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Sample records for regulates adrenocortical development

  1. Adrenocortical Activity and Emotion Regulation.

    ERIC Educational Resources Information Center

    Stansbury, Kathy; Gunnar, Megan R.

    1994-01-01

    This essay argues that the activity of the hypothalamic-pituitary-adrenocortical (HPA) system does not appear to be related to emotion regulation processes in children, although individual differences in emotion processes related to negative emotion temperaments appear to be associated with individual differences in HPA reactivity among normally…

  2. Gene expression and regulation in adrenocortical tumorigenesis.

    PubMed

    Fonseca, Annabelle L; Healy, James; Kunstman, John W; Korah, Reju; Carling, Tobias

    2012-12-27

    Adrenocortical tumors are frequently found in the general population, and may be benign adrenocortical adenomas or malignant adrenocortical carcinomas. Unfortunately the clinical, biochemical and histopathological distinction between benign and malignant adrenocortical tumors may be difficult in the absence of widely invasive or metastatic disease, and hence attention has turned towards a search for molecular markers. The study of rare genetic diseases that are associated with the development of adrenocortical carcinomas has contributed to our understanding of adrenocortical tumorigenesis. In addition, comprehensive genomic hybridization, methylation profiling, and genome wide mRNA and miRNA profiling have led to improvements in our understanding, as well as demonstrated several genes and pathways that may serve as diagnostic or prognostic markers.

  3. Emotional and Adrenocortical Regulation in Early Adolescence: Prediction by Attachment Security and Disorganization in Infancy

    ERIC Educational Resources Information Center

    Spangler, Gottfried; Zimmermann, Peter

    2014-01-01

    The aim of the present study was to examine differences in emotion expression and emotion regulation in emotion-eliciting situations in early adolescence from a bio-psycho-social perspective, specifically investigating the influence of early mother-infant attachment and attachment disorganization on behavioural and adrenocortical responses. The…

  4. GATA4 Is a Critical Regulator of Gonadectomy-Induced Adrenocortical Tumorigenesis in Mice

    PubMed Central

    Krachulec, Justyna; Vetter, Melanie; Schrade, Anja; Löbs, Ann-Kathrin; Bielinska, Malgorzata; Cochran, Rebecca; Kyrönlahti, Antti; Pihlajoki, Marjut; Parviainen, Helka; Jay, Patrick Y.; Heikinheimo, Markku

    2012-01-01

    In response to gonadectomy certain inbred mouse strains develop sex steroidogenic adrenocortical neoplasms. One of the hallmarks of neoplastic transformation is expression of GATA4, a transcription factor normally present in gonadal but not adrenal steroidogenic cells of the adult mouse. To show that GATA4 directly modulates adrenocortical tumorigenesis and is not merely a marker of gonadal-like differentiation in the neoplasms, we studied mice with germline or conditional loss-of-function mutations in the Gata4 gene. Germline Gata4 haploinsufficiency was associated with attenuated tumor growth and reduced expression of sex steroidogenic genes in the adrenal glands of ovariectomized B6D2F1 and B6AF1 mice. At 12 months after ovariectomy, wild-type B6D2F1 mice had biochemical and histological evidence of adrenocortical estrogen production, whereas Gata4+/− B6D2F1 mice did not. Germline Gata4 haploinsufficiency exacerbated the secondary phenotype of postovariectomy obesity in B6D2F1 mice, presumably by limiting ectopic estrogen production in the adrenal glands. Amhr2-cre-mediated deletion of floxed Gata4 (Gata4F) in nascent adrenocortical neoplasms of ovariectomized B6.129 mice reduced tumor growth and the expression of gonadal-like markers in a Gata4F dose-dependent manner. We conclude that GATA4 is a key modifier of gonadectomy-induced adrenocortical neoplasia, postovariectomy obesity, and sex steroidogenic cell differentiation. PMID:22461617

  5. Transforming growth factor beta 1: an autocrine regulator of adrenocortical steroidogenesis.

    PubMed

    Feige, J J; Cochet, C; Savona, C; Shi, D L; Keramidas, M; Defaye, G; Chambaz, E M

    1991-01-01

    Transforming growth factor beta 1 (TGF beta 1) is a member of a large family of structurally related regulatory polypeptides which comprises both functionally similar (TGF beta 1, TGF beta 2, TGF beta 3, TGF beta 4 and TGF beta 5) and functionally distinct proteins. In the past few years, TGF beta 1 has emerged as a multifunctional protein. One of its remarkable properties is its capacity to negatively modulate the differentiated, steroidogenic adrenocortical functions. We present here a review of the results from our recent work related to the effects of TGF beta 1 on bovine adrenocortical cell (zona fasciculata-reticularis) functions. We identified the steroid 17 alpha-hydroxylase (P-450 17 alpha) biosynthetic enzyme and the angiotensin II receptor as major targets whose expression are negatively regulated by TGF beta 1 in these cells. We characterized TGF beta 1 receptors at the surface of adrenocortical cells (mainly type I and type III receptors) and observed that their number is increased under ACTH treatment. Furthermore, we could detect the presence of immunoreactive TGF beta 1 in the bovine adrenal cortex whereas it was undetectable in the adrenal medulla and in the capsule. We also observed that adrenocortical cells secrete TGF beta 1 under a latent form together with large amounts of alpha 2-macroglobulin, a protease inhibitor known to be implied in the latency of TGF beta in serum. Taken together, these observations led us to a working hypothesis, proposing TGF beta 1 as an autocrine and/or paracrine regulator of adrenocortical steroidogenic functions. This concept points out the physiological activation of the latent TGF beta 1 complex as the important limiting step controlling its action in the adrenal cortex.

  6. Adrenocortical endocrine disruption.

    PubMed

    Harvey, Philip W

    2016-01-01

    The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the

  7. Endothelial cells regulate β-catenin activity in adrenocortical cells via secretion of basic fibroblast growth factor.

    PubMed

    Schwafertz, Carolin; Schinner, Sven; Kühn, Markus C; Haase, Matthias; Asmus, Amelie; Mülders-Opgenoorth, Birgit; Ansurudeen, Ishrath; Hornsby, Peter J; Morawietz, Henning; Oetjen, Elke; Schott, Matthias; Willenberg, Holger S

    2017-02-05

    Endothelial cell-derived products influence the synthesis of aldosterone and cortisol in human adrenocortical cells by modulating proteins such as steroidogenic acute-regulatory (StAR) protein, steroidogenic factor (SF)-1 and CITED2. However, the potential endothelial cell-derived factors that mediate this effect are still unknown. The current study was perfomed to look into the control of β-catenin activity by endothelial cell-derived factors and to identify a mechanism by which they affect β-catenin activity in adrenocortical NCIH295R cells. Using reporter gene assays and Western blotting, we found that endothelial cell-conditioned medium (ECCM) led to nuclear translocation of β-catenin and an increase in β-catenin-dependent transcription that could be blocked by U0126, an inhibitor of the mitogen-activated protein kinase pathway. Furthermore, we found that a receptor tyrosin kinase (RTK) was involved in ECCM-induced β-catenin-dependent transcription. Through selective inhibition of RTK using Su5402, it was shown that receptors responding to basic fibroblast growth factor (bFGF) mediate the action of ECCM. Adrenocortical cells treated with bFGF showed a significant greater level of bFGF mRNA. In addition, HUVECs secrete bFGF in a density-dependent manner. In conclusion, the data suggest that endothelial cells regulate β-catenin activity in adrenocortical cells also via secretion of basic fibroblast growth factor.

  8. Integrated genome-wide analysis of genomic changes and gene regulation in human adrenocortical tissue samples.

    PubMed

    Gara, Sudheer Kumar; Wang, Yonghong; Patel, Dhaval; Liu-Chittenden, Yi; Jain, Meenu; Boufraqech, Myriem; Zhang, Lisa; Meltzer, Paul S; Kebebew, Electron

    2015-10-30

    To gain insight into the pathogenesis of adrenocortical carcinoma (ACC) and whether there is progression from normal-to-adenoma-to-carcinoma, we performed genome-wide gene expression, gene methylation, microRNA expression and comparative genomic hybridization (CGH) analysis in human adrenocortical tissue (normal, adrenocortical adenomas and ACC) samples. A pairwise comparison of normal, adrenocortical adenomas and ACC gene expression profiles with more than four-fold expression differences and an adjusted P-value < 0.05 revealed no major differences in normal versus adrenocortical adenoma whereas there are 808 and 1085, respectively, dysregulated genes between ACC versus adrenocortical adenoma and ACC versus normal. The majority of the dysregulated genes in ACC were downregulated. By integrating the CGH, gene methylation and expression profiles of potential miRNAs with the gene expression of dysregulated genes, we found that there are higher alterations in ACC versus normal compared to ACC versus adrenocortical adenoma. Importantly, we identified several novel molecular pathways that are associated with dysregulated genes and further experimentally validated that oncostatin m signaling induces caspase 3 dependent apoptosis and suppresses cell proliferation. Finally, we propose that there is higher number of genomic changes from normal-to-adenoma-to-carcinoma and identified oncostatin m signaling as a plausible druggable pathway for therapeutics.

  9. Animal models of adrenocortical tumorigenesis

    PubMed Central

    Beuschlein, Felix; Galac, Sara; Wilson, David B.

    2011-01-01

    Over the past decade, research on human adrenocortical neoplasia has been dominated by gene expression profiling of tumor specimens and by analysis of genetic disorders associated with a predisposition to these tumors. Although these studies have identified key genes and associated signaling pathways that are dysregulated in adrenocortical neoplasms, the molecular events accounting for the frequent occurrence of benign tumors and low rate of malignant transformation remain unknown. Moreover, the prognosis for patients with adrenocortical carcinoma remains poor, so new medical treatments are needed. Naturally occurring and genetically engineered animal models afford a means to investigate adrenocortical tumorigenesis and to develop novel therapeutics. This comparative review highlights adrenocortical tumor models useful for either mechanistic studies or preclinical testing. Three model species – mouse, ferret, and dog – are reviewed, and their relevance to adrenocortical tumors in humans is discussed. PMID:22100615

  10. Adrenocortical regulation, eating in the absence of hunger and BMI in young children.

    PubMed

    Francis, L A; Granger, D A; Susman, E J

    2013-05-01

    The purpose of this study was to examine relations among adrenocortical regulation, eating in the absence of hunger, and body mass index (BMI) in children ages 5-9years (N=43). Saliva was collected before and after the Trier Social Stress Test for Children (TSST-C), and was later assayed for cortisol. Area under the curve with respect to increase (AUCi) was used as a measure of changes in cortisol release from baseline to 60min post-TSST-C. Age- and sex-specific BMI scores were calculated from measured height and weight, and eating in the absence of hunger was assessed using weighed food intake during a behavioral procedure. We also included a measure of parents' report of child impulsivity, as well as family demographic information. Participants were stratified by age into younger (5-7years) and older (8-9years) groups. In younger children, parents' reports of child impulsivity were significantly and positively associated with BMI; cortisol AUCi was not associated with BMI or eating in the absence of hunger. In older children, however, greater stress-related cortisol AUCi was related to higher BMI scores and greater energy intake in the absence of hunger. The results suggest that cortisol AUCi in response to psychosocial stress may be linked to problems with energy balance in children, with some variation by age.

  11. Adrenocorticotropic hormone in serial cerebrospinal fluid in man - Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?

    PubMed

    Kellner, Michael; Wortmann, Viola; Salzwedel, Cornelie; Kober, Daniel; Petzoldt, Martin; Urbanowicz, Tatiana; Pulic, Mersija; Boelmans, Kai; Yassouridis, Alexander; Wiedemann, Klaus

    2016-05-30

    Acute regulation of adrenocorticotropic hormone (ACTH) in cerebrospinal fluid (CSF) by the hypothalamic-pituitary-adrenocortical system has not been investigated in man. In a pilot study in healthy male volunteers we measured ACTH every twenty minutes in serial CSF for three hours after an intravenous placebo, hydrocortisone (100mg) or insulin (2mg/kg) injection. No acute inhibitory or stimulatory effects of these interventions were discovered. Our results corroborate previous findings in rhesus monkeys. The regulation of CSF ACTH and its potential relevance for behavioral alterations in health and disease (e.g. major depression or anorexia nervosa) in humans need further study.

  12. Adrenocortical carcinoma

    MedlinePlus

    ... Adrenocortical carcinoma (ACC) is a cancer of the adrenal glands . The adrenal glands are two triangle-shaped glands. One gland is ... unknown. Symptoms Symptoms of increased cortisol or other adrenal gland hormones may include: Fatty, rounded hump high on ...

  13. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia

    PubMed Central

    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune–Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1–3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID:27512387

  14. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia.

    PubMed

    Villares Fragoso, Maria Candida Barisson; Wanichi, Ingrid Quevedo; Cavalcante, Isadora Pontes; Mariani, Beatriz Marinho de Paula

    2016-01-01

    Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune-Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1-3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia.

  15. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis.

    PubMed

    Li, Ping; Sun, Fei; Cao, Huang-Ming; Ma, Qin-Yun; Pan, Chun-Ming; Ma, Jun-Hua; Zhang, Xiao-Na; Jiang, He; Song, Huai-Dong; Chen, Ming-Dao

    2009-12-25

    Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.

  16. The Role of the Pituitary-Adrenocortical Axis System in the Regulation of Secretion of Digestive Glands of Wrestlers during Sports and Postsports Ontogenesis

    ERIC Educational Resources Information Center

    Panov, Sergei F.; Panova, Irina P.; Volunskaya, Elena V.; Chebotarev, Andrei V.

    2016-01-01

    According to many researchers its necessary to research a hormonal profile in order to determine mechanisms of regulation of functions of the digestive conveyor during sports activities. In the paper the results of the carried out research on studying of a role of pituitary-adrenocortical axis system of adaptive reactions in activities of the…

  17. Adrenocortical Carcinoma

    PubMed Central

    Kim, Alex C.; Sabolch, Aaron; Raymond, Victoria M.; Kandathil, Asha; Caoili, Elaine M.; Jolly, Shruti; Miller, Barbra S.; Giordano, Thomas J.

    2014-01-01

    Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC. PMID:24423978

  18. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

    ERIC Educational Resources Information Center

    Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which…

  19. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo

    PubMed Central

    Kertes, Darlene A.; Kamin, Hayley S.; Hughes, David A.; Rodney, Nicole C.; Bhatt, Samarth; Mulligan, Connie J.

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight, and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. Birth weight data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at transcription factor binding sites, was associated with birth weight. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes. PMID:26822443

  20. Prenatal Maternal Stress Predicts Methylation of Genes Regulating the Hypothalamic-Pituitary-Adrenocortical System in Mothers and Newborns in the Democratic Republic of Congo.

    PubMed

    Kertes, Darlene A; Kamin, Hayley S; Hughes, David A; Rodney, Nicole C; Bhatt, Samarth; Mulligan, Connie J

    2016-01-01

    Exposure to stress early in life permanently shapes activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the brain. Prenatally, glucocorticoids pass through the placenta to the fetus with postnatal impacts on brain development, birth weight (BW), and HPA axis functioning. Little is known about the biological mechanisms by which prenatal stress affects postnatal functioning. This study addresses this gap by examining the effect of chronic stress and traumatic war-related stress on epigenetic changes in four key genes regulating the HPA axis in neonatal cord blood, placenta, and maternal blood: CRH, CRHBP, NR3C1, and FKBP5. Participants were 24 mother-newborn dyads in the conflict-ridden region of the eastern Democratic Republic of Congo. BW data were collected at delivery and maternal interviews were conducted to assess culturally relevant chronic and war-related stressors. Chronic stress and war trauma had widespread effects on HPA axis gene methylation, with significant effects observed at transcription factor binding (TFB) sites in all target genes tested. Some changes in methylation were unique to chronic or war stress, whereas others were observed across both stressor types. Moreover, stress exposures impacted maternal and fetal tissues differently, supporting theoretical models that stress impacts vary according to life phase. Methylation in several NR3C1 and CRH CpG sites, all located at TFB sites, was associated with BW. These findings suggest that prenatal stress exposure impacts development via epigenetic changes in HPA axis genes.

  1. Corticotropin (ACTH) regulates alternative RNA splicing in Y1 mouse adrenocortical tumor cells.

    PubMed

    Schimmer, Bernard P; Cordova, Martha

    2015-06-15

    The stimulatory effect of ACTH on gene expression is well documented and is thought to be a major mechanism by which ACTH maintains the functional and structural integrity of the gland. Previously, we showed that ACTH regulates the accumulation of over 1200 transcripts in Y1 adrenal cells, including a cluster with functions in alternative splicing of RNA. On this basis, we postulated that some of the effects of ACTH on the transcription landscape of Y1 cells are mediated by alternative splicing. In this study, we demonstrate that ACTH regulates the alternative splicing of four transcripts - Gnas, Cd151, Dab2 and Tia1. Inasmuch as alternative splicing potentially affects transcripts from more than two-thirds of the mouse genome, we suggest that these findings are representative of a genome-wide effect of ACTH that impacts on the mRNA and protein composition of the adrenal cortex.

  2. Orexin-A regulates cell apoptosis in human H295R adrenocortical cells via orexin receptor type 1 through the AKT signaling pathway.

    PubMed

    Chang, Xiaocen; Zhao, Yuyan; Ju, Shujing; Guo, Lei

    2015-11-01

    Numerous studies have demonstrated the ability of orexin-A to regulate adrenocortical cells through the mitogen-activated protein kinase signaling pathway. In the present study, human H295R adrenocortical cells were exposed to orexin‑A (10‑10-10‑6 M), with orexin receptor type 1 (OX1 receptor) antagonist SB334867 or AKT antagonist PF‑04691502. It was found that orexin‑A stimulated H295R cell proliferation, reduced the pro‑apoptotic activity of caspase‑3 to protect against apoptotic cell death and increased cortisol secretion. Furthermore, phospho‑AKT protein was increased by orexin‑A. SB334867 (10‑6 M) and PF‑04691502 (10‑6 M) abolished the effects of orexin‑A (10‑6 M). These results suggested that the orexin‑A/OX1 receptor axis has a significant pro-survival function in adrenal cells, which is mediated by AKT activation. Further studies investigating the effects of orexin-A-upregulation may further elucidate the diverse biological effects of orexin-A in adrenal cells.

  3. Adrenocortical Gap Junctions and Their Functions

    PubMed Central

    Bell, Cheryl L.; Murray, Sandra A.

    2016-01-01

    Adrenal cortical steroidogenesis and proliferation are thought to be modulated by gap junction-mediated direct cell–cell communication of regulatory molecules between cells. Such communication is regulated by the number of gap junction channels between contacting cells, the rate at which information flows between these channels, and the rate of channel turnover. Knowledge of the factors regulating gap junction-mediated communication and the turnover process are critical to an understanding of adrenal cortical cell functions, including development, hormonal response to adrenocorticotropin, and neoplastic dedifferentiation. Here, we review what is known about gap junctions in the adrenal gland, with particular attention to their role in adrenocortical cell steroidogenesis and proliferation. Information and insight gained from electrophysiological, molecular biological, and imaging (immunocytochemical, freeze fracture, transmission electron microscopic, and live cell) techniques will be provided. PMID:27445985

  4. Adiponectin and adiponectin receptor system in the rat adrenal gland: ontogenetic and physiologic regulation, and its involvement in regulating adrenocortical growth and steroidogenesis.

    PubMed

    Paschke, Lukasz; Zemleduch, Tomasz; Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Malendowicz, Ludwik K

    2010-09-01

    Adiponectin (ADN) is a regulatory peptide secreted mostly by adipose tissue and acting via two receptors: AdipoR1 and AdipoR2. Our aim was to investigate expression of adiponectin system genes in the rat adrenal gland as well as its ontogenetic and physiological control. Furthermore, we examined the effects of acute and prolonged activation of HPA axis on ADN system in adipose tissue. By means of QPCR, ADN and AdipoR1 expression was demonstrated in rat adrenal cortex both at mRNA and protein levels, while AdipoR2 could only be detected at mRNA levels. ADN expression level was significantly upregulated in a developing and regenerating adrenal cortex. Globular domain of adiponectin at 10(-9) M stimulated corticosterone output and BrdU incorporation by cultured rat adrenocortical cells. Moreover, both acute (ACTH and ether stress) and prolonged (ACTH) adrenal stimulation resulted in lowered ADN levels, while expression of AdipoR1 and AdipoR2 was upregulated by the acute treatment. Depending on its site of origin, visceral (VAT) or subcutaneous (SAT) adipose tissue responded differently to alterations in HPA axis. VAT expression of ADN and its receptors remained almost unchanged by experimental manipulations. In SAT, on the other hand, expression of ADN and AdipoR2 was markedly increased by ACTH treatment and stress, while dexamethasone suppressed ADN and AdipoR1 mRNA levels. The results of this study provide new evidence for direct and indirect interactions between adipokines and HPA axis.

