processes governing geospace dynamics is presented and discussed.

  14. Lithographically defined 3-dimensional graphene scaffolds

    Science.gov (United States)

    Burckel, D. Bruce; Xiao, Xiaoyin; Polsky, Ronen

    2015-09-01

    Interferometrically defined 3D photoresist scaffolds are formed through a series of three successive two-beam interference exposures, a post exposure bake and development. Heating the resist scaffold in a reducing atmosphere to > 1000 °C, results in the conversion of the resist structure into a carbon scaffold through pyrolysis, resulting in a 3D sp3- bonded glassy carbon scaffold which maintains the same in-plane morphology as the resist despite significant shrinkage. The carbon scaffolds are readily modified using a variety of deposition methods such as electrochemical, sputtering and CVD/ALD. Remarkably, sputtering metal into scaffolds with ~ 5 unit cells tall results in conformal coating of the scaffold with the metal. When the metal is a transition metal such as nickel, the scaffold can be re-annealed, during which time the carbon diffuses through the nickel, emerging on the exterior of the nickel as sp2-bonded carbon, termed 3D graphene. This paper details the fabrication, characterization and some potential applications for these structures.

  15. Defining the mechanisms of borderline personality disorder.

    Science.gov (United States)

    Clarkin, John F; Posner, Michael

    2005-01-01

    Understanding the biological connections to mental processes was one of the original goals of psychoanalysis, and the development of cognitive and affective neuroscience and its methods might contribute to actualizing this goal. Personality disorders provide an opportunity to examine the complex mental structures of individuals experiencing extreme difficulties in interacting with their social environment. We provide initial information on a collaboration exploring an approach to one of the most serious personality disorders, borderline personality disorder, based upon the study of normal attention, individual differences in temperament, self definition and attachment organization, with the potential to illuminate the psychology and psychobiology of the disorder and to contribute to psychotherapeutic intervention. This developing model of borderline personality disorder can relate the symptoms to more enduring temperamental aspects of the patients. The goal is to understand the development of neural networks that underlie the abnormalities of adults, and eventually work out the interaction between temperament, genes, and experience that produce the disorder, and potentially inform intervention. PMID:15802943

  16. Defining the Human Deubiquitinating Enzyme Interaction Landscape

    Science.gov (United States)

    Sowa, Mathew E.; Bennett, Eric J.; Gygi, Steven P.; Harper, J. Wade

    2009-01-01

    Summary Deubiquitinating enzymes (Dubs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. For most Dubs, their functions, targets, and regulation are poorly understood. To systematically investigate Dub function, we initiated a global proteomic analysis of Dubs and their associated protein complexes. This was accomplished through the development of a software platform, called CompPASS, which uses unbiased metrics to assign confidence measurements to interactions from parallel non-reciprocal proteomic datasets. We identified 774 candidate interacting proteins associated with 75 Dubs. Using Gene Ontology, interactome topology classification, sub-cellular localization and functional studies, we link Dubs to diverse processes, including protein turnover, transcription, RNA processing, DNA damage, and endoplasmic reticulum-associated degradation. This work provides the first glimpse into the Dub interaction landscape, places previously unstudied Dubs within putative biological pathways, and identifies previously unknown interactions and protein complexes involved in this increasingly important arm of the ubiquitin-proteasome pathway. PMID:19615732

  17. Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer

    International Nuclear Information System (INIS)

    After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function

  18. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295r adrenocortical carcinoma cells

    International Nuclear Information System (INIS)

    The present study investigated the effects of the known xenoestrogen bisphenol A (BPA) relative to eight BPA-related diphenylalkanes on estrogen receptor (ER)-mediated vitellogenin (vtg) production in hepatocytes from male carp (Cyprinus carpio), and on aromatase (CYP19) activity in the human adrenocortical H295R carcinoma cell line. Of the eight diphenylalkanes, only 4,4'-(hexafluoropropylidene)diphenol (BHF) and 2,2'-bis(4-hydroxy-3-methylphenyl)propane (BPRO) induced vtg, i.e., to a maximum of 3% to 4% (at 100 μM) compared with 8% for BPA relative to the maximum induction by 17β-estradiol (E2, 1 μM). Bisphenol A diglycidyl ether (BADGE) was a potent antagonist of vtg production with an IC50 of 5.5 μM, virtually 100% inhibition of vtg at 20 μM, and an inhibitive (IC50) potency about one-tenth that of the known ER antagonist tamoxifen (IC50, 0.6 μM). 2,2'-Diallyl bisphenol A, 4,4'-(1,4-phenylene-diisopropylidene)bisphenol, BPRO, and BHF were much less inhibitory with IC50 concentrations of 20-70 μM, and relative potencies of 0.03 and 0.009 with tamoxifen. Bisphenol ethoxylate showed no anti-estrogenicity (up to 100 μM), and 4,4'-isopropylidene-diphenol diacetate was only antagonistic at 100 μM. When comparing the (anti)estrogenic potencies of these bisphenol A analogues/diphenylalkanes, anti-estrogenicity occurred at lower concentrations than estrogenicity. 4,4'-Isopropylidenebis(2,6-dimethylphenol) (IC50, 2.0 μM) reduced E2-induced (EC50, 100 nM) vtg production due to concentration-dependent cytotoxicity as indicated by a parallel decrease in MTT activity and vtg, whereas the remaining diphenylalkanes did not cause any cytotoxicity relative to controls. None of the diphenylalkanes (up to 100 μM) induced EROD activity indicating that concentration-dependent, CYP1A enzyme-mediated metabolism of E2, or any Ah-receptor-mediated interaction with the ER, was not a likely explanation for the observed anti-estrogenic effects. At concentrations as great as 100

  19. Estudio de análogos de la sulfonanilida que actúan como supresores de la expresión de la aromatasa Study of sulfonanilide analogues acting as suppressants of the aromatase expression

    Directory of Open Access Journals (Sweden)

    Ricardo Vivas-Reyes

    2009-12-01

    Full Text Available Se realizó un estudio tridimensional cuantitativo de relación-estructura con nuevos análogos de la sulfonanilida que actúan como supresores de la expresión y actividad de la aromatasa en células de cáncer de mama, independientemente de la inhibición de la ciclooxigenasa-2 (COX-2. La superposición molecular de los ligandos en la plantilla fue llevada a cabo por el método Database Alignment. El mejor modelo estuvo constituido por la combinación de los campos estérico e hidrofóbico, los cuales arrojaron los siguientes parámetros: q² = 0,613 con siete componentes, R² no validado igual a 0,976, valor de F igual a 81,695; 0,347 y 0,047 para los errores estándar de predicción y estimación, respectivamente. Las contribuciones estérica e hidrofóbica fueron de 50,5 y 49,5% respectivamente. Los datos generados por el presente estudio podrían impulsar el diseño de nuevos y más potentes reguladores selectivos de la expresión de la aromatasa.A three-dimensional quantitative structure-activity relationship study was performed with new Sulfonanilide analogue molecules acting as aromatase expression and activity suppressors in breast cancer cells independent of COX-2 inhibition. The molecular supression of the ligands in the grid was carried out by the DATA-BASE ALIGNMENT method. The best model formed by combining the esteric fields and hydrophobic fields yielded the following parameters: q² = 0.613 with seven components, not validated R² equal to 0.976, with an F value of 81.695, 0.347 and 0.047 for the standard errors of prediction and estimate, respectively. The contribution of esteric and hydrophobic fields was 50.5 and 49.5% respectively. data generated from this study may be used to design new and more potent selective aromatase expression regulators.

  20. 20 CFR 404.430 - Monthly and annual exempt amounts defined; excess earnings defined.

    Science.gov (United States)

    2010-04-01

    ... year prior to the year of full retirement age, as defined in § 404.409(a). A larger “annual” exempt... you attain full retirement age. The full annual exempt amount applies to the earnings of these pre-full retirement age months, even though they are earned in less than a year. For beneficiaries using...