  5. Pediatric Adrenocortical Tumors: What They Can Tell Us on Adrenal Development and Comparison with Adult Adrenal Tumors

    PubMed Central

    Lalli, Enzo; Figueiredo, Bonald C.

    2015-01-01

    Adrenocortical tumors (ACT) in children are very rare and are most frequently diagnosed in the context of the Li-Fraumeni syndrome, a multiple cancer syndrome linked to germline mutations of the tumor suppressor gene TP53 with loss of heterozygosity in the tumors. A peak of children ACT incidence is present in the states of southern Brazil, where they are linked to the high prevalence in the population of a specific TP53 mutation (R337H). Children ACT have specific features distinguishing them from adult tumors in their pathogenetic mechanisms, genomic profiles, and prognosis. Epidemiological and molecular evidence suggests that in most cases they are derived from the fetal adrenal. PMID:25741319

  6. Global gene expression response to telomerase in bovine adrenocortical cells

    SciTech Connect

    Perrault, Steven D.; Hornsby, Peter J.; Betts, Dean H. . E-mail: bettsd@uoguelph.ca

    2005-09-30

    The infinite proliferative capability of most immortalized cells is dependent upon the presence of the enzyme telomerase and its ability to maintain telomere length and structure. However, telomerase may be involved in a greater system than telomere length regulation, as recent evidence has shown it capable of increasing wound healing in vivo, and improving cellular proliferation rate and survival from apoptosis in vitro. Here, we describe the global gene expression response to ectopic telomerase expression in an in vitro bovine adrenocortical cell model. Telomerase-immortalized cells showed an increased ability for proliferation and survival in minimal essential medium above cells transgenic for GFP. cDNA microarray analyses revealed an altered cell state indicative of increased adrenocortical cell proliferation regulated by the IGF2 pathway and alterations in members of the TGF-B family. As well, we identified alterations in genes associated with development and wound healing that support a model that high telomerase expression induces a highly adaptable, progenitor-like state.

  7. Update in adrenocortical carcinoma.

    PubMed

    Fassnacht, Martin; Kroiss, Matthias; Allolio, Bruno

    2013-12-01

    Adrenocortical carcinoma (ACC) is an orphan malignancy that has attracted increasing attention during the last decade. Here we provide an update on advances in the field since our last review published in this journal in 2006. The Wnt/β-catenin pathway and IGF-2 signaling have been confirmed as frequently altered signaling pathways in ACC, but recent data suggest that they are probably not sufficient for malignant transformation. Thus, major players in the pathogenesis are still unknown. For diagnostic workup, comprehensive hormonal assessment and detailed imaging are required because in most ACCs, evidence for autonomous steroid secretion can be found and computed tomography or magnetic resonance imaging (if necessary, combined with functional imaging) can differentiate benign from malignant adrenocortical tumors. Surgery is potentially curative in localized tumors. Thus, we recommend a complete resection including lymphadenectomy by an expert surgeon. The pathology report should demonstrate the adrenocortical origin of the lesion (eg, by steroidogenic factor 1 staining) and provide Weiss score, resection status, and quantitation of the proliferation marker Ki67 to guide further treatment. Even after complete surgery, recurrence is frequent and adjuvant mitotane treatment improves outcome, but uncertainty exists as to whether all patients benefit from this therapy. In advanced ACC, mitotane is still the standard of care. Based on the FIRM-ACT trial, mitotane plus etoposide, doxorubicin, and cisplatin is now the established first-line cytotoxic therapy. However, most patients will experience progress and require salvage therapies. Thus, new treatment concepts are urgently needed. The ongoing international efforts including comprehensive "-omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully lead to better therapies.

  8. Psychobiological mechanisms underlying the social buffering of the hypothalamic-pituitary-adrenocortical axis: a review of animal models and human studies across development.

    PubMed

    Hostinar, Camelia E; Sullivan, Regina M; Gunnar, Megan R

    2014-01-01

    Discovering the stress-buffering effects of social relationships has been one of the major findings in psychobiology in the last century. However, an understanding of the underlying neurobiological and psychological mechanisms of this buffering is only beginning to emerge. An important avenue of this research concerns the neurocircuitry that can regulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. The present review is a translational effort aimed at integrating animal models and human studies of the social regulation of the HPA axis from infancy to adulthood, specifically focusing on the process that has been named social buffering. This process has been noted across species and consists of a dampened HPA axis stress response to threat or challenge that occurs with the presence or assistance of a conspecific. We describe aspects of the relevant underlying neurobiology when enough information exists and expose major gaps in our understanding across all domains of the literatures we aimed to integrate. We provide a working conceptual model focused on the role of oxytocinergic systems and prefrontal neural networks as 2 of the putative biological mediators of this process, and propose that the role of early experiences is critical in shaping later social buffering effects. This synthesis points to both general future directions and specific experiments that need to be conducted to build a more comprehensive model of the HPA social buffering effect across the life span that incorporates multiple levels of analysis: neuroendocrine, behavioral, and social.

  9. Alterations of Phosphodiesterases in Adrenocortical Tumors

    PubMed Central

    Hannah-Shmouni, Fady; Faucz, Fabio R.; Stratakis, Constantine A.

    2016-01-01

    Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs. PMID:27625633

  10. Mouse models of adrenocortical tumors

    PubMed Central

    Basham, Kaitlin J.; Hung, Holly A.; Lerario, Antonio M.; Hammer, Gary D.

    2016-01-01

    The molecular basis of the organogenesis, homeostasis, and tumorigenesis of the adrenal cortex has been the subject of intense study for many decades. Specifically, characterization of tumor predisposition syndromes with adrenocortical manifestations and molecular profiling of sporadic adrenocortical tumors have led to the discovery of key molecular pathways that promote pathological adrenal growth. However, given the observational nature of such studies, several important questions regarding the molecular pathogenesis of adrenocortical tumors have remained. This review will summarize naturally occurring and genetically engineered mouse models that have provided novel tools to explore the molecular and cellular underpinnings of adrenocortical tumors. New paradigms of cancer initiation, maintenance, and progression that have emerged from this work will be discussed. PMID:26678830

  11. Development of mitotane lipid nanocarriers and enantiomers: two-in-one solution to efficiently treat adreno-cortical carcinoma.

    PubMed

    Menaa, F; Menaa, B

    2012-01-01

    Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Treatment options for advanced ACC are limited. Indeed, radical tumor resection can lead to local or metastatic recurrence, and mitotane (Lysodren(®)), the only recognized adrenolytic drug, offers modest response rates, notably due to some of its physico-chemical and pharmacological properties (i.e. hydrophobicity, low bioavailability). Meantime, high cumulative doses of Lysodren(®) usually cause systemic toxicities. To reduce adverse health effects, the search of safe and efficient mitotane nano-formulations as well as the full characterization and testing of its enantiomers can represent valuable therapeutic options. Interestingly, recent investigations showed that solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) could considerably improve the efficacy of mitotane (i.e. enhanced solubility and bioavailability, progressive release of the loaded drug into blood and targeted tissues) as well as its safety (i.e. lower toxicity, higher biocompatibility). These two nano-carriers for mitotane delivery and targeting are of particular interest over other polymeric particles (i.e. low-cost, efficient and simple scaling to an industrial production level following green methods). Besides, emerging studies suggested that the S-(-)- mitotane is more potent than the R-(+)-mitotane for ACC treatment. Therefore, the production of pure and active S-(-)-mitotane might offer synergic or additive benefits for ACC patients when combined to solid lipid-based nanocarriers. In this review, we first provide an updated overview of the ACC disease before emphasizing on the promising mitotane drug nano-systems, as well as on the separation, purification and production of single mitotane enantiomer using state-of-art chromatographic-based methods.

  12. [Adrenocortical tumors--new perspectives].

    PubMed

    Latronico, Ana Claudia; Mendonça, Berenice B de

    2004-10-01

    A high frequency of adrenocortical tumors has been observed in Brazilian children and adults from South and Southwestern regions. The valuable national experience in the management of these tumors have resulted in several and relevant basic and clinical reports. However, the creation of an adrenocortical tumor national registry, the uniformity of approaches and collaborative studies are target to pursue. In this review article, we briefly described the fundamental points which were discussed in two scientific events on adrenocortical tumors: "International Consensus Conference on Treatment of Adrenal Cancer" and "I Simposio de Diagnóstico e Tratamento dos Tumores Adrenocorticais". The task force involving several Brazilian centers will increase the progress in the diagnosis, prognosis and treatment of this devastating disorder.

  13. Adrenocortical reserves in hyperthyroidism.

    PubMed

    Agbaht, Kemal; Gullu, Sevim

    2014-02-01

    Explicit data regarding the changes in adrenocortical reserves during hyperthyroidism do not exist. We aimed to document the capability (response) of adrenal gland to secrete cortisol and DHEA-S during hyperthyroidism compared to euthyroidism, and to describe factors associated with these responses. A standard-dose (0.25 mg/i.v.) ACTH stimulation test was performed to the same patients before hyperthyroidism treatment, and after attainment of euthyroidism. Baseline cortisol (Cor(0)), DHEA-S (DHEA-S(0)), cortisol binding globulin (CBG), ACTH, calculated free cortisol (by Coolen's equation = CFC), free cortisol index (FCI), 60-min cortisol (Cor(60)), and DHEA-S (DHEA-S(60)), delta cortisol (ΔCor), delta DHEA-S (ΔDHEA-S) responses were evaluated. Forty-one patients [22 females, 49.5 ± 15.2 years old, 32 Graves disease, nine toxic nodular goiter] had similar Cor(0), DHEA-S(0), CFC, FCI, and DHEA-S(60) in hyperthyroid and euthyroid states. Cor(60), ΔCor, and ΔDHEA-S were lower in hyperthyroidism. In four (10 %) patients the peak ACTH-stimulated cortisol values were lower than 18 μg/dL. When the test repeated after attainment of euthyroidism, all of the patients had normal cortisol response. Regression analysis demonstrated an independent association of Cor(60) with free T3 in hyperthyroidism. However, the predictors of CFC, FCI, and DHEA-S levels were serum creatinine levels in hyperthyroidism, and both creatinine and transaminase levels in euthyroidism. ACTH-stimulated peak cortisol, delta cortisol, and delta DHEA-S levels are decreased during hyperthyroidism, probably due to increased turnover. Since about 10 % of the subjects with hyperthyroidism are at risk for adrenal insufficiency, clinicians dealing with Graves' disease should be alert to the possibility of adrenal insufficiency during hyperthyroid stage.

  14. [Adrenocortical carcinoma: Update in 2014].

    PubMed

    Libé, Rossella; Assié, Guillaume

    2014-04-01

    All adrenal masses with atypical characteristics at conventional imaging must be explored as potential adrenocortical cancer. CT scan with delayed contrast media wash-out and/or abdominal MRI including chemical shift and/or wash-out analysis and 18F-FDG PET help to characterize the adrenal mass. Open adrenalectomy is the first step in the treatment of resectables adrenocortical cancer, as potentially curative. It must be complete (R0), without tumoral dissemination. The management of the adrenocortical cancer requires a multidisciplinary approach, including the endocrinologist, oncologist, surgeons, radiologist, nuclear medicine, pathologist, and geneticians in order to guarantee to the patient the best care. At the national level, the French network COMETE (supported by the Institut National du Cancer) and the international level, the European Network for the Study of Adrenal tumors -ENS@T- (supported by ESF and FP7) contribute to improve the clinical management and the understanding of the pathogenesis of the adrenocortical cancers. Recently, a new insight on molecular markers has been done. These approaches will be soon used "in routine".

  15. Maternal Dietary Restriction During the Periconceptional Period in Normal-Weight or Obese Ewes Results in Adrenocortical Hypertrophy, an Up-Regulation of the JAK/STAT and Down-Regulation of the IGF1R Signaling Pathways in the Adrenal of the Postnatal Lamb

    PubMed Central

    Zhang, Song; Morrison, Janna L.; Gill, Amreet; Rattanatray, Leewen; MacLaughlin, Severence M.; Kleemann, David; Walker, Simon K.

    2013-01-01

    Maternal dietary restriction during the periconceptional period results in an increase in adrenal growth and in the cortisol stress response in the offspring. The intraadrenal mechanisms that result in the programming of these changes are not clear. Activation of the IGF and the signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways regulate adrenal growth. We have used an embryo transfer model in sheep to investigate the impact of exposure to either dietary restriction in normal or obese mothers or to maternal obesity during the periconceptional period on adrenal growth and function in the offspring. We assessed the adrenal abundance of key signaling molecules in the IGF-I and Janus kinase/STAT/SOCS pathways including IGF-I receptor, IGF-II receptor, Akt, mammalian target of rapamycin, ribosomal protein S6, eukaryotic translation initiation factor 4E-binding protein 1, eukaryotic translation initiation factor 4E, STAT1, STAT3, STAT5, SOCS1, and SOCS3 in female and male postnatal lambs. Maternal dietary restriction in the periconceptional period resulted in the hypertrophy of the adrenocortical cells in the zona fasciculata-reticularis and an up-regulation in STAT1, phospho-STAT1, and phospho-STAT3 (Ser727) abundance and a down-regulation in IGF-I receptor, Akt, and phospho-Akt abundance in the adrenal cortex of the postnatal lamb. These studies highlight that weight loss around the time of conception, independent of the starting maternal body weight, results in the activation of the adrenal Janus kinase/STAT pathway and adrenocortical hypertrophy. Thus, signals of adversity around the time of conception have a long-term impact on the mechanisms that regulate adrenocortical growth. PMID:24108072

  16. Feminizing Adrenocortical Carcinoma with Distinct Histopathological Findings

    PubMed Central

    Hatano, Masako; Takenaka, Yasuhiro; Inoue, Ikuo; Homma, Keiko; Hasegawa, Tomonobu; Sasano, Hisanobu; Awata, Takuya; Katayama, Shigehiro

    2016-01-01

    We herein present a 60-year-old man with adrenocortical carcinoma who had gynecomastia. An endocrinological examination revealed increased levels of serum estradiol and dehydroepiandrosterone-sulfate (DHEA-S) and reduced levels of free testosterone. Magnetic resonance imaging showed an adrenal tumor with heterogeneous intensity. Iodine-131 adosterol scintigraphy showed an increased uptake at the same site. Because feminizing adrenocortical carcinoma was suspected, right adrenalectomy was performed; the pathological diagnosis was adrenocortical carcinoma. The results of immunostaining indicated a virilizing tumor. Aromatase activity was identified on RT-PCR. As disorganized steroidogenesis is pathologically present in adrenocortical carcinoma, this diagnosis should be made with caution. PMID:27853073

  17. H295R Human Adrenocortical Carcinoma Cells as a Screening Platform for Steroidogenesis (NC SOT)

    EPA Science Inventory

    Proper biosynthesis and metabolism of steroid hormones is essential for development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carc...

  18. Isolation of rat adrenocortical mitochondria

    SciTech Connect

    Solinas, Paola; Fujioka, Hisashi; Tandler, Bernard; Hoppel, Charles L.

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A method for isolation of adrenocortical mitochondria from the adrenal gland of rats is described. Black-Right-Pointing-Pointer The purified isolated mitochondria show excellent morphological integrity. Black-Right-Pointing-Pointer The properties of oxidative phosphorylation are excellent. Black-Right-Pointing-Pointer The method increases the opportunity of direct analysis of adrenal mitochondria from small animals. -- Abstract: This report describes a relatively simple and reliable method for isolating adrenocortical mitochondria from rats in good, reasonably pure yield. These organelles, which heretofore have been unobtainable in isolated form from small laboratory animals, are now readily accessible. A high degree of mitochondrial purity is shown by the electron micrographs, as well as the structural integrity of each mitochondrion. That these organelles have retained their functional integrity is shown by their high respiratory control ratios. In general, the biochemical performance of these adrenal cortical mitochondria closely mirrors that of typical hepatic or cardiac mitochondria.

  19. Neuropeptides and the hypothalamic-pituitary-adrenocortical (HPA) system: review of recent research strategies in depression.

    PubMed

    Hatzinger, M

    2000-04-01

    Depressed patients show a variety of alterations in hypothalamic-pituitary-adrenocortical (HPA) system regulation which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function tests. The latter include the combined dexamethasone (DEX) suppression/corticotropin-releasing hormone (CRH) challenge test, in which CRH was able to override DEX induced suppression of ACTH and cortisol secretion. Whereas the abnormal HPA activation in these patients improved in parallel with clinical remission, persistent HPA dysregulation was associated with an increased risk of relapse. Moreover, healthy subjects at high genetic risk for depression also showed this phenomenon as a trait marker. In consequence, it has been concluded that HPA alteration and development as well as course of depression may be causally related. As evidenced from clinical and preclinical studies, underlying mechanisms of these abnormalities involve impairment of central corticosteroid receptor function which leads to enhanced activity of hypothalamic neurons synthesising and releasing vasopressin and CRH. These neuropeptides mediate not only neuroendocrine but also behavioural effects. Recent research provided evidence that CRH can induce depression-like symptoms in animals and that these signs are mediated through the CRH1 receptor subtype. Hence, therapeutical application of new compounds acting more specifically on the HPA system such as CRH1 receptor antagonists appear to be a promising approach for future treatment options of depression. In conclusion, research in neuroendocrinology provided new insights into the underlying pathophysiology of depression and, in consequence, may lead to the development of new therapeutic tools.

  20. Feminizing adrenocortical tumors: Literature review

    PubMed Central

    Chentli, Farida; Bekkaye, Ilyes; Azzoug, Said

    2015-01-01

    Feminizing adrenal tumors (FAT) are extremely rare tumors prevailing in males. Clinical manifestations are gynecomastia and/or other hypogonadism features in adults. They are rarer in pediatric population and their main manifestation is peripheral sexual precocity. In women genital bleeding, uterus hypertrophy, high blood pressure and/or abdomen mass may be the only manifestations. On the biological point, estrogen overproduction with or without increase in other adrenal hormones are the main abnormalities. Radiological examination usually shows the tumor, describes its limits and its eventual metastases. Adrenal and endocrine origins are confirmed by biochemical assessments and histology, but that one is unable to distinguish between benign and malignant tumors, except if metastases are already present. Immunostaining using anti-aromatase antibodies is the only tool that distinguishes FAT from other adrenocortical tumors. Abdominal surgery is the best and the first line treatment. For large tumors (≥10 cm), an open access is preferred to coeliosurgery, but for the small ones, or when the surgeon is experienced, endoscopic surgery seems to give excellent results. Surgery can be preceded by adrenolytic agents such as ortho paraprime dichloro diphenyl dichloroethane (Mitotane), ketoconazole or by aromatase inhibitors, but till now there is not any controlled study to compare the benefit of different drugs. New anti-estrogens can be used too, but their results need to be confirmed in malignant tumors resistant to classical chemotherapy and to conventional radiotherapy. Targeted therapy can be used too, as in other adrenocortical tumors, but the results need to be confirmed. PMID:25932386

  1. Mouse Models Recapitulating Human Adrenocortical Tumors: What Is Lacking?

    PubMed Central

    Leccia, Felicia; Batisse-Lignier, Marie; Sahut-Barnola, Isabelle; Val, Pierre; Lefrançois-Martinez, A-Marie; Martinez, Antoine

    2016-01-01

    Adrenal cortex tumors are divided into benign forms, such as primary hyperplasias and adrenocortical adenomas (ACAs), and malignant forms or adrenocortical carcinomas (ACCs). Primary hyperplasias are rare causes of adrenocorticotropin hormone-independent hypercortisolism. ACAs are the most common type of adrenal gland tumors and they are rarely “functional,” i.e., producing steroids. When functional, adenomas result in endocrine disorders, such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (hyperaldosteronism). By contrast, ACCs are extremely rare but highly aggressive tumors that may also lead to hypersecreting syndromes. Genetic analyses of patients with sporadic or familial forms of adrenocortical tumors (ACTs) led to the identification of potentially causative genes, most of them being involved in protein kinase A (PKA), Wnt/β-catenin, and P53 signaling pathways. Development of mouse models is a crucial step to firmly establish the functional significance of candidate genes, to dissect mechanisms leading to tumors and endocrine disorders, and in fine to provide in vivo tools for therapeutic screens. In this article, we will provide an overview on the existing mouse models (xenografted and genetically engineered) of ACTs by focusing on the role of PKA and Wnt/β-catenin pathways in this context. We will discuss the advantages and limitations of models that have been developed heretofore and we will point out necessary improvements in the development of next generation mouse models of adrenal diseases. PMID:27471492

  2. Pubertal outcome in a female with virilizing adrenocortical carcinoma

    PubMed Central

    Breidbart, Emily; Cameo, Tamara; Garvin, James H.; Hibshoosh, Hanina

    2016-01-01

    Adrenocortical tumors are neoplasms that rarely occur in pediatric patients. Adrenocortical carcinoma (ACC) is even more uncommon, and is an aggressive malignancy with 5-year survival of 55% in a registry series. There is a lack of information on long-term endocrine outcome in survivors. We describe a 10-year follow-up in a patient who presented at 3 years 5 months with a 1-year history of axillary odor and 6 months’ history of pubic hair development with an increased clitoral size. Androgen levels were increased and a pelvic sonogram revealed a suprarenal mass of the left kidney. The tumor was successfully removed. At 6 years 11 months, androgen levels increased again. Workup for tumor recurrence was negative and the findings likely represented early adrenarche. The patient had menarche at an appropriate time and attained a height appropriate for her family. PMID:26812773

  3. Occult Adrenocortical Carcinoma and Unexpected Early Childhood Death.

    PubMed

    Pilla, Mark; Gilbert, John; Moore, Lynette; Byard, Roger W

    2017-01-01

    A four-year-old previously well boy collapsed unexpectedly and was taken immediately to hospital, where he developed seizures and cardiogenic shock with lethal, rapidly progressing multi-organ failure. At autopsy, the height was >90th percentile and there were indications of early virilization. Internally, a friable tumor of the left adrenal gland was identified that had invaded the left renal vein and inferior vena cava. Histology revealed typical features of an adrenocortical carcinoma with aggregated trabeculae of cells containing abundant eosinophilic cytoplasm and large pleomorphic nuclei. There was strong positive cytoplasmic staining for inhibin; mitochondria were shown on electron microscopy to contain prominent electron-dense granules. Death was due to massive pulmonary tumor embolism. Although adrenocortical carcinomas are very rare and are more commonly found in adults, the current case demonstrates that they may also occur in childhood and be responsible for unexpected death by the very unusual mechanism of tumor embolism.

  4. TCGA analysis of adrenocortical carcinoma - TCGA

    Cancer.gov

    In the most comprehensive molecular characterization to date of adrenocortical carcinoma, a rare cancer of the adrenal cortex, researchers extensively analyzed 91 cases for alterations in the tumor genomes.

  5. Retroperitoneoscopic partial adrenalectomy for large adrenocortical oncocytoma.

    PubMed

    Modi, Pranjal; Goel, Rajiv; Kadam, Gaurang

    2007-04-01

    A young woman had mild hypertension, and on evaluation, a large tumor arising from the right adrenal gland was found. The tumor was hormonally inactive. Retroperitoneoscopic partial adrenalectomy was carried out. The histopathology report described adrenocortical oncocytoma.

  6. Effects of ToxCast Phase I Chemicals on Steroidogenesis in H295R Human Adrenocortical Carcinoma cells (SOT)

    EPA Science Inventory

    Steroid hormones are essential for proper development and reproduction. Disruption of steroidogenesis by environmental toxicants results in altered hormone levels causing adverse reproductive and developmental effects. H295R human adrenocortical carcinoma cells were used to evalu...

  7. Role of intramitochondrial arachidonic acid and acyl-CoA synthetase 4 in angiotensin II-regulated aldosterone synthesis in NCI-H295R adrenocortical cell line.

    PubMed

    Mele, Pablo G; Duarte, Alejandra; Paz, Cristina; Capponi, Alessandro; Podestá, Ernesto J

    2012-07-01

    Although the role of arachidonic acid (AA) in angiotensin II (ANG II)- and potassium-stimulated steroid production in zona glomerulosa cells is well documented, the mechanism responsible for AA release is not fully described. In this study we evaluated the mechanism involved in the release of intramitochondrial AA and its role in the regulation of aldosterone synthesis by ANG II in glomerulosa cells. We show that ANG II and potassium induce the expression of acyl-coenzyme A (CoA) thioesterase 2 and acyl-CoA synthetase 4, two enzymes involved in intramitochondrial AA generation/export system well characterized in other steroidogenic systems. We demonstrate that mitochondrial ATP is required for AA generation/export system, steroid production, and steroidogenic acute regulatory protein induction. We also demonstrate the role of protein tyrosine phosphatases regulating acyl-CoA synthetase 4 and steroidogenic acute regulatory protein induction, and hence ANG II-stimulated aldosterone synthesis.

  8. Genetics and epigenetics of adrenocortical tumors.

    PubMed

    Lerario, Antonio M; Moraitis, Andreas; Hammer, Gary D

    2014-04-05

    Adrenocortical tumors are common neoplasms. Most are benign, nonfunctional and clinically irrelevant. However, adrenocortical carcinoma is a rare disease with a dismal prognosis and no effective treatment apart from surgical resection. The molecular genetics of adrenocortical tumors remain poorly understood. For decades, molecular studies relied on a small number of samples and were directed to candidate-genes. This approach, based on the elucidation of the genetics of rare genetic syndromes in which adrenocortical tumors are a manifestation, has led to the discovery of major dysfunctional molecular pathways in adrenocortical tumors, such as the IGF pathway, the Wnt pathway and TP53. However, with the advent of high-throughput methodologies and the organization of international consortiums to obtain a larger number of samples and high-quality clinical data, this paradigm is rapidly changing. In the last decade, genome-wide expression profile studies, microRNA profiling and methylation profiling allowed the identification of subgroups of tumors with distinct genetic markers, molecular pathways activation patterns and clinical behavior. As a consequence, molecular classification of tumors has proven to be superior to traditional histological and clinical methods in prognosis prediction. In addition, this knowledge has also allowed the proposal of molecular-targeted approaches to provide better treatment options for advanced disease. This review aims to summarize the most relevant data on the rapidly evolving field of genetics of adrenal disorders.

  9. Interparental Aggression and Adolescent Adjustment: The Role of Emotional Insecurity and Adrenocortical Activity.

    PubMed

    Bergman, Kathleen N; Cummings, E Mark; Davies, Patrick T

    2014-10-01

    Adolescents exposed to interparental aggression are at increased risk for developing adjustment problems. The present study explored intervening variables in these pathways in a community sample that included 266 adolescents between 12 and 16 years old (M = 13.82; 52.5% boys, 47.5% girls). A moderated mediation model examined the moderating role of adrenocortical reactivity on the meditational capacity of their emotional insecurity in this context. Information from multiple reporters and adolescents' adrenocortical response to conflict were obtained during laboratory sessions attended by mothers, fathers and their adolescent child. A direct relationship was found between marital aggression and adolescents' internalizing behavior problems. Adolescents' emotional insecurity mediated the relationship between marital aggression and adolescents' depression and anxiety. Adrenocortical reactivity moderated the pathway between emotional insecurity and adolescent adjustment. The implications for further understanding the psychological and physiological effects of adolescents' exposure to interparental aggression and violence are discussed.

  10. Glucocorticoid control of steroidogenesis in isolated rat adrenocortical cells.

    PubMed

    Carsia, R V; Malamed, S

    1983-08-17

    The role of end-product glucocorticoids in the regulation of corticosteroidogenesis in isolated adrenocortical cells was investigated. Trypsin-isolated cells from male rat adrenal glands were incubated with or without corticotropin (ACTH) and with or without corticosterone. Endogenous corticosterone production was determined by radioimmunoassay at the end of incubation. Cessation of ACTH-induced corticosterone production was apparent after 2-4 h of incubation. The suppression occurred later with lower cell concentrations. Corticosterone production was partially restored after washing the suppressed cells. Supernatant fluid from suppressed cell suspensions also suppressed steroidogenesis of a fresh population of cells. However, the suppressing property of the supernatant fluid was abolished after the removal of corticosterone by charcoal-dextran treatment, suggesting that corticosterone or other steroids caused the suppression. Exogenous corticosterone induced suppression over a wide range of ACTH concentrations, but did not change the half-maximal steroidogenic concentration of ACTH, indicating that the suppression does not change the sensitivity of the cells to ACTH. Suppression occurred within 30-60 min after corticosterone had been added to the incubation medium either at the start of incubation or while steroidogenesis was in progress. Suppression varied directly with the concentration of exogenous corticosterone. These data indicate that glucocorticoids can directly and acutely suppress corticosteroidogenesis and thus control adrenocortical function in concert with other regulators such as ACTH and Ca2+.

  11. Pubertal development and regulation

    PubMed Central

    Abreu, Ana Paula; Kaiser, Ursula B

    2016-01-01

    Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation. The mechanisms underlying this reactivation are not completely known. The age of puberty onset varies between individuals and the timing of puberty initiation is associated with several health outcomes in adult life. In this Series paper, we discuss pubertal markers, epidemiological trends of puberty initiation over time, and the mechanisms whereby genetic, metabolic, and other factors control secretion of gonadotropin-releasing hormone to determine initiation of puberty. PMID:26852256

  12. Pubertal development and regulation.

    PubMed

    Abreu, Ana Paula; Kaiser, Ursula B

    2016-03-01

    Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation. The mechanisms underlying this reactivation are not completely known. The age of puberty onset varies between individuals and the timing of puberty initiation is associated with several health outcomes in adult life. In this Series paper, we discuss pubertal markers, epidemiological trends of puberty initiation over time, and the mechanisms whereby genetic, metabolic, and other factors control secretion of gonadotropin-releasing hormone to determine initiation of puberty.

  13. 5th International ACC Symposium: Classification of Adrenocortical Cancers from Pathology to Integrated Genomics: Real Advances or Lost in Translation?

    PubMed

    de Krijger, Ronald E; Bertherat, Jérôme

    2016-02-01

    For the clinician, despite its rarity, adrenocortical cancer is a heterogeneous tumor both in term of steroid excess and tumor evolution. For patient management, it is crucial to have an accurate vision of this heterogeneity, in order to use a correct tumor classification. Pathology is the best way to classify operated adrenocortical tumors: to recognize their adrenocortical nature and to differentiate benign from malignant tumors. Among malignant tumors pathology also aims at prognosis assessment. Although progress has being made for prognosis assessment, there is still a need for improvement. Recent studies have established the value of Ki67 for adrenocortical cancer (ACC) prognostication, aiming also at standardization to reduce variability. The use of genomics to study adrenocortical tumors gives a very new insight in their pathogenesis and molecular classification. Genomics studies of ACC give now a clear description of the mRNA (transcriptome) and miRNA expression profile, as well as chromosomal and methylation alterations. Exome sequencing also established firmly the list of the main ACC driver genes. Interestingly, genomics study of ACC also revealed subtypes of malignant tumors with different pattern of molecular alterations, associated with different outcome. This leads to a new vision of adrenocortical tumors classification based on molecular analysis. Interestingly, these molecular classifications meet also the results of pathological analysis. This opens new perspectives on the development and use of various molecular tools to classify, along with pathological analysis, ACC, and guides patient management at the area of precision medicine.

  14. The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease.

    PubMed

    Hellesen, A; Edvardsen, K; Breivik, L; Husebye, E S; Bratland, E

    2014-06-01

    Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD.

  15. Evening Activities as a Potential Confound in Research on the Adrenocortical System in Children

    ERIC Educational Resources Information Center

    Kertes, Darlene A.; Gunnar, Megan R.

    2004-01-01

    The relation among children's evening activities, behavioral characteristics, and activity of the hypothalamic-pituitary-adrenocortical axis was assessed in normally developing children ages 7 to 10 years. Salivary cortisol at bedtime was compared on evenings when children had structured activities outside of the home with unstructured evenings at…

  16. Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer

    PubMed Central

    Legendre, Christophe R.; Demeure, Michael J.; Whitsett, Timothy G.; Gooden, Gerald C.; Bussey, Kimberly J.; Jung, Sungwon; Waibhav, Tembe; Kim, Seungchan; Salhia, Bodour

    2016-01-01

    Context Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options. Objective Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC. Design In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors. Results This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC. Conclusions DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors. PMID:26963385

  17. Cytochrome b5 Expression in Gonadectomy-induced Adrenocortical Neoplasms of the Domestic Ferret (Mustela putorius furo)

    PubMed Central

    Wagner, S.; Kiupel, M.; Peterson, R.A.; Heikinheimo, M.; Wilson, D.B.

    2008-01-01

    Whereas the adrenal glands of healthy ferrets produce only limited amounts of androgenic steroids, adrenocortical neoplasms that arise in neutered ferrets typically secrete androgens or their derivative, estrogen. The 17,20-lyase activity of cytochrome P450 17α-hydroxylase/17,20-lyase (P450c17) must increase to permit androgen biosynthesis in neoplastic adrenal tissue. We screened ferret adrenocortical tumor specimens for expression of cytochrome b5 (cyt b5), an allosteric regulator that selectively enhances the 17,20-lyase activity of P450c17. Cyt b5 immunoreactivity was evident in 24 of 25 (96 %) adrenocortical adenomas/carcinomas from ferrets with signs of ectopic sex steroid production. Normal adrenocortical cells lacked cyt b5, which may account for the low production of adrenal androgens in healthy ferrets. Other markers characteristic of gonadal somatic cells, such as luteinizing hormone receptor, aromatase, and GATA4, were co-expressed with cyt b5 in some of the tumors. We conclude that cyt b5 is upregulated during gonadectomy-induced adrenocortical neoplasia and is a marker of androgen synthetic potential in these tumors. PMID:18587089

  18. Novel markers of gonadectomy-induced adrenocortical neoplasia in the mouse and ferret

    PubMed Central

    Schillebeeckx, Maximiliaan; Pihlajoki, Marjut; Gretzinger, Elisabeth; Yang, Wei; Thol, Franziska; Hiller, Theresa; Löbs, Ann-Kathrin; Röhrig, Theresa; Schrade, Anja; Cochran, Rebecca; Jay, Patrick Y.; Heikinheimo, Markku; Mitra, Robi D.; Wilson, David B.

    2014-01-01

    Gonadectomy (GDX) induces sex steroid-producing adrenocortical tumors in certain mouse strains and in the domestic ferret. Transcriptome analysis and DNA methylation mapping were used to identify novel genetic and epigenetic markers of GDX-induced adrenocortical neoplasia in female DBA/2J mice. Markers were validated using a combination of laser capture microdissection, quantitative RT-PCR, in situ hybridization, and immunohistochemistry. Microarray expression profiling of whole adrenal mRNA from ovariectomized vs. intact mice demonstrated selective upregulation of gonadal-like genes including Spinlw1 and Insl3 in GDX-induced adrenocortical tumors of the mouse. A complementary candidate gene approach identified Foxl2 as another gonadal-like marker expressed in GDX-induced neoplasms of the mouse and ferret. That both “male-specific” (Spinlw1) and “female-specific” (Foxl2) markers were identified is noteworthy and implies that the neoplasms exhibit mixed characteristics of male and female gonadal somatic cells. Genome-wide methylation analysis showed that two genes with hypomethylated promoters, Igfbp6 and Foxs1, are upregulated in GDX-induced adrenocortical neoplasms. These new genetic and epigenetic markers may prove useful for studies of steroidogenic cell development and for diagnostic testing. PMID:25289806

  19. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  20. Epigenetic regulation of muscle development.

    PubMed

    Barreiro, Esther; Tajbakhsh, Shahragim

    2017-03-28

    In eukaryote cells, chromatin appears in several forms and is composed of genomic DNA, protein and RNA. The protein content of chromatin is composed primarily of core histones that are packaged into nucleosomes resulting in the condensation of the DNA. Several epigenetic mechanisms regulate the stability of the nucleosomes and the protein-protein interactions that modify the transcriptional activity of the DNA. Interestingly, epigenetic control of gene expression has recently emerged as a relevant mechanism involved in the regulation of many different biological processes including that of muscle development, muscle mass maintenance, function, and phenotype in health and disease. Recent investigations have shed light into the epigenetic control of biological mechanisms that are key regulators of embryonic muscle development and postnatal myogenesis. In the present review article, we provide a summary of the contents discussed in session 08, titled "Epigenetics of muscle regeneration", during the course of the 45th European Muscle Conference, which was celebrated in Montpellier (France) in September 2016. The main theme of that session was to highlight the most recent progress on the role of epigenetics in the regulation of muscle development and regeneration. The current mini-review has been divided into two major sections. On the one hand, a brief introduction on the topic of myogenesis is offered for the non-specialized reader. On the other, a brief overview of the most relevant epigenetic players that have been shown to control muscle development and regeneration is given.

  1. Cerebellin and des-cerebellin exert ACTH-like effects on corticosterone secretion and the intracellular signaling pathway gene expression in cultured rat adrenocortical cells--DNA microarray and QPCR studies.

    PubMed

    Rucinski, Marcin; Ziolkowska, Agnieszka; Szyszka, Marta; Malendowicz, Ludwik K

    2009-04-01

    Precerebellins (Cbln) belong to the C1q/TNF superfamily of secreted proteins which have diverse functions. They are abundantly expressed in the cerebellum, however, three of them are also expressed in the rat adrenal gland. All members of the Cbln family form homomeric and heteromeric complexes with each other in vitro and it was suggested that such complexes play a crucial role in normal development of the cerebellum. The aim of our study was to investigate whether Cbln1-derived peptides, cerebellin (CER) and des-Ser1-cerebellin (desCER) are involved in regulating biological functions of rat adrenocortical cells. In the primary culture of rat adrenocortical cells, 24 h exposure to CER or desCER notably stimulated corticosterone output and inhibited proliferative activity and similar effects were evoked by ACTH. To study gene transcript regulation by CER, desCER and ACTH, we applied Oligo GEArray DNA Microarray: Rat Signal Transduction Pathway Finder. In relation to the control culture, 13 of the 113 transcripts present on the array were differentially expressed. These transcripts were either up- or down-regulated by ACTH and/or CER or desCER treatment. Validation of DNA Microarray data by QPCR revealed that only 5 of 13 genes studied were differentially expressed. Of those genes, Fos and Icam1 were up-regulated and Egr1 was down-regulated by ACTH, CER and desCER. The remaining two genes, Fasn (insulin signaling pathway) and Hspb1 (HSP27) (stress signaling pathway), were regulated only by CER and desCER, but not by ACTH. Thus, both CER and desCER have effects similar to and different from corticotrophin on the intracellular signaling pathway gene expression in cultured rat adrenocortical cells.

  2. A case of pediatric virilizing adrenocortical tumor resulting in hypothalamic-pituitary activation and central precocious puberty following surgical removal.

    PubMed

    Miyoshi, Yoko; Oue, Takaharu; Oowari, Mitsugu; Soh, Hideki; Tachibana, Makiko; Kimura, Sadami; Kiyohara, Yuki; Yamada, Hiroyuki; Bessyo, Kazuhiko; Mushiake, Sotaro; Homma, Keiko; Hasegawa, Tomonobu; Sasano, Hironobu; Ozono, Keiichi

    2009-01-01

    We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.

  3. Redox Regulation of Plant Development

    PubMed Central

    Considine, Michael J.