  1. A Methodology to Define Flood Resilience

    Science.gov (United States)

    Tourbier, J.

    2012-04-01

    Flood resilience has become an internationally used term with an ever-increasing number of entries on the Internet. The SMARTeST Project is looking at approaches to flood resilience through case studies at cities in various countries, including Washington D.C. in the United States. In light of U.S. experiences a methodology is being proposed by the author that is intended to meet ecologic, spatial, structural, social, disaster relief and flood risk aspects. It concludes that: "Flood resilience combines (1) spatial, (2) structural, (3) social, and (4) risk management levels of flood preparedness." Flood resilience should incorporate all four levels, but not necessarily with equal emphasis. Stakeholders can assign priorities within different flood resilience levels and the considerations they contain, dividing 100% emphasis into four levels. This evaluation would be applied to planned and completed projects, considering existing conditions, goals and concepts. We have long known that the "road to market" for the implementation of flood resilience is linked to capacity building of stakeholders. It is a multidisciplinary enterprise, involving the integration of all the above aspects into the decision-making process. Traditional flood management has largely been influenced by what in the UK has been called "Silo Thinking", involving constituent organizations that are responsible for different elements, and are interested only in their defined part of the system. This barrier to innovation also has been called the "entrapment effect". Flood resilience is being defined as (1) SPATIAL FLOOD RESILIENCE implying the management of land by floodplain zoning, urban greening and management to reduce storm runoff through depression storage and by practicing Sustainable Urban Drainage (SUD's), Best Management Practices (BMP's, or Low Impact Development (LID). Ecologic processes and cultural elements are included. (2) STRUCTURAL FLOOD RESILIENCE referring to permanent flood defense

  2. Ramifications of defining high-level waste

    International Nuclear Information System (INIS)

    The Nuclear Regulatory Commission (NRC) is considering rule making to provide a concentration-based definition of high-level waste (HLW) under authority derived from the Nuclear Waste Policy Act (NWPA) of 1982 and the Low Level Waste Policy Amendments Act of 1985. The Department of Energy (DOE), which has the responsibility to dispose of certain kinds of commercial waste, is supporting development of a risk-based classification system by the Oak Ridge National Laboratory to assist in developing and implementing the NRC rule. The system is two dimensional, with the axes based on the phrases highly radioactive and requires permanent isolation in the definition of HLW in the NWPA. Defining HLW will reduce the ambiguity in the present source-based definition by providing concentration limits to establish which materials are to be called HLW. The system allows the possibility of greater-confinement disposal for some wastes which do not require the degree of isolation provided by a repository. The definition of HLW will provide a firm basis for waste processing options which involve partitioning of waste into a high-activity stream for repository disposal, and a low-activity stream for disposal elsewhere. Several possible classification systems have been derived and the characteristics of each are discussed. The Defense High Level Waste Technology Lead Office at DOE - Richland Operations Office, supported by Rockwell Hanford Operations, has coordinated reviews of the ORNL work by a technical peer review group and other DOE offices. The reviews produced several recommendations and identified several issues to be addressed in the NRC rule making. 10 references, 3 figures

  3. Defining the critical hurdles in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Fox Bernard A

    2011-12-01

    Full Text Available Abstract Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC, convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

  4. Optimisation in radiotherapy I. Defining the problem

    International Nuclear Information System (INIS)