    2014-01-01

    Abstract Significance: We provide a conceptual framework for the interactions between the cellular redox signaling hub and the phytohormone signaling network that controls plant growth and development to maximize plant productivity under stress-free situations, while limiting growth and altering development on exposure to stress. Recent Advances: Enhanced cellular oxidation plays a key role in the regulation of plant growth and stress responses. Oxidative signals or cycles of oxidation and reduction are crucial for the alleviation of dormancy and quiescence, activating the cell cycle and triggering genetic and epigenetic control that underpin growth and differentiation responses to changing environmental conditions. Critical Issues: The redox signaling hub interfaces directly with the phytohormone network in the synergistic control of growth and its modulation in response to environmental stress, but a few components have been identified. Accumulating evidence points to a complex interplay of phytohormone and redox controls that operate at multiple levels. For simplicity, we focus here on redox-dependent processes that control root growth and development and bud burst. Future Directions: The multiple roles of reactive oxygen species in the control of plant growth and development have been identified, but increasing emphasis should now be placed on the functions of redox-regulated proteins, along with the central roles of reductants such as NAD(P)H, thioredoxins, glutathione, glutaredoxins, peroxiredoxins, ascorbate, and reduced ferredoxin in the regulation of the genetic and epigenetic factors that modulate the growth and vigor of crop plants, particularly within an agricultural context. Antioxid. Redox Signal. 21, 1305–1326. PMID:24180689

  4. Laparoscopic Adrenalectomy for Large Adrenocortical Carcinoma

    PubMed Central

    al Qadhi, Hani; al Wahaibi, Khalifa; Rizvi, Syed G.

    2015-01-01

    Background: Adrenocortical cancer (ACC) is a rare disease that is difficult to treat. Laparoscopic adrenalectomy (LA) is performed, even for large adrenocortical carcinomas. However, the oncological effectiveness of LA remains unclear. This review presents the current knowledge of the feasibility and oncological effectiveness of laparoscopic surgery for ACC, with an analysis of data for outcomes and other parameters. Database: A systematic review of the literature was performed by searching the PubMed and Medline databases for all relevant articles in English, published between January 1992 and August 2014 on LA for adrenocortical carcinoma. Discussion: The search resulted in retrieval of 29 studies, of which 10 addressed the outcome of LA versus open adrenalectomy (OA) and included 844 patients eligible for this review. Among these, 206 patients had undergone LA approaches, and 638 patients had undergone OA. Among the 10 studies that compared the outcomes obtained with LA and OA for ACC, 5 noted no statistically significant difference between the 2 groups in the oncological outcomes of recurrence and disease-free survival, whereas the remaining 5 reported inferior outcomes in the LA group. Using a paired t test for statistical analysis, except for tumor size, we found no significant difference in local recurrence, peritoneal carcinomatosis, positive resection margin, and time to recurrence between the LA and OA groups. The overall mean tumor size in patients undergoing LA and OA was 7.1 and 11.2 cm, respectively (P = .0003), and the mean overall recurrence was 61.5 and 57.9%, respectively. The outcome of LA is believed to depend to a large extent on the size and stage of the lesion (I and II being favorable) and the surgical expertise in the center where the patient undergoes the operation. However, the present review shows no difference in the outcome between the 2 approaches across all stages. A poor outcome is likely to result from inadequate surgery

  5. Virilizing Adrenocortical Carcinoma Advancing to Central Precocious Puberty after Surgery

    PubMed Central

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han

    2015-01-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery. PMID:26019766

  6. Virilizing adrenocortical carcinoma advancing to central precocious puberty after surgery.

    PubMed

    Kim, Min Sun; Yang, Eu Jeen; Cho, Dong Hyu; Hwang, Pyung Han; Lee, Dae-Yeol

    2015-05-01

    Adrenocortical carcinoma (ACC) in pediatric and adolescent patients is rare, and it is associated with various clinical symptoms. We introduce the case of an 8-year-old boy with ACC who presented with peripheral precocious puberty at his first visit. He displayed penis enlargement with pubic hair and facial acne. His serum adrenal androgen levels were elevated, and abdominal computed tomography revealed a right suprarenal mass. After complete surgical resection, the histological diagnosis was ACC. Two months after surgical removal of the mass, he subsequently developed central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist to delay further pubertal progression. In patients with functioning ACC and surgical removal, clinical follow-up and hormonal marker examination for the secondary effects of excessive hormone secretion may be a useful option at least every 2 or 3 months after surgery.

  7. Current and Emerging Therapeutic Options in Adrenocortical Cancer Treatment

    PubMed Central

    Stigliano, Antonio; Cerquetti, Lidia; Sampaoli, Camilla; Bucci, Barbara; Toscano, Vincenzo

    2012-01-01

    Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia. PMID:22934112

  8. Regulation Development for Drinking Water Contaminants

    EPA Pesticide Factsheets

    To explain what process and information underlies regulations including how the Safe Drinking Water Act applies to regulation development i.e. how does the drinking water law translate into regulations.

  9. Regulated proteolysis in bacterial development

    PubMed Central

    Konovalova, Anna; Søgaard-Andersen, Lotte; Kroos, Lee

    2013-01-01

    Bacteria use proteases to control three types of events temporally and spatially during processes of morphological development. These events are destruction of regulatory proteins, activation of regulatory proteins, and production of signals. While some of these events are entirely cytoplasmic, others involve intramembrane proteolysis of a substrate, trans-membrane signaling, or secretion. In some cases, multiple proteolytic events are organized into pathways, e.g., turnover of a regulatory protein activates a protease that generates a signal. We review well-studied and emerging examples, and identify recurring themes and important questions for future research. We focus primarily on paradigms learned from studies of model organisms, but we note connections to regulated proteolytic events that govern bacterial adaptation, biofilm formation and disassembly, and pathogenesis. PMID:24354618

  10. Modulation of the adrenocortical response to acute stress with respect to brood value, reproductive success and survival in the Eurasian hoopoe.

    PubMed

    Schmid, Baptiste; Tam-Dafond, Laura; Jenni-Eiermann, Susanne; Arlettaz, Raphaël; Schaub, Michael; Jenni, Lukas

    2013-09-01

    Reproducing parents face the difficult challenge of trading-off investment in current reproduction against presumed future survival and reproduction. Glucocorticoids are supposed to mediate this trade-off because the adrenocortical response to stress disrupts normal reproductive behaviour in favour of self-maintenance and own survival. According to the brood-value hypothesis, individuals with a low survival probability until the next reproductive season have to invest in current reproduction, a process driven by a down-regulation of their adrenocortical response. If the adrenocortical response to stress effectively mediates the trade-off between current reproduction versus future survival and reproduction, we expect a negative relationship with reproductive success and a positive correlation of the adrenocortical stress response with survival. We studied the relationship between corticosterone secretion in parents and their current brood value, reproductive success and survival in a short-lived multi-brooded bird, the Eurasian hoopoe Upupa epops. The adrenocortical response to acute handling stress was correlated with the brood value within the individual (first and second broods of the year) and between individuals. Birds breeding late in the season mounted a lower total corticosterone response to acute stress than birds breeding earlier, while females showed lower levels than males. We observed a negative relationship between the adrenocortical stress response and rearing success or fledging success in females, as predicted by the brood-value hypothesis. However, we could not evidence a clear link between the adrenocortical stress response and survival. Future research testing the brood-value hypothesis and trade-offs between current reproduction and future survival should also measure free corticosterone and carefully differentiate between cross-sectional (i.e. between-individual) and individual-based experimental studies.

  11. The Social Buffering of the Hypothalamic-Pituitary-Adrenocortical Axis in Humans: Developmental and Experiential Determinants

    PubMed Central

    Gunnar, Megan R.; Hostinar, Camelia E.

    2015-01-01

    Social buffering, a subset of social support, is the process through which the availability of a conspecific reduces the activity of stress-mediating neurobiological systems. While its role in coping and resilience is significant, we know little about its developmental history in humans. This brief review presents an integrative developmental account of the social buffering of hypothalamic-pituitary-adrenocortical (HPA) stress reactivity in humans, from infancy to adulthood. During infancy, parents are powerful stress-regulators for children, but child temperament also plays a role and interacts with parenting quality to predict the magnitude of stress responses to fear or pain stimuli. Recent work indicates that parental support remains a potent stress buffer into late childhood, but that it loses its effectiveness as a buffer of the HPA axis by adolescence. Puberty may be the switch that alters the potency of parental buffering. In Beginning in middle childhood, friends may serve as stress buffers, particularly when other peers are the source of stress. By adulthood romantic partners assume this protective role, though studies often reveal sex differences that are currently not well understood. Translational research across species will be critical for developing a mechanistic understanding of social buffering and the processes involved in developmental changes noted in this review. PMID:26230646

  12. Aging of the rat adrenocortical cell: response to ACTH and cyclic AMP in vitro.

    PubMed

    Malamed, S; Carsia, R V

    1983-03-01

    To study intrinsic age-related changes in adrenocortical steroid production, cells isolated from rats of different ages (3 to 24 months) were used. Acute (2 hour) corticosterone production in response to stimulation by adrenocorticotrophic hormone (ACTH) and adenosine 3':5'-cyclic monophosphate (cAMP) was measured by radioimmunoassay. With age, adrenocortical cells lose much of their ability to produce corticosterone in the absence or presence of ACTH or cAMP. The loss is progressive from 6 to 24 months of age. Analysis of the data suggests that from 6 to 12 months, an intracellular steroidogenic lesion develops; in addition there may be a loss in ACTH receptors on the plasma membrane. After 12 months these defects increase and are accompanied by a decrease in receptor sensitivity to ACTH.

  13. Adrenocortical suppression in highland chick embryos is restored during incubation at sea level.

    PubMed

    Salinas, Carlos E; Villena, Mercedes; Blanco, Carlos E; Giussani, Dino A

    2011-01-01

    By combining the chick embryo model with incubation at high altitude, this study tested the hypothesis that development at high altitude is related to a fetal origin of adrenocortical but not adrenomedullary suppression and that hypoxia is the mechanism underlying the relationship. Fertilized eggs from sea-level or high altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at altitude with oxygen supplementation. At day 20 of incubation, embryonic blood was taken for measurement of plasma corticotropin, corticosterone, and Po(2). Following biometry, the adrenal glands were collected and frozen for measurement of catecholamine content. Development of chick embryos at high altitude led to pronounced adrenocortical blunting, but an increase in adrenal catecholamine content. These effects were similar whether the fertilized eggs were laid by sea-level or high altitude hens. The effects of high altitude on the stress axes were completely prevented by incubation at high altitude with oxygen supplementation. When chick embryos from high altitude hens were incubated at sea level, plasma hormones and adrenal catecholamine content were partially restored toward levels measured in sea-level chick embryos. There was a significant correlation between adrenocortical blunting and elevated adrenal catecholamine content with both asymmetric growth restriction and fetal hypoxia. The data support the hypothesis tested and provide evidence to isolate the direct contribution of developmental hypoxia to alterations in the stress system.

  14. Marked transient hypercholesterolemia caused by low-dose mitotane as adjuvant chemotherapy for adrenocortical carcinoma.

    PubMed

    Tada, Hayato; Nohara, Atsushi; Kawashiri, Masa-Aki; Inazu, Akihiro; Mabuchi, Hiroshi; Yamagishi, Masakazu

    2014-01-01

    We herein report a case of marked transient hypercholesterolemia in a man receiving low-dose mitotane as adjuvant chemotherapy for adrenocortical carcinoma.A 58-year-old man without any clinical symptoms or history of hypercholesterolemia was admitted to our hospital to treat an adrenocortical carcinoma detected on general screening using computed tomography. He reported no chest symptom and did not exhibit any established risk factors for coronary artery disease, such as diabetes, obesity, hypertension or relevant family history, with the exception of current smoking, on admission. A stress electrocardiogram showed negative findings. The left adrenal tumor as well as left kidney, spleen and distal portion of the pancreas were subsequently resected using radical surgery. The histopathological findings confirmed the preoperative diagnosis of adrenocortical carcinoma. After the operation, treatment with low-dose mitotane (1g/day) was introduced as adjuvant chemotherapy. Interestingly, the patient developed marked hyper-LDL cholesterolemia at a level equivalent to that of familial hypercholesterolemia (LDL cholesterol level ~ 300 mg/dL) following the introduction of mitotane, without evidence of primary or secondary hypercholesterolemia due to other causes. A coronary angiogram performed to assess the new-onset angina revealed three-vessel disease, which was later revascularized via percutaneous coronary intervention eight months after the start of mitotane therapy. The cholesterol level normalized with the suspension of mitotane. This case suggests that mitotane can cause severe hypercholesterolemia, potentially resulting in coronary atherosclerosis.

  15. Celecoxib reduces glucocorticoids in vitro and in a mouse model with adrenocortical hyperplasia

    PubMed Central

    Liu, Sisi; Saloustros, Emmanouil; Berthon, Annabel; Starost, Matthew F.; Sahut-Barnola, Isabelle; Salpea, Paraskevi; Szarek, Eva; Faucz, Fabio R.; Martinez, Antoine; Stratakis, Constantine A.

    2015-01-01

    Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to adrenocorticotropin hormone (ACTH) - independent Cushing’s syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP–dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with Celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1,500 mg/kg Celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, Celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, Celecoxib caused histological changes that reversed, at least in part, BAH and this was associated with a reduction of corticosterone levels. PMID:26438728

  16. The challenge of developmental therapeutics for adrenocortical carcinoma

    PubMed Central

    Costa, Ricardo; Carneiro, Benedito A.; Tavora, Fabio; Pai, Sachin G.; Kaplan, Jason B.; Chae, Young Kwang; Chandra, Sunandana; Kopp, Peter A.; Giles, Francis J.

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare disease with an estimated incidence of only 0.7 new cases per million per year. Approximately 30-70% of the patients present with advanced disease with very poor prognosis and without effective therapeutic options. In the recent years, unprecedented progresses in cancer biology and genomics have fostered the development of numerous targeted therapies for various malignancies. Immunotherapy has also transformed the treatment landscape of malignancies such as melanoma, among others. However, these advances have not brought meaningful benefits for patients with ACC. Extensive genomic analyses of ACC have revealed numerous signal transduction pathway aberrations (e.g., insulin growth factor receptor and Wnt/β-catenin pathways) that play a central role in pathophysiology. These molecular alterations have been explored as potential therapeutic targets for drug development. This manuscript summarizes recent discoveries in ACC biology, reviews the results of early clinical studies with targeted therapies, and provides the rationale for emerging treatment strategies such as immunotherapy. PMID:27102148

  17. Strigolactones are regulators of root development.

    PubMed

    Koltai, Hinanit

    2011-05-01

    Strigolactones (SLs) have been defined as a new group of plant hormones or their derivatives that suppress lateral shoot branching. Recently, a new role for SLs was discovered, in the regulation of root development. Strigolactones were shown to alter root architecture and affect root-hair elongation. Here, I review the recent findings regarding the effects of SLs on root growth and development, and their association with changes in auxin flux. The networking between SLs and other plant hormones that regulate root development is also presented. Strigolactone regulation of plant development suggests that they are coordinators of shoot and root development and mediators of plant responses to environmental conditions.

  18. Mitotane treatment for adrenocortical carcinoma: an overview.

    PubMed

    De Francia, S; Ardito, A; Daffara, F; Zaggia, B; Germano, A; Berruti, A; Di Carlo, F

    2012-03-01

    Adrenocortical carcinoma (ACC) is a rare aggressive endocrine neoplasm characterized by a 5-year survival of less than 50%. Due to the widespread use of imaging techniques in clinics, ACC is increasingly recognized as an incidentally discovered tumor. Mostly characterized by poor prognosis, ACC is often diagnosed at an advanced stage of disease. Early diagnosis is uncommon; when diagnosed, ACCs are usually large and have invaded adjacent organs, even if metastatic spread to distant sites can be absent. Complete surgical resection is the only potentially curative treatment for patients with localized disease; however, due to a recurrence rate of 50-70% after apparent radical surgery, there is a strong rationale for a concomitant systemic treatment. Adrenolytic therapy with mitotane (o,p›-DDD), administered alone or in combination with others antineoplastic agents, is the primary treatment for patients with advanced ACC and is increasingly used also in an adjuvant setting, even if controversy exists on this issue due to the limitations of the available literature. Despite being in use for many years, the rarity of ACC precluded the organization of randomized trials; thus, many areas of uncertainty and controversy remain regarding the role of this old drug in the clinical management of patients with ACC. The purpose of this paper is to review the current evidence on mitotane treatment in patients with advanced disease and in ACC patients after complete surgical resection as adjuvant treatment.

  19. Aging effects on oxidative phosphorylation in rat adrenocortical mitochondria.

    PubMed

    Solinas, Paola; Fujioka, Hisashi; Radivoyevitch, Tomas; Tandler, Bernard; Hoppel, Charles L

    2014-06-01

    Does aging in itself lead to alteration in adrenocortical mitochondrial oxidative phosphorylation? Mitochondria from Fischer 344 (F344) rats (6 and 24 months old), Brown Norway rats (6 and 32 months old) and F344-Brown Norway hybrid rats (6 and 30 months old) were compared. Mitochondria were isolated from extirpated adrenal cortex. The yields of mitochondria were quantitatively similar in all rat strains irrespective of age. In order to assess the activity of each mitochondrial complex, several different substrates were tested and the rate of oxidative phosphorylation measured. Aging does not affect mitochondrial activity except in the F344 rat adrenal cortex where the maximal ADP-stimulated oxidative phosphorylation decreased with age. We hypothesize that impaired synthesis of steroid hormones by the adrenal cortex with age in F344 rats might be due to decreased adrenocortical mitochondrial oxidative phosphorylation. We conclude that aging results in adrenocortical mitochondria effects that are non-uniform across different rat strains.

  20. Brain Metastasis in Patients With Adrenocortical Carcinoma: A Clinical Series

    PubMed Central

    Tageja, Nishant; Rosenberg, Avi; Mahalingam, Sowmya; Quezado, Martha; Velarde, Margarita; Edgerly, Maureen; Fojo, Tito

    2015-01-01

    Introduction: Adrenocortical carcinoma (ACC) is a heterogeneous and rare disease. At presentation or at the time of a recurrence, the disease commonly spreads to the liver, lungs, lymph nodes, and bones. The brain has only rarely been reported as a site of metastases. Objective: The aims of this report were to describe the clinical characteristics of patients with ACC who developed brain metastasis and were evaluated at the National Cancer Institute. Methods: We describe the history and clinical presentation of six patients with ACC and metastatic disease in the brain. Images of the six patients and pathology slides were reviewed when available. Results: The median age at the time of the diagnosis of ACC was 42 years. The median time from the initial diagnosis until the presentation of brain metastasis was 43 months. As a group the patients had previously received multiples lines of chemotherapy (median of three), and they presented with one to three metastatic brain lesions. Four patients underwent metastasectomy, one had radiosurgery, and one had both modalities. Two patients are still alive, three died, between 2 and 14 months after the diagnosis of brain metastases, and one was lost to follow-up. Conclusion: Patients with advanced ACC can rarely present with metastasis to the brain, most often long after the initial diagnosis. Timely diagnosis of brain metastasis with appropriate intervention after discussion in a multidisciplinary meeting can improve the prognosis in this particular scenario. PMID:25412413

  1. Outcomes after resection of cortisol-secreting adrenocortical carcinoma

    PubMed Central

    Margonis, Georgios Antonios; Kim, Yuhree; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Glenn, Jason A.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Poultsides, George A.; Pawlik, Timothy M.