    Optimisation in radiotherapy should incorporate a very wide set of variables, including the combinations of dose due to external beam radiotherapy, brachytherapy, internally administered radionuclides and the effects of chemotherapy, surgery, hyperthermia, other biological and chemical defenses, alternative treatment techniques, lifestyle and mental state of the patient, the economics of cancer treatment and consideration of tolerable levels of adverse effects and palliation. A full treatment optimisation would consider the influence and covariance of all these variables and any future techniques, as well as the complex constraints imposed by the biological systems being irradiated. This series of reviews concentrates on optimisation of radiotherapy through the treatment planning component of the treatment process - an area of radiotherapy research that has received a great deal of attention as the attached lists of references will testify. It hopes to provide the medical physics and engineering community (and hopefully the clinical community) with a background into the mathematical bases for the manipulation of radiation for clinical benefit. It also examines the potential benefits of research into these techniques in the light of recent approaches to optimisation in radiotherapy, and provides pointers to more concise accounts in the literature. In this first article, the incentive for radiotherapy optimisation research is established, and the actual radiotherapy optimisation problem (in terms of the manipulation of degrees of freedom in radiation delivery) is defined. The degrees of freedom associated with radiotherapy treatment are identified, and it is shown how these degrees of freedom translate into the mathematical parameters of the problem, including the dose distributions they produce. The constraints and objectives of the problem are also discussed from both physical and radiobiological perspectives. (author)

  5. Pressure ulcer classification: defining early skin damage.

    Science.gov (United States)

    Russell, Linda

    2002-09-01

    This article is the second of a two-part series. The first part (Russell, 2002) looked at various systems and pitfalls of pressure ulcer classification systems. This article focuses on the difficulties of defining early skin damage. Patients' quality of life suffers significantly with a pressure ulcer. The smell of the exudate may be an embarrassment to the patient. The pain and the distress the patient will experience will not easily be forgotten, i.e. the number of dressings required for a deep pressure ulcer, even after the pressure ulcer has healed, will be a memorable intrusion to the patient's daily routine. Early detection of pressure ulcers and timely intervention are essential in the management of patients with pressure ulcers. Controversy exists over the definition of the first three stages of pressure ulcers, but there is consensus on the definition of deep tissue damage. If the pressure ulcer is covered with black necrotic tissue it is difficult to establish depth of the tissue damage. Intact skin can cause problems, as a sacrum may be purple but intact. There is still considerable debate with regard to reactive hyperaemia, as the exact time parameters for persistent erythema to occur are unknown. Little is understood with regard to the exact pathophysiology of reactive hyperaemia and this area requires further investigation. Blistered skin and skin tone also cause confusion in grading of pressure ulcers. The problems associated with classification of pressure ulcers, using colour classification systems, are discussed and the implications for practice are considered. The confusion surrounding early classification of pressure ulcers is discussed and it is hoped that such confusion can be addressed by standardizing training using one national classification system. PMID:12362151

  6. A hierarchical approach to defining marine heatwaves

    Science.gov (United States)

    Hobday, Alistair J.; Alexander, Lisa V.; Perkins, Sarah E.; Smale, Dan A.; Straub, Sandra C.; Oliver, Eric C. J.; Benthuysen, Jessica A.; Burrows, Michael T.; Donat, Markus G.; Feng, Ming; Holbrook, Neil J.; Moore, Pippa J.; Scannell, Hillary A.; Sen Gupta, Alex; Wernberg, Thomas

    2016-02-01

    Marine heatwaves (MHWs) have been observed around the world and are expected to increase in intensity and frequency under anthropogenic climate change. A variety of impacts have been associated with these anomalous events, including shifts in species ranges, local extinctions and economic impacts on seafood industries through declines in important fishery species and impacts on aquaculture. Extreme temperatures are increasingly seen as important influences on biological systems, yet a consistent definition of MHWs does not exist. A clear definition will facilitate retrospective comparisons between MHWs, enabling the synthesis and a mechanistic understanding of the role of MHWs in marine ecosystems. Building on research into atmospheric heatwaves, we propose both a general and specific definition for MHWs, based on a hierarchy of metrics that allow for different data sets to be used in identifying MHWs. We generally define a MHW as a prolonged discrete anomalously warm water event that can be described by its duration, intensity, rate of evolution, and spatial extent. Specifically, we consider an anomalously warm event to be a MHW if it lasts for five or more days, with temperatures warmer than the 90th percentile based on a 30-year historical baseline period. This structure provides flexibility with regard to the description of MHWs and transparency in communicating MHWs to a general audience. The use of these metrics is illustrated for three 21st century MHWs; the northern Mediterranean event in 2003, the Western Australia 'Ningaloo Niño' in 2011, and the northwest Atlantic event in 2012. We recommend a specific quantitative definition for MHWs to facilitate global comparisons and to advance our understanding of these phenomena.

  7. How to define valvular atrial fibrillation?

    Science.gov (United States)

    Fauchier, Laurent; Philippart, Raphael; Clementy, Nicolas; Bourguignon, Thierry; Angoulvant, Denis; Ivanes, Fabrice; Babuty, Dominique; Bernard, Anne

    2015-10-01

    Atrial fibrillation (AF) confers a substantial risk of stroke. Recent trials comparing vitamin K antagonists (VKAs) with non-vitamin K antagonist oral anticoagulants (NOACs) in AF were performed among patients with so-called "non-valvular" AF. The distinction between "valvular" and "non-valvular" AF remains a matter of debate. Currently, "valvular AF" refers to patients with mitral stenosis or artificial heart valves (and valve repair in North American guidelines only), and should be treated with VKAs. Valvular heart diseases, such as mitral regurgitation, aortic stenosis (AS) and aortic insufficiency, do not result in conditions of low flow in the left atrium, and do not apparently increase the risk of thromboembolism brought by AF. Post-hoc analyses suggest that these conditions probably do not make the thromboembolic risk less responsive to NOACs compared with most forms of "non-valvular" AF. The pathogenesis of thrombosis is probably different for blood coming into contact with a mechanical prosthetic valve compared with what occurs in most other forms of AF. This may explain the results of the only trial performed with a NOAC in patients with a mechanical prosthetic valve (only a few of whom had AF), where warfarin was more effective and safer than dabigatran. By contrast, AF in the presence of a bioprosthetic heart valve or after valve repair appears to have a risk of thromboembolism that is not markedly different from other forms of "non-valvular" AF. Obviously, we should no longer consider the classification of AF as "valvular" (or not) for the purpose of defining the aetiology of the arrhythmia, but for the determination of a different risk of thromboembolic events and the need for a specific antithrombotic strategy. As long as there is no better new term or widely accepted definition, "valvular AF" refers to patients with mitral stenosis or artificial heart valves. Patients with "non-valvular AF" may have other types of valvular heart disease. One should

  8. Defining Features of Steady-State Timbres

    Science.gov (United States)

    Hall, Michael D.

    1995-01-01

    Three experiments were conducted to define steady -state features of timbre for a group of well-trained musicians. Experiment 1 evaluated whether or not pairs of three critical dimensions of timbre--spectral slope (6 or 12 dB/octave), formant structure (/a/ or /i/ vowel), and inharmonicity of partials (harmonic or inharmonic)--were processed in a separable or integral fashion. Accuracy and speed for classification of values along one dimension were examined under different conditions of variability along a second dimension (fixed, correlated, or orthogonal). Spectral slope and formant structure were integral, with classification speed for the target dimension depending upon variability along the orthogonal dimension. In contrast, evidence of asymmetric separability was obtained for inharmonicity. Classification speed for slope and formant structure did not depend on inharmonicity, whereas RT for the target dimension of inharmonicity was strongly influenced by variability along either slope or formant structure. Since the results of Experiment 1 provided a basis for manipulating spectral slope and formant structure as a single feature, these dimensions were correlated in Experiment 2. Subjects searched for targets containing potential features of timbre within arrays of 1-4 inharmonic distractor pitches. Distractors were homogeneous with respect to the dimensions of timbre. When targets had /a/ formants with shallow spectral slopes, search time increased nonlinearly with array size in a manner consistent with the parallel processing of items, and thus feature search. Feature search was not obtained for targets with /i/ formants and steep slopes. Thus, the feature was coded as the presence or absence of /a/ formants with shallow spectral slopes. A search task using heterogeneous distractor values along slope/formant structure was used in Experiment 3 to evaluate whether or not the feature of timbre and pitch were automatically conjoined (integral). Search times for