    2016-01-01

    BACKGROUND We sought to define the impact of cortisol-secreting status on outcomes after surgical resection of adrenocortical carcinoma (ACC). METHODS The U.S ACC group database was queried to identify patients who underwent ACC resection between 1993 and 2014. The short-term and long-term outcomes were assessed. RESULTS The incidence of all functional and cortisol-secreting tumors was 40.6% and 22.6%, respectively. On multivariable analysis, cortisol secretion remained associated with an increased risk of postoperative complications (odds ratio = 2.25, 95 % confidence interval = 1.04 to 4.88; P = .04). At a median follow-up of 17.6 months, 118 patients (50.4%) had developed a recurrence. On multivariable analysis, after adjusting for patient and disease-related factors cortisol secretion independently predicted shorter recurrence-free survival (Hazard ratio = 2.05, 95% confidence interval = 1.16 to 3.60; P = .01). CONCLUSIONS Cortisol secretion was associated with an increased risk of postoperative morbidity. Recurrence remains high among patients with ACC after surgery; cortisol secretion was independently associated with a shorter recurrence-free survival. Tailoring postoperative surveillance of ACC patients based on their cortisol secreting status may be important. PMID:26810939

  2. Familial Adrenocortical Carcinoma in Association With Lynch Syndrome

    PubMed Central

    Challis, Benjamin G.; Kandasamy, Narayanan; Powlson, Andrew S.; Koulouri, Olympia; Annamalai, Anand Kumar; Happerfield, Lisa; Marker, Alison J.; Arends, Mark J.; Nik-Zainal, Serena

    2016-01-01

    Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes. PMID:27144940

  3. How is Adrenocortical Cancer being Managed in the UK?

    PubMed Central

    Aspinall, Sebastian R; Imisairi, AH; Bliss, RD; Scott-Coombes, D; Harrison, BJ; Lennard, TWJ

    2009-01-01

    INTRODUCTION Adrenocortical carcinomas are rare. This case series is reported to give an overview of how adrenocortical carcinoma is currently managed in the UK. PATIENTS AND METHODS A retrospective review was made of case notes from patients with adrenocortical carcinomas presenting to the authors (TWJL, RDB, BJH, and DS-C) over the past 10 years in Newcastle, Sheffield and Cardiff. RESULTS Newcastle treated twelve, Sheffield eleven and Cardiff seven cases. The median follow-up was 25.5 months (range, 1–102 months). All tumours were greater than 5 cm in diameter. The majority presented with symptoms of hormone excess. Adrenalectomy was performed in 83% – this was radical in 30% and followed by excision of recurrence in 13%. Adjuvant mitotane was given in 64% of patients, in combination with cytotoxic chemotherapy in 20%. One-third of patients did not receive any adjuvant therapy. There was no significant difference in survival between the three centres. The majority of patients (57%) died during the period of follow-up of this study. The median survival was 37 months (range, 2–102 months). CONCLUSIONS The size of tumour, stage and mode of presentation, age and overall survival of patients in this study are comparable to published series of adrenocortical carcinomas from major endocrine surgical centres world-wide. Despite controversies about benefits, adjuvant mitotane was used in the majority of cases, whereas cytotoxic chemotherapy was only used in the minority. The exact role of adjuvant therapy in the management of adrenocortical carcinoma is not as well established as for other more common malignancies. Establishing a database for adrenocortical carcinomas in the UK would contribute to our understanding of the management of this disease. PMID:19558758

  4. Phenotypic checkpoints regulate neuronal development.

    PubMed

    Ben-Ari, Yehezkel; Spitzer, Nicholas C

    2010-11-01

    Nervous system development proceeds by sequential gene expression mediated by cascades of transcription factors in parallel with sequences of patterned network activity driven by receptors and ion channels. These sequences are cell type- and developmental stage-dependent and modulated by paracrine actions of substances released by neurons and glia. How and to what extent these sequences interact to enable neuronal network development is not understood. Recent evidence demonstrates that CNS development requires intermediate stages of differentiation providing functional feedback that influences gene expression. We suggest that embryonic neuronal functions constitute a series of phenotypic checkpoint signatures; neurons failing to express these functions are delayed or developmentally arrested. Such checkpoints are likely to be a general feature of neuronal development and constitute presymptomatic signatures of neurological disorders when they go awry.

  5. Chronic effects of mercuric chloride ingestion on rat adrenocortical function

    SciTech Connect

    Agrawal, R.; Chansouria, J.P.N. )

    1989-09-01

    Mercurial contamination of environment has increased. Mercury accumulates in various organs and adversely affects their functions. Some of the most prominent toxic effects of inorganic mercury compounds include neurotoxicity, hepatotoxicity and nephrotoxicity. Besides this, mercury has also been reported to affect various endocrine glands like pituitary, thyroid, gonadal and adrenal glands. There have been no reports on the toxic effects of chronic oral administration of varying doses of mercuric chloride on adrenocortical function in albino rats. The present work was undertaken to study the adrenocortical response to chronic oral administration of mercuric chloride of varying dose and duration in albino rats.

  6. Ephrin regulation of palate development

    PubMed Central

    Benson, M. Douglas; Serrano, Maria J.

    2012-01-01

    Studies of palate development are motivated by the all too common incidence of cleft palate, a birth defect that imposes a tremendous health burden and can leave lasting disfigurement. Although, mechanistic studies of palate growth and fusion have focused on growth factors such as Transforming Growth Factor ß-3 (Tgfß3), recent studies have revealed that the ephrin family of membrane bound ligands and their receptors, the Ephs, play central roles in palatal morphogenesis, growth, and fusion. In this mini-review, we will discuss the recent findings by our group and others on the functions of ephrins in palatal development. PMID:23055980

  7. Adrenocortical carcinoma (ACC): diagnosis, prognosis, and treatment

    PubMed Central

    Libé, Rossella

    2015-01-01

    Adrenocortical carticnoma (ACC) is a rare malignancy with an incidence of 0.7–2.0 cases/million habitants/year. The diagnosis of malignancy relies on careful investigations of clinical, biological, and imaging features before surgery and pathological examination after tumor removal. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC is initially diagnosed incidentally. After the diagnosis, in order to assess the ACC prognosis and establish an adequate basis for treatment decisions different tools are proposed. The stage classification proposed by the European Network for the Study of Adrenal Tumors (ENSAT) is recommended. Pathology reports define the Weiss score, the resection status and the proliferative index, including the mitotic count and the Ki67 index. As far as the treatment is concerned, in case of tumor limited to the adrenal gland, the complete resection of the tumor is the first option. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Recently, the First International Randomized (FIRM-ACT) Trial in metastatic ACC reported the association between mitotane and etoposide/doxorubicin/cisplatin (EDP) as the new standard in first line treatment of ACC. In last years, new targeted therapies, including the IGF-1 receptor inhibitors, have been investigated, but their efficacy remains limited. Thus, new treatment concepts are urgently needed. The ongoing “omic approaches” and next-generation sequencing will improve our understanding of the pathogenesis and hopefully will lead to better therapies. PMID:26191527

  8. 5th International ACC Symposium: Future and Current Therapeutic Trials in Adrenocortical Carcinoma.

    PubMed

    Hoff, Ana O; Berruti, Alfredo

    2016-02-01

    Adrenocortical carcinoma (ACC) is a rare and complex disease associated with a high mortality rate. Despite intensive translational and clinical research, prognosis remains poor. Over the past decade, a significant effort has been made to develop multinational, collaborative studies to better understand the pathogenesis and clinical features of this rare disease in attempt to improve the therapeutic strategies and patient outcome. The results of both standard and newer treatments are discussed in this review as well as the recent discovery of pathways involved in ACC pathogenesis that provide the rationale to introduce new molecular target therapies. Finally, remaining issues regarding how to improve available therapies in adjuvant setting are raised and addressed.

  9. Gene Regulation Networks for Modeling Drosophila Development

    NASA Technical Reports Server (NTRS)

    Mjolsness, E.

    1999-01-01

    This chapter will very briefly introduce and review some computational experiments in using trainable gene regulation network models to simulate and understand selected episodes in the development of the fruit fly, Drosophila Melanogaster.

  10. P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model.

    PubMed

    Batisse-Lignier, M; Sahut-Barnola, I; Tissier, F; Dumontet, T; Mathieu, M; Drelon, C; Pointud, J-C; Damon-Soubeyrand, C; Marceau, G; Kemeny, J-L; Bertherat, J; Tauveron, I; Val, P; Martinez, A; Lefrançois-Martinez, A-M

    2017-04-03

    Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/β-catenin signaling pathways as main contributors to the disease. However, isolated β-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/β-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.Oncogene advance online publication, 3 April 2017; doi:10.1038/onc.2017.54.

  11. Shale gas development: a smart regulation framework.

    PubMed

    Konschnik, Katherine E; Boling, Mark K

    2014-01-01

    Advances in directional drilling and hydraulic fracturing have sparked a natural gas boom from shale formations in the United States. Regulators face a rapidly changing industry comprised of hundreds of players, operating tens of thousands of wells across 30 states. They are often challenged to respond by budget cuts, a brain drain to industry, regulations designed for conventional gas developments, insufficient information, and deeply polarized debates about hydraulic fracturing and its regulation. As a result, shale gas governance remains a halting patchwork of rules, undermining opportunities to effectively characterize and mitigate development risk. The situation is dynamic, with research and incremental regulatory advances underway. Into this mix, we offer the CO/RE framework--characterization of risk, optimization of mitigation strategies, regulation, and enforcement--to design tailored governance strategies. We then apply CO/RE to three types of shale gas risks, to illustrate its potential utility to regulators.

  12. Different expression of protein kinase A (PKA) regulatory subunits in cortisol-secreting adrenocortical tumors: Relationship with cell proliferation

    SciTech Connect

    Mantovani, G.; Lania, A.G.; Bondioni, S.; Peverelli, E.; Pedroni, C.; Ferrero, S.; Pellegrini, C.; Vicentini, L.; Arnaldi, G.; Bosari, S.; Beck-Peccoz, P.; Spada, A.

    2008-01-01

    The four regulatory subunits (R1A, R1B, R2A, R2B) of protein kinase A (PKA) are differentially expressed in several cancer cell lines and exert distinct roles in growth control. Mutations of the R1A gene have been found in patients with Carney complex and in a minority of sporadic primary pigmented nodular adrenocortical disease (PPNAD). The aim of this study was to evaluate the expression of PKA regulatory subunits in non-PPNAD adrenocortical tumors causing ACTH-independent Cushing's syndrome and to test the impact of differential expression of these subunits on cell growth. Immunohistochemistry demonstrated a defective expression of R2B in all cortisol-secreting adenomas (n = 16) compared with the normal counterpart, while both R1A and R2A were expressed at high levels in the same tissues. Conversely, carcinomas (n = 5) showed high levels of all subunits. Sequencing of R1A and R2B genes revealed a wild type sequence in all tissues. The effect of R1/R2 ratio on proliferation was assessed in mouse adrenocortical Y-1 cells. The R2-selective cAMP analogue 8-Cl-cAMP dose-dependently inhibited Y-1 cell proliferation and induced apoptosis, while the R1-selective cAMP analogue 8-HA-cAMP stimulated cell proliferation. Finally, R2B gene silencing induced up-regulation of R1A protein, associated with an increase in cell proliferation. In conclusion, we propose that a high R1/R2 ratio favors the proliferation of well differentiated and hormone producing adrenocortical cells, while unbalanced expression of these subunits is not required for malignant transformation.

  13. Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors

    PubMed Central

    Longatto-Filho, Adhemar; Faria, André M.; Fragoso, Maria C. B. V.; Lovisolo, Silvana M.; Lerário, Antonio M.; Almeida, Madson Q.

    2015-01-01

    Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis. PMID:26587828

  14. Multi-column chromatography of urinary steriods and adrenocortical dysfunction.

    PubMed

    Sayegh, J F; Vestergaard, P

    1978-01-01

    The potential of the multi-column assay for urinary neutral steroids in work with samples from patients with adrenocortical pathology is demonstrated through analyses performed on urine samples from Cushing and congenital adrenal hyperplasia cases, after modification of the routine methodology to include the quantitation of additional steroids of particular importance for pathological samples.

  15. Stress, reproduction, and adrenocortical modulation in amphibians and reptiles.

    PubMed

    Moore, Ignacio T; Jessop, Tim S

    2003-01-01

    While the hypothalamo-pituitary-adrenocortical (HPA) response to stress appears to be conserved in vertebrates, the manner in which it is activated and its actions vary. We examine two trends in the stress biology literature that have been addressed in amphibian and reptilian species: (1). variable interactions among stress, corticosterone, and reproduction and (2). adrenocortical modulation. In the first topic we examine context-dependent interactions among stress, corticosterone, and reproduction. An increasing number of studies report positive associations between reproduction and corticosterone that contradict the generalization that stress inhibits reproduction. Moderately elevated levels of stress hormones appear to facilitate reproduction by mobilizing energy stores. In contrast, pronounced activation of the HPA axis and extremely elevated levels of stress hormones appear to inhibit reproduction. Much of these contrasting effects of stress and reproduction can be explained by expanding the Energetics-Hormone Vocalization Model, proposed for anuran calling behavior, to other taxa. In the second topic, a number of amphibians and reptiles modulate their HPA stress response. Adrenocortical modulation can occur at multiple levels and due to a variety of factors. However, we have little information as to the physiological basis for the variability. We suggest that several ecologically based ideas, such as variability in the length of the breeding season and lifetime reproductive opportunities, can be used to explain the utility of adrenocortical modulation in these taxa.

  16. Investigation of N-cadherin/β-catenin expression in adrenocortical tumors.

    PubMed

    Rubin, Beatrice; Regazzo, Daniela; Redaelli, Marco; Mucignat, Carla; Citton, Marilisa; Iacobone, Maurizio; Scaroni, Carla; Betterle, Corrado; Mantero, Franco; Fassina, Ambrogio; Pezzani, Raffaele; Boscaro, Marco

    2016-10-01

    β-catenin is a multifunctional protein; it is a key component of the Wnt signaling, and it plays a central role in cadherin-based adhesions. Cadherin loss promotes tumorigenesis by releasing membrane-bound β-catenin, hence stimulating Wnt signaling. Cadherins seem to be involved in tumor development, but these findings are limited in adrenocortical tumors (ACTs). The objective of this study was to evaluate alterations in key components of cadherin/catenin adhesion system and of Wnt pathway. This study included eight normal adrenal samples (NA) and 95 ACT: 24 adrenocortical carcinomas (ACCs) and 71 adrenocortical adenomas (ACAs). β-catenin mutations were evaluated by sequencing, and β-catenin and cadherin (E-cadherin and N-cadherin) expression was analyzed by quantitative reverse transcription PCR (qRT-PCR) and by immunohistochemistry (IHC). We identified 18 genetic alterations in β-catenin gene. qRT-PCR showed overexpression of β-catenin in 50 % of ACC (12/24) and in 48 % of ACA (21/44). IHC data were in accordance with qRT-PCR results: 47 % of ACC (7/15) and 33 % of ACA (11/33) showed increased cytoplasmic or nuclear β-catenin accumulation. N-cadherin downregulation has been found in 83 % of ACC (20/24) and in 59 % of ACA (26/44). Similar results were obtained by IHC: N-cadherin downregulation was observed in 100 % (15/15) of ACC and in 55 % (18/33) of ACA. β-catenin overexpression together with the aberrant expression of N-cadherin may play important role in ACT tumorigenesis. The study of differentially expressed genes (such as N-cadherin and β-catenin) may enhance our understanding of the biology of ACT and may contribute to the discovery of new diagnostic and prognostic tools.

  17. [Effect of fetal adrenal hormones on the reactivity of the hypothalamo-hypophyseal-adrenocortical system in the adult rat].

    PubMed

    Dygalo, N N; Naumenko, E V

    1984-01-01

    It was found in the experiments on adult males, descendants of the intact or adrenalectomized (prior to mating) female rats which were injected during the pregnancy with adrenaline, hydrocortisone or saline solution, that the reaction of their hypophysial-adrenocortical system to emotional stress or injection of noradrenaline into brain were inversely proportional to the content of corticosteroids, rather than of adrenaline, in the blood of their mothers during the pregnancy. On the other hand, the coupled changes of the levels of corticosteroids and adrenaline in the blood of pregnant mothers only was accompanied by the marked decrease in the sensitivity of brain cholinergic mechanisms in descendants. Hence, the changes of the levels of both adrenaline and corticosterids in the blood of pregnant females modify the reactivity of hypophysial-adrenocortical system of adult descendants, apparently, via the development of brain neurochemical mechanisms in the foetuses. But the role of these hormones is different.

  18. Adrenocortical cancer (ACC) - literature overview and own experience.

    PubMed

    Dworakowska, Dorota; Drabarek, Agata; Wenzel, Ingrid; Babińska, Anna; Świątkowska-Stodulska, Renata; Sworczak, Krzysztof

    2014-01-01

    Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers.

  19. Honduras geothermal development: Regulations and opportunities

    SciTech Connect

    Goff, S.J.; Winchester, W.W.

    1994-09-01

    The US Department of Energy (DOE) through the Assistant Secretary for Policy, Planning, and Evaluation funded a project to review and evaluate existing power sector laws and regulations in Honduras. Also included in the scope of the project was a review of regulations pertaining to the privatization of state-run companies. We paid particular attention to regulations which might influence opportunities to develop and commercialize Honduras` geothermal resources. We believe that Honduras is well on the road to attracting foreign investment and has planned or has already in place much of the infrastructure and legal guarantees which encourage the influx of private funds from abroad. In addition, in light of current power rationing and Honduras` new and increasing awareness of the negative effects of power sector development on the environment, geothermal energy development is even more attractive. Combined, these factors create a variety of opportunities. The potential for private sector development of geothermal positive.

  20. Orion Suit Loop Variable Pressure Regulator Development

    NASA Technical Reports Server (NTRS)

    Mosher, Michael; Lewis, John F.; Campbell, Melissa

    2012-01-01

    The Orion Multi Purpose Crew Vehicle (MPCV) integrates the cabin and pressure suits with the core life support systems to provide life support during contingency depressurized cabin operations. To provide the multiple suit pressures between nominal pressurized cabin suited operations, suit leak checks, depressurized cabin suited operations, and elevated suit pressure for denitrification, a variable pressure regulator is needed. This paper documents the development of the suit loop regulator for Orion.

  1. Laparoscopic bilateral partial adrenalectomy for adrenocortical adenomas causing Cushing's syndrome: report of a case.

    PubMed

    Inoue, Tomoko; Ishiguro, Kiyosuke; Suda, Takako; Ito, Norimasa; Suzuki, Yoshimasa; Taniguchi, Yuji; Ohgi, Shigetsugu

    2006-01-01

    Laparoscopic total adrenalectomy has become a standard technique for small adrenal tumors; however, bilateral adrenalectomy results in postoperative adrenal insufficiency, necessitating lifelong steroid replacement. To preserve adrenocortical function in a 41-year-old woman with bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome, we performed laparoscopic bilateral partial adrenalectomy. We based our preoperative diagnosis of bilateral adrenocortical tumors causing Cushing's syndrome on the results of endocrinological investigations and imaging findings. Thus, we performed lateral transperitoneal laparoscopic bilateral partial adrenalectomy, preserving the adrenal glands, which were normal. Pathological examination of both tumors confirmed the diagnosis of adrenocortical adenoma. The patient had no postoperative complications, and her adrenocortical function was normal without steroid replacement at her 10-month follow-up. This report shows that Cushing's syndrome resulting from bilateral adenomas can be effectively treated by laparoscopic bilateral partial adrenalectomy as a minimally invasive, adrenocortical-preserving operation.

  2. Regulation of Murine Natural Killer Cell Development

    PubMed Central

    Goh, Wilford; Huntington, Nicholas D.