  9. Defining the Thrombotic Risk in Patients with Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Fabrizio Vianello

    2011-01-01

    Full Text Available Polycythemia vera (PV and essential thrombocythemia (ET are two Philadelphia-negative myeloproliferative neoplasms (MPN associated with an acquired mutation in the JAK2 tyrosine kinase gene. There is a rare incidence of progression to myelofibrosis and myeloid metaplasia in both disorders, which may or may not precede transformation to acute myeloid leukemia, but thrombosis is the main cause of morbidity and mortality. The pathophysiology of thrombosis in patients with MPN is complex. Traditionally, abnormalities of platelet number and function have been claimed as the main players, but increased dynamic interactions between platelets, leukocytes, and the endothelium do probably represent a fundamental interplay in generating a thrombophilic state. In addition, endothelial dysfunction, a well-known risk factor for vascular disease, may play a role in the thrombotic risk of patients with PV and ET. The identification of plasma markers translating the hemostatic imbalance in patients with PV and ET would be extremely helpful in order to define the subgroup of patients with a significant clinical risk of thrombosis.

  10. Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes

    Science.gov (United States)

    Asai, Akihiro; Miethke, Alexander; Bezerra, Jorge A.

    2016-01-01

    Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease. PMID:26008129

  11. Psychosocial and ethical implications of defining genetic risk for cancers.

    Science.gov (United States)

    Kash, K M

    1995-09-30

    In summary, we need to provide fully informed consent regarding the hazards and the benefits of genetic testing and defining risk. This reflects the first ethical principle of autonomy. It is the responsibility of the counseling team to make sure that the individual is psychologically equipped to deal with the emotional distress that may result from testing. An undue burden must not be placed on someone and harm must not be inflicted. This is the second ethical principle of beneficence. Third, awareness of the potential problems of testing is extremely important. These issues are those of disclosure, insurance problems, and employment problems--the third ethical principle of confidentiality. Recommendations for screening guidelines, regardless of testing results, should be provided. It is important for women who are not gene carriers to know that they still need to go for screening. Lastly, we need to find ways to help individuals cope with their risk status, whether it is actual high risk or perceived high risk. Helping women to develop positive coping strategies and to adhere to screening is extremely important. As the Huntington's data indicated, over time, regardless of their risk levels, individuals do learn how to cope and adapt with the outcome of testing. Women and men need to learn how to live with their risk status so that the negative psychological sequelae will be minimized. PMID:8526383

  12. Phylogenetic reconstruction of South American felids defined by protein electrophoresis.

    Science.gov (United States)

    Slattery, J P; Johnson, W E; Goldman, D; O'Brien, S J

    1994-09-01

    Phylogenetic associations among six closely related South American felid species were defined by changes in protein-encoding gene loci. We analyzed proteins isolated from skin fibroblasts using two-dimensional electrophoresis and allozymes extracted from blood cells. Genotypes were determined for multiple individuals of ocelot, margay, tigrina, Geoffroy's cat, kodkod, and pampas cat at 548 loci resolved by two-dimensional electrophoresis and 44 allozyme loci. Phenograms were constructed using the methods of Fitch-Margoliash and neighbor-joining on a matrix of Nei's unbiased genetic distances for all pairs of species. Results of a relative-rate test indicate changes in two-dimensional electrophoresis data are constant among all South American felids with respect to a hyena outgroup. Allelic frequencies were transformed to discrete character states for maximum parsimony analysis. Phylogenetic reconstruction indicates a major split occurred approximately 5-6 million years ago, leading to three groups within the ocelot lineage. The earliest divergence led to Leopardus tigrina, followed by a split between an ancestor of an unresolved trichotomy of three species (Oncifelis guigna, O. geoffroyi, and Lynchailuris colocolo) and a recent common ancestor of Leopardus pardalis and L. wiedii. The results suggest that modern South American felids are monophyletic and evolved rapidly after the formation of the Panama land bridge between North and South America. PMID:7932791

  13. A model to compare a defined benefit pension fund with a defined contribution provident fund

    OpenAIRE

    J.M. Nevin; J. Swart

    2003-01-01

    During 1994 universities and certain other institutions were given the option of setting up private retirement funds as an alternative to the AIPF. Because of the underfundedness of the AIPF only a substantially reduced Actuarial Reserve Value could be transferred to the new fund on behalf of each member. Employees at these institutions had to make the difficult decision of whether to remain a member of the AIPF or to join a new fund. Several institutions created defined contribution funds as...

  14. DEFINED CONTRIBUTION PLANS, DEFINED BENEFIT PLANS, AND THE ACCUMULATION OF RETIREMENT WEALTH.

    Science.gov (United States)

    Poterba, James; Rauh, Joshua; Venti, Steven; Wise, David

    2007-11-01

    The private pension structure in the United States, once dominated by defined benefit (DB) plans, is currently divided between defined contribution (DC) and DB plans. Wealth accumulation in DC plans depends on the participant's contribution behavior and on financial market returns, while accumulation in DB plans is sensitive to a participant's labor market experience and to plan parameters. This paper simulates the distribution of retirement wealth under representative DB and DC plans. It uses data from the Health and Retirement Study (HRS) to explore how asset returns, earnings histories, and retirement plan characteristics contribute to the variation in retirement wealth outcomes. We simulate DC plan accumulation by randomly assigning individuals a share of wages that they and their employer contribute to the plan. We consider several possible asset allocation strategies, with asset returns drawn from the historical return distribution. Our DB plan simulations draw earnings histories from the HRS, and randomly assign each individual a pension plan drawn from a sample of large private and public defined benefit plans. The simulations yield distributions of both DC and DB wealth at retirement. Average retirement wealth accruals under current DC plans exceed average accruals under private sector DB plans, although DC plans are also more likely to generate very low retirement wealth outcomes. The comparison of current DC plans with more generous public sector DB plans is less definitive, because public sector DB plans are more generous on average than their private sector counterparts. PMID:21057597

  15. Human gene copy number spectra analysis in congenital heart malformations

    OpenAIRE

    Tomita-Mitchell, Aoy; Mahnke, Donna K.; Struble, Craig A; Tuffnell, Maureen E.; Stamm, Karl D.; Hidestrand, Mats; Harris, Susan E.; Goetsch, Mary A; Simpson, Pippa M; Bick, David P.; Broeckel, Ulrich; Pelech, Andrew N.; Tweddell, James S.; Mitchell, Michael E.

    2012-01-01

    The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical appro...

  16. Identity Gene Expression in Proteus Mirabilis

    OpenAIRE

    Gibbs, Karine Alexine; Wenren, Larissa Man-Yin; Greenberg, E. Peter

    2011-01-01

    Swarming colonies of independent Proteus mirabilis isolates recognize each other as foreign and do not merge together, whereas apposing swarms of clonal isolates merge with each other. Swarms of mutants with deletions in the ids gene cluster do not merge with their parent. Thus, ids genes are involved in the ability of P. mirabilis to distinguish self from nonself. Here we have characterized expression of the ids genes. We show that idsABCDEF genes are transcribed as an operon, and we define ...

  17. Covers of groups definable in o-minimal structures

    OpenAIRE

    Edmundo, Mário Jorge

    2005-01-01

    We develop in this paper the theory of covers for Hausdorff properly $\\bigvee $-definable manifolds with definable choice in an o-minimal structure $\\N$. In particular, we show that given an $\\N$-definably connected $\\N$-definable group $G$ we have $1\\to \\pi_1(G)\\to \\tilde{G}\\stackrel{p}\\to G\\to 1$ in the category of strictly properly $\\bigvee $-definable groups with strictly properly $\\bigvee $-definable homomorphisms, where $\\pi_1(G)$ is the o-minimal fundamental group of $G$.