    2017-01-01

    Natural killer (NK) cells are effector lymphocytes of the innate immune system that are known for their ability to kill transformed and virus-infected cells. NK cells originate from hematopoietic stem cells in the bone marrow, and studies on mouse models have revealed that NK cell development is a complex, yet tightly regulated process, which is dependent on both intrinsic and extrinsic factors. The development of NK cells can be broadly categorized into two phases: lineage commitment and maturation. Efforts to better define the developmental framework of NK cells have led to the identification of several murine NK progenitor populations and mature NK cell subsets, each defined by a varied set of cell surface markers. Nevertheless, the relationship between some of these NK cell subsets remains to be determined. The classical approach to studying both NK cell development and function is to identify the transcription factors involved and elucidate the mechanistic action of each transcription factor. In this regard, recent studies have provided further insight into the mechanisms by which transcription factors, such as ID2, FOXO1, Kruppel-like factor 2, and GATA-binding protein 3 regulate various aspects of NK cell biology. It is also becoming evident that the biology of NK cells is not only transcriptionally regulated but also determined by epigenetic alterations and posttranscriptional regulation of gene expression by microRNAs. This review summarizes recent progress made in NK development, focusing primarily on transcriptional regulators and their mechanistic actions. PMID:28261203

  3. Genetic regulation of vertebrate eye development.

    PubMed

    Zagozewski, J L; Zhang, Q; Eisenstat, D D

    2014-11-01

    Eye development is a complex and highly regulated process that consists of several overlapping stages: (i) specification then splitting of the eye field from the developing forebrain; (ii) genesis and patterning of the optic vesicle; (iii) regionalization of the optic cup into neural retina and retina pigment epithelium; and (iv) specification and differentiation of all seven retinal cell types that develop from a pool of retinal progenitor cells in a precise temporal and spatial manner: retinal ganglion cells, horizontal cells, cone photoreceptors, amacrine cells, bipolar cells, rod photoreceptors and Müller glia. Genetic regulation of the stages of eye development includes both extrinsic (such as morphogens, growth factors) and intrinsic factors (primarily transcription factors of the homeobox and basic helix-loop helix families). In the following review, we will provide an overview of the stages of eye development highlighting the role of several important transcription factors in both normal developmental processes and in inherited human eye diseases.

  4. Advanced Power Regulator Developed for Spacecraft

    NASA Technical Reports Server (NTRS)

    1996-01-01

    The majority of new satellites generate electrical power using photovoltaic solar arrays and store energy in batteries for use during eclipse periods. Careful regulation of battery charging during insolation can greatly increase the expected lifetime of the satellite. The battery charge regulator is usually custom designed for each satellite and its specific mission. Economic competition in the small satellite market requires battery charge regulators that are lightweight, efficient, inexpensive, and modular enough to be used in a wide variety of satellites. A new battery charge regulator topology has been developed at the NASA Lewis Research Center to address these needs. The new regulator topology uses industry-standard dc-dc converters and a unique interconnection to provide size, weight, efficiency, fault tolerance, and modularity benefits over existing systems. A transformer-isolated buck converter is connected such that the high input line is connected in series with the output. This "bypass connection" biases the converter's output onto the solar array voltage. Because of this biasing, the converter only processes the fraction of power necessary to charge the battery above the solar array voltage. Likewise, the same converter hookup can be used to regulate the battery output to the spacecraft power bus with similar fractional power processing.

  5. Metastatic virilizing adrenocortical carcinoma: a rare case of cure with surgery and mitotane therapy.

    PubMed

    Chalasani, Sreelatha; Vats, Hemender Singh; Banerjee, Tarit K; McKenzie, Alan K

    2009-06-01

    A 57-year-old white woman with metastases to lungs and liver from virilizing adrenocortical carcinoma (ACC) was treated with radical nephroadrenalectomy followed by oral mitotane 3 to 6 g/day for 5 months. She developed complete response and remained free of disease for more than 25 years. Here we present the case and review the literature. ACC is a rare tumor and may occur at any age. About 60% are functional tumors with hormonal secretions and clinical manifestations due to specific hormone secretions: Cushing's syndrome due to cortisone, virilizing tumor due to androgens, feminizing tumor due to estrogens, or hypertension due to aldosterone. Stage I and II disease is curable with surgery. Stage III and IV disease may benefit from mitotane orally with gradual adjustment of the dosage to a tolerable level. Plasma mitotane level at 14 to 20 g/L results in optimal response both in hormonal secretion and symptom control, as well as tumor regression. Addition of chemotherapy (streptozotocin or a combination of etoposide, cisplatin and doxorubicin) to mitotane also produced responses along with increased survival among responders. An international study has been started by randomizing between two of the above combinations by the Collaborative Group for Adrenocortical Carcinoma Treatment.

  6. Feminizing adrenocortical adenoma presenting as heterosexual precocious puberty: report of one case.

    PubMed

    Hsiao, Hui-Pin; Chao, Mei-Chyn; Lin, Chao-Yu; Chen, Hsiu-Lin; Chen, Shiu-Lin; Chiou, Shyh-Shin; Chen, Bai-Hsiun

    2005-01-01

    We report on a case of a 2 2/12-year-old boy with heterosexual precocious puberty secondary to a feminizing adrenocortical adenoma. The boy, with no previous history of disease or treatment, presented with bilateral gynecomastia and pubic hair development (Tanner III breasts and Tanner II pubic hair). Plasma estradiol and testosterone were 410.9 pg/ml and 126.2 ng/dl respectively. Basal plasma LH and FSH levels were within the normal range. Bolus i.v. injection of GnRH showed unresponsiveness of LH and FSH. Abdominal echography and abdominal magnetic resonance imaging revealed a well-defined mass at the left suprarenal region (measuring 4.0 x 2.7 x 3.6 cm in size). After removal of the adrenal tumor, the estradiol and testosterone levels fell to normal in 2 weeks. The gynecomastia and pubic hair regressed with time. The pathology of the tumor showed compact pattern with polygonal cells containing moderate eosinophilic cytoplasm without mitotic figure. These findings were consistent with an adrenocortical adenoma secreting estradiol and testosterone as the cause of the patient's heterosexual precocious puberty.

  7. Sustainable development in British land use regulation

    SciTech Connect

    Basiago, A.D.

    1995-12-01

    Sustainable development is a new international theory of development founded on principles of futurity, environment, equity and participation. It is the legacy of twenty years of international environmental law that has established a doctrine of global trusteeship. Sustainable development has entered British land use regulation through the Maastricth Treaty; the EU`s Fifth Environmental Action Program; as well as the British government`s Planning Policy Guidance notes on land use principles, local plans, transport and historic preservation, and its white papers. The Earth Summit accord Agenda 21 is a blueprint on how to make development socially, economically and environmentally sustainable. Under its terms, Britain has prepared a national sustainable development strategy for the UN`s Commission on Sustainable Development. It features Local Agenda 21 strategies in which local authorities develop policies for sustainable development and establish partnerships with other sectors. In this paper, the Local Agenda 21 strategies of seven local authorities are evaluated according to the paradigm introduced in Agenda 21 and elaborated by Kahn that describes sustainable development as a dynamic system of integrated and interlinked economic, social and environmental sustainability. The author concludes that sustainable development in British land use regulation is guided by notions of economic development, social justice and environmental planning and not by the dynamic, integrated model of Agenda 21. 46 refs., 3 figs.

  8. Development of Critical Thinking with Metacognitive Regulation

    ERIC Educational Resources Information Center

    Gotoh, Yasushi

    2016-01-01

    In this research the author defines critical thinking as the set of skills and dispositions which enable one to solve problems logically and to attempt to reflect autonomously by means of Metacognitive regulation on one's own problem-solving processes. In order to develop their critical thinking, it is important for students to be able to use this…

  9. Regulative development of Xenopus laevis in microgravity

    NASA Technical Reports Server (NTRS)

    Black, S.; Larkin, K.; Jacqmotte, N.; Wassersug, R.; Pronych, S.; Souza, K.

    1996-01-01

    To test whether gravity is required for normal amphibian development, Xenopus leavis females were induced to ovulate aboard the orbiting Space Shuttle. Eggs were fertilized in vitro, and although early embryonic stages showed some abnormalities, the embryos were able to regulate and produce nearly normal larvae. These results demonstrate for the first time that a vertebrate can ovulate in the virtual absence of gravity, and that the eggs can develop to a free-living stage.

  10. Regulative development of Xenopus laevis in microgravity

    NASA Astrophysics Data System (ADS)

    Black, S.; Larkin, K.; Jacqmotte, N.; Wassersug, R.; Pronych, S.; Souza, K.

    To test whether gravity is required for normal amphibian development, Xenopus leavis females were induced to ovulate aboard the orbiting Space Shuttle. Eggs were fertilized in vitro, and although early embryonic stages showed some abnormalities, the embryos were able to regulate and produce nearly normal larvae. These results demonstrate for the first time that a vertebrate can ovulate in the virtual absence of gravity, and that the eggs can develop to a free-living stage.

  11. Gallium-67 uptake by a benign adrenocortical adenoma

    SciTech Connect

    Jackson, J.A.; Naul, L.G.; Montgomery, J.L.; Carpentier, W.R.; Roberts, J.W.

    1988-08-01

    A 55-yr-old man presented with an atypical relapsing meningitis and was found to have intense unilateral adrenal uptake by /sup 67/Ga imaging. Computed tomography showed a 4-cm right adrenal mass which was hypointense on the T1-weighted images and mildly hyperintense on the T2-weighted images of a magnetic resonance (MR) scan. At surgery, a coincidental benign adrenocortical adenoma was found. Because /sup 67/Ga uptake is usually associated with inflammatory or malignant lesions and malignant adrenal lesions are hyperintense on T2-weighted MR images, these findings contributed to diagnostic uncertainty in this patient. Thus, a nonhyperfunctional adrenocortical adenoma may be associated with abnormal /sup 67/Ga uptake and atypical MR findings.

  12. Acute self-suppression of corticosteroidogenesis in isolated adrenocortical cells.

    PubMed

    Carsia, R V; Malamed, S

    1979-10-01

    The relation between steroidogenesis induced by ACTH and that induced by exogenous concentrations of glucocorticoids was studied in isolated adrenocortical cells. Exogenous corticosterone and cortisol, in concentrations within the production capacity of the adrenal gland, suppressed steroidogenesis induced by ACTH in rat and beef cells, respectively. The precursors pregnenolone and progesterone enhanced steroidogenesis in both rat and beef cells. Aldosterone in rat cells and 17 beta-estradiol in rat and beef cells had little if any effect on steroidogenesis. Either suppression or stimulation by exogenous steroids was acute, that is, after 2-h incubation for rat cells and 1-h incubation for beef cells. A direct suppressive action of end product glucocorticoids is indicated. This observed self-suppression of adrenocortical cells suggests the existence of a mechanism for the find adjustment of steroidogenesis that operates in addition to the classical control exerted by the anterior pituitary.

  13. [Irreversible coma following hypoglycemia in Sheehan syndrome with adrenocortical insufficiency].

    PubMed

    Sas, A M; Meynaar, I A; Laven, J S; Bakker, S L; Feelders, R A

    2003-08-23

    A 24-year-old woman of Somali origin delivered at term after an uncomplicated pregnancy. Post-partum haemorrhage resulted in hypovolaemic shock which was treated by hysterectomy. Five days later she became comatose due to unrecognised hypoglycaemia which caused severe irreversible brain damage and status epilepticus. Treatment in the intensive care unit with artificial respiration, prednisolone, desmopressin, inotropic support, barbiturates and an anaesthetic under EEG guidance was unsuccessful. The patient died 28 days post-partum. The hypoglycaemia was due to a combination of (a) inadequate glucose intake and (b) lack of counter-regulatory mechanisms due to a deficiency of steroids and growth hormone as a result of loss of pituitary function (Sheehan syndrome) together with adrenocortical insufficiency. The combination of Sheehan syndrome and primary adrenocortical insufficiency has not been described previously in the literature.

  14. Plurihormonal Cosecretion by a Case of Adrenocortical Oncocytic Neoplasm

    PubMed Central

    Corrales, J. J.; Robles-Lázaro, C.; Sánchez-Marcos, A. I.; González-Sánchez, M. C.; Antúnez-Plaza, P.; Miralles, J. M.

    2016-01-01

    Adrenocortical oncocytic neoplasms (oncocytomas) are extremely rare; only approximately 159 cases have been described so far. The majority are nonfunctional and benign. We describe an unusual case of a functional oncocytoma secreting an excess of glucocorticoids (cortisol) and androgens (androstenedione and DHEAS), a pattern of plurihormonal cosecretion previously not reported in men, presenting with endocrine manifestations of Cushing's syndrome. The neoplasm was considered to be of uncertain malignant potential (borderline) according to the Lin-Weiss-Bisceglia criteria. PMID:27413559

  15. Chylous ascites after resection of giant adrenocortical carcinoma

    PubMed Central

    Karakoyun, Rojbin; Demirci, Erkan; Alikanoglu, Arsenal Sezgin

    2016-01-01

    Postoperative chylous ascites (PCA) is a rare clinical state that occurs during abdominal surgery. Despite its rarity, the need to diagnose and treat PCA is increasing in importance with the increased number of wide resections and lymph node dissections being performed and the serious consequences of treatment. Here we describe the PCA complications we observed after resection for treating a case of giant adrenocortical carcinoma and we have the brief review of the PCA complication. PMID:28149812

  16. Adrenocortical carcinoma: modern management and evolving treatment strategies

    PubMed Central

    McDuffie, Lucas A; Aufforth, Rachel D

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Unlike many other cancers, there has been little improvement in patient outcome over the past several decades. However, as scientific advancements are made and our understanding of the molecular genetics involved in ACC improve then progress may be achieved in this devastating disease. This review focuses on recent literature published in the field of ACC from 2010 to 2015 with an emphasis on improving diagnosis, staging and treatment for ACC. PMID:27213037

  17. [Adrenalectomy for preservation of adrenocortical function. Indication and results].

    PubMed

    Walz, M K

    2009-02-01

    The standard procedure for adrenal tumors is total adrenalectomy. In order to preserve adrenocortical function, partial adrenalectomy has become an accepted and proven option in bilateral hereditary pheochromocytomas. For this at least one third of one gland has to be maintained. In unilateral adrenal tumors, partial adrenalectomy has mainly been used in Conn's syndrome. Studies demonstrate results identical to those of total adrenalectomy. All other adrenal tumors are exceptional indications for partial adrenalectomy.

  18. Regulators of ovarian preantral follicle development.

    PubMed

    McGee, Elizabeth A; Raj, Renju S

    2015-05-01

    Preantral follicle development has become an increasingly recognized area of study in the last two decades. Factors that regulate the growth survival and differentiation of these small, yet complex structures have been identified. The field of fertility preservation and a need for increased numbers of mature oocytes for stem cell research revealed how little we knew of how follicles got from the primordial stage to the antral stage with a healthy and competent oocyte inside. This work discusses the role of gonadotropins in regulating preantral follicles and also the role of the TGF-β family members and their associated Smad signaling molecules in preantral follicle development. Preantral follicle development is a necessary step to fertility in females and further understanding of this process is essential for progress in both infertility care and the enlarging field of in vitro folliculogenesis.

  19. Interparental Aggression and Infant Patterns of Adrenocortical and Behavioral Stress Responses

    PubMed Central

    Towe-Goodman, Nissa R.; Stifter, Cynthia A.; Mills-Koonce, W. Roger; Granger, Douglas A.

    2011-01-01

    Drawing on emotional security theory, this study examined linkages between interparental aggression, infant self-regulatory behaviors, and patterns of physiological and behavioral stress responses in a diverse sample of 735 infants residing in predominately low-income, nonmetropolitan communities. Latent profile analysis revealed four classes of adrenocortical and behavioral stress response patterns at 7-months of age, using assessments of behavioral and cortisol reactivity to an emotion eliciting challenge, as well as global ratings of the child’s negative affect and basal cortisol levels. The addition of covariates within the latent profile model suggested that children with more violence in the home and who used less caregiver-oriented regulation strategies were more likely to exhibit a pattern of high cortisol reactivity with moderate signs of distress rather than the average stress response, suggesting possible patterns of adaptation in violent households. PMID:22127795

  20. The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development.

    PubMed

    Handwerger, S; Freemark, M

    2000-04-01

    The human growth hormone (hGH)/human placental lactogen (hPL) gene family, which consists of two GH and three PL genes, is important in the regulation of maternal and fetal metabolism and the growth and development of the fetus. During pregnancy, pituitary GH (hGH-N) expression in the mother is suppressed; and hGH-V, a GH variant expressed by the placenta, becomes the predominant GH in the mother. hPL, which is the product of the hPL-A and hPL-B genes, is secreted into both the maternal and fetal circulations after the sixth week of pregnancy. hGH-V and hPL act in concert in the mother to stimulate insulin-like growth factor (IGF) production and modulate intermediary metabolism, resulting in an increase in the availability of glucose and amino acids to the fetus. In the fetus, hPL acts via lactogenic receptors and possibly a unique PL receptor to modulate embryonic development, regulate intermediary metabolism and stimulate the production of IGFs, insulin, adrenocortical hormones and pulmonary surfactant. hGH-N, which is expressed by the fetal pituitary, has little or no physiological actions in the fetus until late in pregnancy due to the lack of functional GH receptors on fetal tissues. hGH-V, which is also a potent somatogenic hormone, is not released into the fetus. Taken together, studies of the hGH/hPL gene family during pregnancy reveal a complex interaction of the hormones with one another and with other growth factors. Additional investigations are necessary to clarify the relative roles of the family members in the regulation of fetal growth and development and the factors that modulate the expression of the genes.

  1. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model.

    PubMed

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology.

  2. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model

    PubMed Central

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology. PMID:26885453

  3. Energy-conserving development regulations: current practice

    SciTech Connect

    Not Available

    1980-05-01

    Almost every aspect of land development has an effect on energy use, from minute architectural details to broad considerations of urban density. Energy-efficiency depends in part on how development is planned and carried out. Conventional development regulations, such as zoning ordinances and subdivision regulations, can be adapted in many ways to promote energy conservation at the community level. This report is about energy-efficient site and neighborhood design. It examines recent experiences of local governments that have adopted new development regulations or amended existing ones to promote energy conservation, more efficient generation and distribution, or a switch to alternative, renewable sources. Although much has been written in recent years about saving energy through community design, actual experience in applying these new ideas is still limited. To date, most communities have focused their efforts on studying the problem, documenting consumption patterns, and writing reports and plans. Only a handful have amended their land-use controls for the express purpose of saving energy. This study identifies 13 of these pioneering communities, after undertaking a survey of over 1400 local, regional, and state planning agencies. It takes a look at their experiences, to learn what has been done, how well it has worked, and what problems have been encountered.