  18. Localization of aromatase in the nervous system, Hatschek's pit and gonad of amphioxus by in situ hybridization and immunocytochemistry%芳香化酶在文昌鱼神经系统、哈氏窝和性腺特异性定位:原位杂交和免疫细胞化学研究

    Institute of Scientific and Technical Information of China (English)

    方永强; 翁幼竹; 黄威权; 孙岚

    2003-01-01

    芳香化酶活性发现在脊椎动物脑、脑垂体和性腺中,但在文昌鱼脑和哈氏窝的组织特异性定位尚无可利用资料.本文用免疫细胞化学和原位杂交技术,首次发现芳香化酶活性组织特异性定位在幼年和性腺发育不同时期雌、雄文昌鱼神经系统(脑和脊髓)、轮器、哈氏窝和性腺中.芳香化酶蛋白和转录物在前脑、中脑、脊髓、轮器和哈氏窝十分丰富,而后脑、早期卵巢和精巢不够丰富;没有芳香化酶表达的部位是哈氏窝另两种细胞(不规则形细胞和带纤毛粘液细胞)以及成熟卵巢和精巢;芳香化酶免疫活性物质分布在胞质,核为阴性.芳香化酶在文昌鱼神经系统、哈氏窝和性腺的分布模式与低等脊椎动物中的分布模式极为类似,尤其是芳香化酶在脑内调节哈氏窝分泌活动的神经内分泌中枢表达,并形成类似脊椎动物的文昌鱼原始的脑-芳香化酶调节系统.这些结果有力地证明,文昌鱼脑和哈氏窝高水平的芳香化酶活性像在其它脊椎动物中一样,对局部介导睾酮芳香化起着关键作用,同时还可能影响脑-芳香化酶系统参与调节哈氏窝的分泌活动[动物学报49(6):800~806,2003].%Aromatase activity has been found in the brain and pituitary as well as gonads of vertebrates, but no information is available on the specific localization in the brain and Hatschek's pit (primitive pituitary) of amphioxus (Branchios-toma belcheri). Using immunocytochemistry and in situ hybridization, we studied definitive tissue specific localization of aromatase in the nervous system (brain and spinal cord), wheel organ, Hatschek's pit and gonads at young and adult female and male amphioxus at different stages of gonadal development. Aromatase protein and its mRNA were abundant in the forebrain, midbrain, spinal cord, wheel organ and Hatschek's pit, but not abundant in the hindbrain or early ovary and testis. No aromatase expression

  19. Extracting gene-gene interactions through curve fitting.

    Science.gov (United States)

    Das, Ranajit; Mitra, Sushmita; Murthy, C A

    2012-12-01

    This paper presents a simple and novel curve fitting approach for generating simple gene regulatory subnetworks from time series gene expression data. Microarray experiments simultaneously generate massive data sets and help immensely in the large-scale study of gene expression patterns. Initial biclustering reduces the search space in the high-dimensional microarray data. The least-squares error between fitting of gene pairs is minimized to extract a set of gene-gene interactions, involving transcriptional regulation of genes. The higher error values are eliminated to retain only the strong interacting gene pairs in the resultant gene regulatory subnetwork. Next the algorithm is extended to a generalized framework to enhance its capability. The methodology takes care of the higher-order dependencies involving multiple genes co-regulating a single gene, while eliminating the need for user-defined parameters. It has been applied to the time-series Yeast data, and the experimental results biologically validated using standard databases and literature. PMID:22997274

  20. Derivation and Maintenance of Murine Trophoblast Stem Cells under Defined Conditions

    OpenAIRE

    Caroline Kubaczka; Claire Senner; Marcos J. Araúzo-Bravo; Neha Sharma; Peter Kuckenberg; Astrid Becker; Andreas Zimmer; Oliver Brüstle; Michael Peitz; Myriam Hemberger; Hubert Schorle

    2014-01-01

    Summary Trophoblast stem cells (TSCs) are in vitro equivalents to the precursor cells of the placenta. TSCs are cultured in serum-rich medium with fibroblast growth factor 4, heparin, and embryonic-fibroblast-conditioned medium. Here, we developed a simple medium consisting of ten chemically defined ingredients for culture of TSCs on Matrigel or synthetic substrates, named TX medium. Gene expression and DNA methylation profiling demonstrated the faithful propagation of expression profiles and...