  4. Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group

    PubMed Central

    Postlewait, Lauren M; Ethun, Cecilia G; Tran, Thuy B; Prescott, Jason D; Pawlik, Timothy M; Wang, Tracy S; Glenn, Jason; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E; Keplinger, Kara; Fields, Ryan C; Jin, Linda X; Weber, Sharon M; Salem, Ahmed; Sicklick, Jason K; Gad, Shady; Yopp, Adam C; Mansour, John C; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C; Kiernan, Colleen M; Votanopoulos, Konstantinos I; Levine, Edward A; Staley, Charles A; Poultsides, George A; Maithel, Shishir K

    2016-01-01

    BACKGROUND Current treatment guidelines recommend adjuvant mitotane after resection of adrenocortical carcinoma with high-risk features (eg, tumor rupture, positive margins, positive lymph nodes, high grade, elevated mitotic index, and advanced stage). Limited data exist on the outcomes associated with these practice guidelines. STUDY DESIGN Patients who underwent resection of adrenocortical carcinoma from 1993 to 2014 at the 13 academic institutions of the US Adrenocortical Carcinoma Group were included. Factors associated with mitotane administration were determined. Primary end points were recurrence-free survival (RFS) and overall survival (OS). RESULTS Of 207 patients, 88 (43%) received adjuvant mitotane. Receipt of mitotane was associated with hormonal secretion (58% vs 32%; p = 0.001), advanced TNM stage (stage IV: 42% vs 23%; p = 0.021), adjuvant chemotherapy (37% vs 5%; p < 0.001), and adjuvant radiation (17% vs 5%; p = 0.01), but was not associated with tumor rupture, margin status, or N-stage. Median follow-up was 44 months. Adjuvant mitotane was associated with decreased RFS (10.0 vs 27.9 months; p = 0.007) and OS (31.7 vs 58.9 months; p = 0.006). On multivariable analysis, mitotane was not independently associated with RFS or OS, and margin status, advanced TNM stage, and receipt of chemotherapy were associated with survival. After excluding all patients who received chemotherapy, adjuvant mitotane remained associated with decreased RFS and similar OS; multivariable analyses again showed no association with recurrence or survival. Stage-specific analyses in both cohorts revealed no association between adjuvant mitotane and improved RFS or OS. CONCLUSIONS When accounting for stage and adverse tumor and treatment-related factors, adjuvant mitotane after resection of adrenocortical carcinoma is not associated with improved RFS or OS. Current guidelines should be revisited and prospective trials are needed. PMID:26775162

  5. Advanced Power Regulator Developed for Spacecraft

    NASA Technical Reports Server (NTRS)

    2005-01-01

    The majority of new satellites generate electrical power using photovoltaic solar arrays and store energy in batteries for use during eclipse periods. Careful regulation of battery charging during insolation can greatly increase the expected lifetime of the satellite. The battery charge regulator is usually custom designed for each satellite and its specific mission. Economic competition in the small satellite market requires battery charge regulators that are lightweight, efficient, inexpensive, and modular enough to be used in a wide variety of satellites. A new battery charge regulator topology has been developed at the NASA Lewis Research Center to address these needs. The new regulator topology uses industry-standard dc-dc converters and a unique interconnection to provide size, weight, efficiency, fault tolerance, and modularity benefits over existing systems. A transformer-isolated buck converter is connected such that the high input line is connected in series with the output. This "bypass connection" biases the converter's output onto the solar array voltage. Because of this biasing, the converter only processes the fraction of power necessary to charge the battery above the solar array voltage. Likewise, the same converter hookup can be used to regulate the battery output to the spacecraft power bus with similar fractional power processing. The advantages of this scheme are: 1) Because only a fraction of the power is processed through the dc-dc converter, the single- stage conversion efficiency is 94 to 98 percent; 2) Costly, high-efficiency dc-dc converters are not necessary for high end-to-end system efficiency; 3) The system is highly fault tolerant because the bypass connection will still deliver power if the dc-dc converter fails; and 4) The converters can easily be connected in parallel, allowing higher power systems to be built from a common building block. This new technology will be spaceflight tested in the Photovoltaic Regulator Kit Experiment

  6. Regulation & Development of Membrane Transport Processes.

    DTIC Science & Technology

    1985-05-15

    Laboratory, Oak Ridge, Tennessee DAVID W. PLMPLIN Department of Anatomy, University of Maryland School of Medicine, Baltimore, Maryland MARILYN D. RESH...Muscle 265 Douglas M. Fambrough, Barry A. Wolitzky, and David W. Pumplin Index 283 REGULATION AND DEVELOPMENT OF MEMBRANE TRANSPORT PROCESSES 77, II PART 1...243 (Cell Physiol. 12). C 124-C132. 16. Huang. C. C.. Tsai. C. M.. and Canellakis, E. S. (1973) Bochiom. Biophys. Acta. 332, 59-68. 17. Hume . S. and

  7. Pregnancy in a patient with adrenocortical carcinoma during treatment with Mitotane - a case report.

    PubMed

    Baszko-Błaszyk, Daria; Ochmańska, Katarzyna; Waśko, Ryszard; Sowiński, Jerzy

    2011-01-01

    We present the case of a female patient with virilising adrenocortical carcinoma treated surgically who conceived during adjuvant treatment with mitotane. We discuss the frequently erroneous routine treatment with oral hormonal contraception without thorough differential diagnosis in female patients with oligo-/amenorrhea and subsequent delay in the proper diagnosis of adrenocortical carcinoma.

  8. PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors

    PubMed Central

    Berthon, Annabel S.; Szarek, Eva; Stratakis, Constantine A.

    2015-01-01

    Cyclic-AMP (cAMP)-dependent protein kinase (PKA) is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH). More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα), were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA's role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway. PMID:26042218

  9. Sterol Regulation of Metabolism, Homeostasis and Development

    PubMed Central

    Wollam, Joshua; Antebi, Adam

    2014-01-01

    Sterol metabolites are critical signaling molecules that regulate metabolism, development, and homeostasis. Oxysterols, bile acids, and steroids work primarily through cognate sterol-responsive nuclear hormone receptors to control these processes through feed-forward and feedback mechanisms. These signaling pathways are conserved from simple invertebrates to mammals. Indeed, results from various model organisms have yielded fundamental insights into cholesterol and bile acid homeostasis, lipid and glucose metabolism, protective mechanisms, tissue differentiation, development, reproduction, and even aging. Here, we review how sterols act through evolutionarily ancient mechanisms to control these processes. PMID:21495846

  10. Brassinosteroids Regulate Root Growth, Development, and Symbiosis.

    PubMed

    Wei, Zhuoyun; Li, Jia

    2016-01-04

    Brassinosteroids (BRs) are natural plant hormones critical for growth and development. BR deficient or signaling mutants show significantly shortened root phenotypes. However, for a long time, it was thought that these phenotypes were solely caused by reduced cell elongation in the mutant roots. Functions of BRs in regulating root development have been largely neglected. Nonetheless, recent detailed analyses, revealed that BRs are not only involved in root cell elongation but are also involved in many aspects of root development, such as maintenance of meristem size, root hair formation, lateral root initiation, gravitropic response, mycorrhiza formation, and nodulation in legume species. In this review, current findings on the functions of BRs in mediating root growth, development, and symbiosis are discussed.

  11. Opposing Transcriptional Mechanisms Regulate Toxoplasma Development

    PubMed Central

    Hong, Dong-Pyo; Radke, Joshua B.

    2017-01-01

    ABSTRACT The Toxoplasma biology that underlies human chronic infection is developmental conversion of the acute tachyzoite stage into the latent bradyzoite stage. We investigated the roles of two alkaline-stress-induced ApiAP2 transcription factors, AP2IV-3 and AP2IX-9, in bradyzoite development. These factors were expressed in two overlapping waves during bradyzoite development, with AP2IX-9 increasing expression earlier than AP2IV-3, which peaked as AP2IX-9 expression was declining. Disruption of the AP2IX-9 gene enhanced, while deletion of AP2IV-3 gene decreased, tissue cyst formation, demonstrating that these factors have opposite functions in bradyzoite development. Conversely, conditional overexpression of FKBP-modified AP2IX-9 or AP2IV-3 with the small molecule Shield 1 had a reciprocal effect on tissue cyst formation, confirming the conclusions of the knockout experiments. The AP2IX-9 repressor and AP2IV-3 activator tissue cyst phenotypes were borne out in gene expression studies that determined that many of the same bradyzoite genes were regulated in an opposite manner by these transcription factors. A common gene target was the canonical bradyzoite marker BAG1, and mechanistic experiments determined that, like AP2IX-9, AP2IV-3 regulates a BAG1 promoter-luciferase reporter and specifically binds the BAG1 promoter in parasite chromatin. Altogether, these results suggest that the AP2IX-9 transcriptional repressor and the AP2IV-3 transcriptional activator likely compete to control bradyzoite gene expression, which may permit Toxoplasma to better adapt to different tissue environments and select a suitable host cell for long-term survival of the dormant tissue cyst. IMPORTANCE Toxoplasma infections are lifelong because of the development of the bradyzoite tissue cyst, which is effectively invisible to the immune system. Despite the important clinical consequences of this developmental pathway, the molecular basis of the switch mechanisms that control tissue

  12. Gpr177 regulates pulmonary vasculature development.

    PubMed

    Jiang, Ming; Ku, Wei-yao; Fu, Jiang; Offermanns, Stefan; Hsu, Wei; Que, Jianwen

    2013-09-01

    Establishment of the functional pulmonary vasculature requires intimate interaction between the epithelium and mesenchyme. Previous genetic studies have led to inconsistent conclusions about the contribution of epithelial Wnts to pulmonary vasculature development. This discrepancy is possibly due to the functional redundancy among different Wnts. Here, we use Shh-Cre to conditionally delete Gpr177 (the mouse ortholog of Drosophila Wntless, Wls), a chaperon protein important for the sorting and secretion of Wnt proteins. Deletion of epithelial Gpr177 reduces Wnt signaling activity in both the epithelium and mesenchyme, resulting in severe hemorrhage and abnormal vasculature, accompanied by branching defects and abnormal epithelial differentiation. We then used multiple mouse models to demonstrate that Wnt/β-catenin signaling is not only required for the proliferation and differentiation of mesenchyme, but also is important for the maintenance of smooth muscle cells through the regulation of the transcription factor Kruppel-like factor 2 (Klf2). Together, our studies define a novel mechanism by which epithelial Wnts regulate the normal development and maintenance of pulmonary vasculature. These findings provide insight into the pathobiology of congenital lung diseases, such as alveolar capillary dysplasia (ACD), that have abnormal alveolar development and dysmorphic pulmonary vasculature.

  13. Integrin function and regulation in development.

    PubMed

    Tarone, G; Hirsch, E; Brancaccio, M; De Acetis, M; Barberis, L; Balzac, F; Retta, S F; Botta, C; Altruda, F; Silengo, L; Retta, F

    2000-01-01

    Integrins are a large family of membrane receptors, consisting of alpha and beta subunits, that play a pivotal role in the interaction of cells with the extracellular matrix. Such interaction regulates the organization of cells in organs and tissues during development as well as cell differentiation and proliferation. We have shown that unfertilized oocytes express integrins that might be important during fertilization. We also analyzed nervous system and muscle tissue development showing that integrin expression is precisely regulated during organization of these tissues. The results indicate that two distinct integrin alpha subunits mediate the outgrowth of processes in nerve and glial cells. Alpha1 integrin, a laminin receptor, is up-regulated by nerve growth factor and other differentiation stimuli and is involved in neurite extension by nerve cells. In contrast, process extension by glial cells is likely to involve the alphaV integrin. Moreover, the latter integrin subunit is also transiently expressed in muscle of the embryo body where it localizes predominantly at developing myotendinous junctions. After birth this integrin disappears and is substituted by the alpha7 subunit. At the same time, important changes also occur in the expression of the associated beta subunit. In fact, the beta1A isoform which is expressed in fetal muscles, is substituted by beta1D. These isoforms are generated by alternative splicing and differ in only a few amino acid residues at the COOH terminus of the protein. This region of the molecule is exposed at the cytoplasmic face of the plasma membrane and is connected to the actin filaments. Our results show that beta1D, which is expressed only in striated muscle tissues, binds to both cytoskeletal and extracellular matrix proteins with an affinity higher than beta1A. Thus, beta1D provides a stronger link between the cytoskeleton and extracellular matrix necessary to support mechanical tension during muscle contraction. These

  14. Comparison of the Effects of PRKAR1A and PRKAR2B Depletion on Signaling Pathways, Cell Growth, and Cell Cycle Control of Adrenocortical Cells

    PubMed Central

    Basso, F.; Rocchetti, F.; Rodriguez, S.; Nesterova, M.; Cormier, F.; Stratakis, C.; Ragazzon, B.; Bertherat, J.; Rizk-Rabin, M.

    2016-01-01

    The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation in the abundance of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-κB pathway. Nonetheless, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression. PMID:25268545

  15. Pten Regulates Epithelial Cytodifferentiation during Prostate Development

    PubMed Central

    Lokody, Isabel B.; Francis, Jeffrey C.; Gardiner, Jennifer R.; Erler, Janine T.; Swain, Amanda

    2015-01-01

    Gene expression and functional studies have indicated that the molecular programmes involved in prostate development are also active in prostate cancer. PTEN has been implicated in human prostate cancer and is frequently mutated in this disease. Here, using the Nkx3.1:Cre mouse strain and a genetic deletion approach, we investigate the role of Pten specifically in the developing mouse prostate epithelia. In contrast to its role in other developing organs, this gene is dispensable for the initial developmental processes such as budding and branching. However, as cytodifferentiation progresses, abnormal luminal cells fill the ductal lumens together with augmented epithelial proliferation. This phenotype resembles the hyperplasia seen in postnatal Pten deletion models that develop neoplasia at later stages. Consistent with this, gene expression analysis showed a number of genes affected that are shared with Pten mutant prostate cancer models, including a decrease in androgen receptor regulated genes. In depth analysis of the phenotype of these mice during development revealed that loss of Pten leads to the precocious differentiation of epithelial cells towards a luminal cell fate. This study provides novel insight into the role of Pten in prostate development as part of the process of coordinating the differentiation and proliferation of cell types in time and space to form a functional organ. PMID:26076167

  16. Pancreatic Mesenchyme Regulates Epithelial Organogenesis throughout Development

    PubMed Central

    Landsman, Limor; Nijagal, Amar; Whitchurch, Theresa J.; VanderLaan, Renee L.; Zimmer, Warren E.; MacKenzie, Tippi C.; Hebrok, Matthias

    2011-01-01

    The developing pancreatic epithelium gives rise to all endocrine and exocrine cells of the mature organ. During organogenesis, the epithelial cells receive essential signals from the overlying mesenchyme. Previous studies, focusing on ex vivo tissue explants or complete knockout mice, have identified an important role for the mesenchyme in regulating the expansion of progenitor cells in the early pancreas epithelium. However, due to the lack of genetic tools directing expression specifically to the mesenchyme, the potential roles of this supporting tissue in vivo, especially in guiding later stages of pancreas organogenesis, have not been elucidated. We employed transgenic tools and fetal surgical techniques to ablate mesenchyme via Cre-mediated mesenchymal expression of Diphtheria Toxin (DT) at the onset of pancreas formation, and at later developmental stages via in utero injection of DT into transgenic mice expressing the Diphtheria Toxin receptor (DTR) in this tissue. Our results demonstrate that mesenchymal cells regulate pancreatic growth and branching at both early and late developmental stages by supporting proliferation of precursors and differentiated cells, respectively. Interestingly, while cell differentiation was not affected, the expansion of both the endocrine and exocrine compartments was equally impaired. To further elucidate signals required for mesenchymal cell function, we eliminated β-catenin signaling and determined that it is a critical pathway in regulating mesenchyme survival and growth. Our study presents the first in vivo evidence that the embryonic mesenchyme provides critical signals to the epithelium throughout pancreas organogenesis. The findings are novel and relevant as they indicate a critical role for the mesenchyme during late expansion of endocrine and exocrine compartments. In addition, our results provide a molecular mechanism for mesenchymal expansion and survival by identifying β-catenin signaling as an essential mediator

  17. Regulation of appressorium development in pathogenic fungi

    PubMed Central

    Ryder, Lauren S; Talbot, Nicholas J

    2015-01-01

    Many plant pathogenic fungi have the capacity to breach the intact cuticles of their plant hosts using specialised infection cells called appressoria. These cells exert physical force to rupture the plant surface, or deploy enzymes in a focused way to digest the cuticle and plant cell wall. They also provide the means by which focal secretion of effectors occurs at the point of plant infection. Development of appressoria is linked to re-modelling of the actin cytoskeleton, mediated by septin GTPases, and rapid cell wall differentiation. These processes are regulated by perception of plant cell surface components, and starvation stress, but also linked to cell cycle checkpoints that control the overall progression of infection-related development. PMID:26043436

  18. Genetic and hormonal regulation of cambial development.

    PubMed

    Ursache, Robertas; Nieminen, Kaisa; Helariutta, Ykä

    2013-01-01

    The stems and roots of most dicot plants increase in diameter by radial growth, due to the activity of secondary meristems. Two types of meristems function in secondary plant body formation: the vascular cambium, which gives rise to secondary xylem and phloem, and the cork cambium, which produces a bark layer that replaces the epidermis and protects the plant stem from mechanical damage and pathogens. Cambial development, the initiation and activity of the vascular cambium, leads to an accumulation of wood, the secondary xylem tissue. The thick, cellulose-rich cell walls of wood provide a source of cellulose and have the potential to be used as a raw material for sustainable and renewable energy production. In this review, we will discuss what is known about the mechanisms regulating the cambium and secondary tissue development.

  19. Effects of centrifugation on gonadal and adrenocortical steroids in rats

    NASA Technical Reports Server (NTRS)

    Kakihana, R.; Butte, J. C.

    1980-01-01

    Many endocrine systems are sensitive to external changes in the environment. Both the pituitary adrenal and pituitary gonadal systems are affected by stress including centrifugation stress. The effect of centrifugation on the pituitary gonadal and pituitary adrenocortical systems was examined by measuring the gonadal and adrenal steroids in the plasma and brain following different duration and intensity of centrifugation stress in rats. Two studies were completed and the results are presented. The second study was carried out to describe the developmental changes of brain, plasma and testicular testosterone and dihydrotestosterone in Sprague Dawley rats so that the effect of centrifugation stress on the pituitary gonadal syatem could be better evaluated in future studies.

  20. Synchronous adrenocortical neoplasms, paragangliomas, and pheochromocytomas: syndromic considerations regarding an unusual constellation of endocrine tumors.

    PubMed

    LeBlanc, Melissa; Tabrizi, Mohsen; Kapsner, Patricia; Hanson, Joshua Anspach

    2014-12-01

    The most common clinical syndromes presenting with paragangliomas and/or pheochromocytomas as their endocrine components are multiple endocrine neoplasia type 2, neurofibromatosis, Von Hippel-Lindau syndrome, Carney-Stratakis syndrome, Carney triad, and the recently described hereditary paraganglioma syndrome. Only Carney triad is known to also present with adrenocortical adenomas, currently representing the only described syndrome in which all 3 of the aforementioned tumors are found together. In most cases, prototypical lesions of the triad such as gastrointestinal stromal tumor and pulmonary chondromas are also seen. We present a case of a young woman with synchronous paragangliomas, adrenal/extra-adrenal cortical neoplasms, and pheochromocytoma without genetic mutations for multiple endocrine neoplasia 2, Von Hippel-Lindau syndrome, neurofibromatosis, and succinate dehydrogenase. We speculate that this represents a previously undescribed presentation of Carney triad and, at the very least, indicates the need for monitoring for the development of other tumors of the triad.

  1. A case report of adrenocortical carcinosarcoma with oncocytic and primitive neuroectodermal-like features.

    PubMed

    Kao, Chia-Sui; Grignon, David J; Ulbright, Thomas M; Idrees, Muhammad T

    2013-09-01

    Adrenocortical carcinosarcomas are rare aggressive neoplasms; only a few have been reported to date, all with dismal prognosis. These were reported as having varying morphology. We have encountered a case of adrenal carcinosarcoma with an undifferentiated component bearing similarities to primitive neuroectodermal tumors and other areas of oncocytic differentiation. The 48-year-old woman patient presented with abdominal pain and unintended, excessive weight loss. Computed tomographic imaging revealed a tumor located adjacent to the liver and kidney necessitating a partial nephrectomy and hepatectomy. Histologically, the tumor exhibited malignant features. Melan-A, inhibin, calretinin, cytokeratin AE1/AE3, synaptophysin, and neuron-specific enolase were positive immunohistochemically. The patient developed metastasis within 2 months of surgery and is currently alive with disease after chemotherapy. Adrenal carcinosarcoma is a rare highly aggressive malignancy with a wide morphologic spectrum. Recognition of variant morphology and applying correct immunohistochemical studies will aid in reaching an accurate diagnosis.

  2. Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758).

    PubMed

    Ferreira, João C P; Fujihara, Caroline J; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C; Teixeira, Carlos R; Pantoja, José C F; Schmidt, Elizabeth M S; Palme, Rupert

    2015-01-01

    Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots' physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3-9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural

  3. Non-Invasive Measurement of Adrenocortical Activity in Blue-Fronted Parrots (Amazona aestiva, Linnaeus, 1758)

    PubMed Central

    Ferreira, João C. P.; Fujihara, Caroline J.; Fruhvald, Erika; Trevisol, Eduardo; Destro, Flavia C.; Teixeira, Carlos R.; Pantoja, José C. F.; Schmidt, Elizabeth M. S.; Palme, Rupert

    2015-01-01

    Parrots kept in zoos and private households often develop psychological and behavioural disorders. Despite knowing that such disorders have a multifactorial aetiology and that chronic stress is involved, little is known about their development mainly due to a poor understanding of the parrots’ physiology and the lack of validated methods to measure stress in these species. In birds, blood corticosterone concentrations provide information about adrenocortical activity. However, blood sampling techniques are difficult, highly invasive and inappropriate to investigate stressful situations and welfare conditions. Thus, a non-invasive method to measure steroid hormones is critically needed. Aiming to perform a physiological validation of a cortisone enzyme immunoassay (EIA) to measure glucocorticoid metabolites (GCM) in droppings of 24 Blue-fronted parrots (Amazona aestiva), two experiments were designed. During the experiments all droppings were collected at 3-h intervals. Initially, birds were sampled for 24 h (experiment 1) and one week later assigned to four different treatments (experiment 2): Control (undisturbed), Saline (0.2 mL of 0.9% NaCl IM), Dexamethasone (1 mg/kg IM) and Adrenocorticotropic hormone (ACTH; 25 IU IM). Treatments (always one week apart) were applied to all animals in a cross-over study design. A daily rhythm pattern in GCM excretion was detected but there were no sex differences (first experiment). Saline and dexamethasone treatments had no effect on GCM (not different from control concentrations). Following ACTH injection, GCM concentration increased about 13.1-fold (median) at the peak (after 3–9 h), and then dropped to pre-treatment concentrations. By a successful physiological validation, we demonstrated the suitability of the cortisone EIA to non-invasively monitor increased adrenocortical activity, and thus, stress in the Blue-fronted parrot. This method opens up new perspectives for investigating the connection between behavioural

  4. Transcriptional Regulation of Mononuclear Phagocyte Development

    PubMed Central

    Tussiwand, Roxane; Gautier, Emmanuel L.

    2015-01-01

    Mononuclear phagocytes (MP) are a quite unique subset of hematopoietic cells, which comprise dendritic cells (DC), monocytes as well as monocyte-derived and tissue-resident macrophages. These cells are extremely diverse with regard to their origin, their phenotype as well as their function. Developmentally, DC and monocytes are constantly replenished from a bone marrow hematopoietic progenitor. The ontogeny of macrophages is more complex and is temporally linked and specified by the organ where they reside, occurring early during embryonic or perinatal life. The functional heterogeneity of MPs is certainly a consequence of the tissue of residence and also reflects the diverse ontogeny of the subsets. In this review, we will highlight the developmental pathways of murine MP, with a particular emphasis on the transcriptional factors that regulate their development and function. Finally, we will discuss and point out open questions in the field. PMID:26539196

  5. Bilateral Adrenocortical Masses Producing Aldosterone and Cortisol Independently

    PubMed Central

    Lee, Seung-Eun; Lee, You-Bin; Seok, Hyeri; Shin, In Seub; Eun, Yeong Hee; Kim, Jung-Han; Oh, Young Lyun

    2015-01-01

    A 31-year-old woman was referred to our hospital with symptoms of hypertension and bilateral adrenocortical masses with no feature of Cushing syndrome. The serum aldosterone/renin ratio was elevated and the saline loading test showed no suppression of the plasma aldosterone level, consistent with a diagnosis of primary hyperaldosteronism. Overnight and low-dose dexamethasone suppression tests showed no suppression of serum cortisol, indicating a secondary diagnosis of subclinical Cushing syndrome. Adrenal vein sampling during the low-dose dexamethasone suppression test demonstrated excess secretion of cortisol from the left adrenal mass. A partial right adrenalectomy was performed, resulting in normalization of blood pressure, hypokalemia, and high aldosterone level, implying that the right adrenal mass was the main cause of the hyperaldosteronism. A total adrenalectomy for the left adrenal mass was later performed, resulting in a normalization of cortisol level. The final diagnosis was bilateral adrenocortical adenomas, which were secreting aldosterone and cortisol independently. This case is the first report of a concurrent cortisol-producing left adrenal adenoma and an aldosterone-producing right adrenal adenoma in Korea, as demonstrated by adrenal vein sampling and sequential removal of adrenal masses. PMID:26248855

  6. SIGNALS AND REGULATORS THAT GOVERN STREPTOMYCES DEVELOPMENT

    PubMed Central

    McCormick, Joseph R.; Flärdh, Klas

    2012-01-01

    Streptomyces coelicolor is the genetically best characterized species of a populous genus belonging to the Gram-positive Actinobacteria. Streptomycetes are filamentous soil organisms, well known for the production of a plethora of biologically active secondary metabolic compounds. The Streptomyces developmental life cycle is uniquely complex, and involves coordinated multicellular development with both physiological and morphological differentiation of several cell types, culminating in production of secondary metabolites and dispersal of mature spores. This review presents a current appreciation of the signaling mechanisms used to orchestrate the decision to undergo morphological differentiation, and the regulators and regulatory networks that direct the intriguing development of multigenomic hyphae, first to form specialized aerial hyphae, and then to convert them into chains of dormant spores. This current view of S. coelicolor development is destined for rapid evolution as data from “-omics” studies shed light on gene regulatory networks, new genetic screens identify hitherto unknown players, and the resolution of our insights into the underlying cell biological processes steadily improve. PMID:22092088

  7. Apoptosis regulates notochord development in Xenopus

    PubMed Central

    Malikova, Marina; Van Stry, Melanie

    2009-01-01

    The notochord is the defining characteristic of the chordate embryo, and plays critical roles as a signaling center and as the primitive skeleton. In this study we show that early notochord development in Xenopus embryos is regulated by apoptosis. We find apoptotic cells in the notochord beginning at the neural groove stage and increasing in number as the embryo develops. These dying cells are distributed in an anterior to posterior pattern that is correlated with notochord extension through vacuolization. In axial mesoderm explants, inhibition of this apoptosis causes the length of the notochord to approximately double compared to controls. In embryos however, inhibition of apoptosis decreases the length of the notochord and it is severely kinked. This kinking also spreads from the anterior with developmental stage such that by the tadpole stage, the notochord lacks any recognizable structure, although notochord markers are expressed in a normal temporal pattern. Extension of the somites and neural plate mirror that of the notochord in these embryos, and the somites are severely disorganized. These data indicate that apoptosis is required for normal notochord development during the formation of the anterior-posterior axis, and its role in this process is discussed. PMID:17920580

  8. Blunted Opiate Modulation of Hypothalamic-Pituitary-Adrenocortical Activity in Men and Women Who Smoke

    PubMed Central

    al’Absi, Mustafa; Wittmers, Lorentz E.; Hatsukami, Dorothy; Westra, Ruth

    2016-01-01

    Objective To examine the extent to which nicotine dependence alters endogenous opioid regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis functions. Endogenous opiates play an important role in regulating mood, pain, and drug reward. They also regulate the HPA functions. Previous work has demonstrated an abnormal HPA response to psychological stress among dependent smokers. Methods Smokers and nonsmokers (total n = 48 participants) completed two sessions during which a placebo or 50 mg of naltrexone was administered, using a double-blind design. Blood and saliva samples, cardiovascular and mood measures were obtained during a resting absorption period, after exposure to two noxious stimuli, and during an extended recovery period. Thermal pain threshold and tolerance were assessed in both sessions. Participants also rated pain during a 90-second cold pressor test. Results Opioid blockade increased adrenocorticotropin, plasma cortisol, and salivary cortisol levels; these increases were enhanced by exposure to the noxious stimuli. These responses were blunted in smokers relative to nonsmokers. Smokers tended to report less pain than nonsmokers, and women reported more pain during both pain procedures, although sex differences in pain were significant only among nonsmokers. Conclusions We conclude that nicotine dependence is associated with attenuated opioid modulation of the HPA. This dysregulation may play a role in the previously observed blunted responses to stress among dependent smokers. PMID:18799426

  9. Role of ALADIN in Human Adrenocortical Cells for Oxidative Stress Response and Steroidogenesis

    PubMed Central

    Jühlen, Ramona; Idkowiak, Jan; Taylor, Angela E.; Kind, Barbara; Arlt, Wiebke; Huebner, Angela; Koehler, Katrin

    2015-01-01

    Triple A syndrome is caused by mutations in AAAS encoding the protein ALADIN. We investigated the role of ALADIN in the human adrenocortical cell line NCI-H295R1 by either over-expression or down-regulation of ALADIN. Our findings indicate that AAAS knock-down induces a down-regulation of genes coding for type II microsomal cytochrome P450 hydroxylases CYP17A1 and CYP21A2 and their electron donor enzyme cytochrome P450 oxidoreductase, thereby decreasing biosynthesis of precursor metabolites required for glucocorticoid and androgen production. Furthermore we demonstrate that ALADIN deficiency leads to increased susceptibility to oxidative stress and alteration in redox homeostasis after paraquat treatment. Finally, we show significantly impaired nuclear import of DNA ligase 1, aprataxin and ferritin heavy chain 1 in ALADIN knock-down cells. We conclude that down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome. PMID:25867024

  10. Single nucleotide polymorphism microarray analysis in cortisol-secreting adrenocortical adenomas identifies new candidate genes and pathways.

    PubMed

    Ronchi, Cristina L; Leich, Ellen; Sbiera, Silviu; Weismann, Dirk; Rosenwald, Andreas; Allolio, Bruno; Fassnacht, Martin

    2012-03-01

    The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≥20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.

  11. The Development of Self-Regulation across Early Childhood

    ERIC Educational Resources Information Center

    Montroy, Janelle J.; Bowles, Ryan P.; Skibbe, Lori E.; McClelland, Megan M.; Morrison, Frederick J.

    2016-01-01

    The development of early childhood self-regulation is often considered an early life marker for later life successes. Yet little longitudinal research has evaluated whether there are different trajectories of self-regulation development across children. This study investigates the development of behavioral self-regulation between the ages of 3 and…

  12. Cyfip1 Regulates Presynaptic Activity during Development

    PubMed Central

    Hsiao, Kuangfu; Harony-Nicolas, Hala; Buxbaum, Joseph D.

    2016-01-01

    Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous for Cyfip1 have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors. SIGNIFICANCE STATEMENT Several developmental brain disorders have been associated with gene duplications and deletions that serve to increase or decrease levels of encoded proteins. Cyfip1 is one such protein, but the role it plays in brain development is poorly understood. We asked whether decreased Cyfip1 levels altered the function of developing synapses. The data show that synapses with reduced Cyfip1 are larger and release neurotransmitter more rapidly. These effects are due to Cyfip1's role in actin polymerization and are reversed by expression of a Cyfip1 mutant protein retaining actin regulatory function or by inhibiting Rac1. Thus, Cyfip1 has a more prominent early role regulating presynaptic activity during a stage of development when

  13. Transcriptional regulation of cranial sensory placode development

    PubMed Central

    Moody, Sally A.; LaMantia, Anthony-Samuel

    2015-01-01

    Cranial sensory placodes derive from discrete patches of the head ectoderm, and give rise to numerous sensory structures. During gastrulation, a specialized “neural border zone” forms around the neural plate in response to interactions between the neural and non-neural ectoderm and signals from adjacent mesodermal and/or endodermal tissues. This zone subsequently gives rise to two distinct precursor populations of the peripheral nervous system: the neural crest and the pre-placodal ectoderm (PPE). The PPE is a common field from which all cranial sensory placodes arise (adenohypophyseal, olfactory, lens, trigeminal, epibranchial, otic). Members of the Six family of transcription factors are major regulators of PPE specification, in partnership with co-factor proteins such as Eya. Six gene activity also maintains tissue boundaries between the PPE, neural crest and epidermis by repressing genes that specify the fates of those adjacent ectodermally-derived domains. As the embryo acquires anterior-posterior identity, the PPE becomes transcriptionally regionalized, and it subsequently subdivides into specific placodes with distinct developmental fates in response to signaling from adjacent tissues. Each placode is characterized by a unique transcriptional program that leads to the differentiation of highly specialized cells, such as neurosecretory cells, somatic sensory receptor cells, chemosensory neurons, peripheral glia and supporting cells. In this review, we summarize the transcriptional and signaling factors that regulate key steps of placode development, influence subsequent sensory neuron specification, and discuss what is known about mutations in some of the essential PPE genes that underlie human congenital syndromes. PMID:25662264

  14. Cytokinin signaling regulates cambial development in poplar.

    PubMed

    Nieminen, Kaisa; Immanen, Juha; Laxell, Marjukka; Kauppinen, Leila; Tarkowski, Petr; Dolezal, Karel; Tähtiharju, Sari; Elo, Annakaisa; Decourteix, Mélanie; Ljung, Karin; Bhalerao, Rishikesh; Keinonen, Kaija; Albert, Victor A; Helariutta, Ykä

    2008-12-16

    Although a substantial proportion of plant biomass originates from the activity of vascular cambium, the molecular basis of radial plant growth is still largely unknown. To address whether cytokinins are required for cambial activity, we studied cytokinin signaling across the cambial zones of 2 tree species, poplar (Populus trichocarpa) and birch (Betula pendula). We observed an expression peak for genes encoding cytokinin receptors in the dividing cambial cells. We reduced cytokinin levels endogenously by engineering transgenic poplar trees (P. tremula x tremuloides) to express a cytokinin catabolic gene, Arabidopsis CYTOKININ OXIDASE 2, under the promoter of a birch CYTOKININ RECEPTOR 1 gene. Transgenic trees showed reduced concentration of a biologically active cytokinin, correlating with impaired cytokinin responsiveness. In these trees, both apical and radial growth was compromised. However, radial growth was more affected, as illustrated by a thinner stem diameter than in WT at same height. To dissect radial from apical growth inhibition, we performed a reciprocal grafting experiment. WT scion outgrew the diameter of transgenic stock, implicating cytokinin activity as a direct determinant of radial growth. The reduced radial growth correlated with a reduced number of cambial cell layers. Moreover, expression of a cytokinin primary response gene was dramatically reduced in the thin-stemmed transgenic trees. Thus, a reduced level of cytokinin signaling is the primary basis for the impaired cambial growth observed. Together, our results show that cytokinins are major hormonal regulators required for cambial development.

  15. Analysis of circulating microRNAs in adrenocortical tumors.

    PubMed

    Szabó, Diana Rita; Luconi, Michaela; Szabó, Peter M; Tóth, Miklós; Szücs, Nikolette; Horányi, János; Nagy, Zoltán; Mannelli, Massimo; Patócs, Attila; Rácz, Károly; Igaz, Peter

    2014-03-01

    Differential diagnosis of adrenocortical adenoma (ACA) and carcinoma is of pivotal clinical relevance, as the prognosis and clinical management of benign and malignant adrenocortical tumors (ACTs) is entirely different. Circulating microRNAs (miRNAs) are promising biomarker candidates of malignancy in several tumors; however, there are still numerous technical problems associated with their analysis. The objective of our study was to investigate circulating miRNAs in ACTs and to evaluate their potential applicability as biomarkers of malignancy. We have also addressed technical questions including the choice of profiling and reference gene used. A total of 25 preoperative plasma samples obtained from patients with ACAs and carcinomas were studied by microarray and quantitative real-time PCR. None of the three miRNAs (hsa-miR-192, hsa-mir-197 and hsa-miR-1281) found as differentially expressed in plasma samples in our microarray screening could be validated by quantitative real-time PCR. In contrast, of the selected eight miRNAs reported in the literature as differentially expressed in ACT tissues, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR-210 and hsa-miR-483-5p) showed a statistically significant overexpression in adrenocortical cancer vs adenoma when normalized on hsa-miR-16 as a reference gene. Receiver operator characteristic analysis of data revealed that the combination of dCThsa-miR-210 - dCThsa-miR-181b and dCThsa-miR-100/dCThsa-miR-181b showed the highest diagnostic accuracy (area under curve 0.87 and 0.85, respectively). In conclusion, we have found significant differences in expression of circulating miRNAs between ACAs and carcinomas, but their diagnostic accuracy is not yet high enough for clinical application. Further studies on larger cohorts of patients are needed to assess the diagnostic and prognostic potential application of circulating miRNA markers.

  16. Development of a Fluidic Oxygen Regulator

    DTIC Science & Technology

    1977-01-01

    IMaJ «aa^^ ■"-i*--’L’ "’"’-—"’"lllMini pp Figure 5a. Breadboard of 0_ Regulator Figure 5b. Breadboard of O , Regulator (second view) 12 "’■■- "max i

  17. Modulation of proteomic profile in H295R adrenocortical cell line induced by mitotane.

    PubMed

    Stigliano, A; Cerquetti, L; Borro, M; Gentile, G; Bucci, B; Misiti, S; Piergrossi, P; Brunetti, E; Simmaco, M; Toscano, V

    2008-03-01

    Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloro-phenyl) ethane (o,p'-DDD), is a compound that represents the effective agent in the treatment of the adrenocortical carcinoma (ACC), able to block cortisol synthesis. In this type of cancer, the biological mechanism induced by this treatment remains still unknown. In this study, we have already shown a greater impairment in the first steps of the steroidogenesis and recognized a little effect on cell cycle. We also evaluated the variation of proteomic profile of the H295R ACC cell line, either in total cell extract or in mitochondria-enriched fraction after treatment with mitotane. In total cell extracts, triose phosphate isomerase, alpha-enolase, D-3-phosphoglycerate dehydrogenase, peroxiredoxin II and VI, heat shock protein 27, prohibitin, histidine triad nucleotide-binding protein, and profilin-1 showed a different expression. In the mitochondrial fraction, the following proteins appeared to be down regulated: aldolase A, peroxiredoxin I, heterogenous nuclear ribonucleoprotein A2/B1, tubulin-beta isoform II, heat shock cognate 71 kDa protein, and nucleotide diphosphate kinase, whereas adrenodoxin reductase, cathepsin D, and heat shock 70 kDa protein 1A were positively up-regulated. This study represents the first proteomic study on the mitotane effects on ACC. It permits to identify some protein classes affected by the drug involved in energetic metabolism, stress response, cytoskeleton structure, and tumorigenesis.

  18. Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

    PubMed

    Phan, Liem M; Fuentes-Mattei, Enrique; Wu, Weixin; Velazquez-Torres, Guermarie; Sircar, Kanishka; Wood, Christopher G; Hai, Tao; Jimenez, Camilo; Cote, Gilbert J; Ozsari, Levent; Hofmann, Marie-Claude; Zheng, Siyuan; Verhaak, Roeland; Pagliaro, Lance; Cortez, Maria Angelica; Lee, Mong-Hong; Yeung, Sai-Ching J; Habra, Mouhammed Amir

    2015-10-01

    Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.

  19. Developing self-regulation in early childhood☆

    PubMed Central

    Rothbart, Mary K.; Tang, Yiyuan

    2014-01-01

    Studies using fMRI at rest and during task performance have revealed a set of brain areas and their connections that can be linked to the ability of children to regulate their thoughts, actions and emotions. Higher self-regulation has also been related favorable outcomes in adulthood. These findings have set the occasion for methods of improving self-regulation via training. A tool kit of such methods is now available. It remains to be seen if educators will use these new findings and tools to forge practical methods for improving the lives of the world's children. PMID:24563845

  20. Complex Glycerol Kinase Deficiency and Adrenocortical Insufficiency in Two Neonates

    PubMed Central

    Korkut, Sabriye; Baştuğ, Osman; Raygada, Margarita; Hatipoğlu, Nihal; Kurtoğlu, Selim; Kendirci, Mustafa; Lyssikatos, Charalampos; Stratakis, Constantine A.

    2016-01-01

    Contiguous gene deletions of chromosome Xp21 can lead to glycerol kinase deficiency and severe adrenocortical insufficiency (AI) in a male newborn among other problems. We describe our experience with two such patients who presented with dysmorphic facies, AI, and pseudo-hypertriglyceridemia. Both infants had normal serum 17-hidroxyprogesterone levels, and adrenal glands could not be observed with ultrasonography. Creatine kinase and triglyceride levels were measured to elucidate the etiology of adrenal hypoplasia and were above normal limits in both cases. Both patients required steroid and salt supplementation. They were both found to have Xp21.2 deletions (DMD, NR0B1, GK, IL1RAPL1). We conclude that AI in the context of other genetic abnormalities should prompt chromosomal investigations in the absence of another unifying explanation. PMID:27087023

  1. Complex Glycerol Kinase Deficiency and Adrenocortical Insufficiency in Two Neonates.

    PubMed

    Korkut, Sabriye; Baştuğ, Osman; Raygada, Margarita; Hatipoğlu, Nihal; Kurtoğlu, Selim; Kendirci, Mustafa; Lyssikatos, Charalampos; Stratakis, Constantine A

    2016-12-01

    Contiguous gene deletions of chromosome Xp21 can lead to glycerol kinase deficiency and severe adrenocortical insufficiency (AI) in a male newborn among other problems. We describe our experience with two such patients who presented with dysmorphic facies, AI, and pseudo-hypertriglyceridemia. Both infants had normal serum 17-hidroxyprogesterone levels, and adrenal glands could not be observed with ultrasonography. Creatine kinase and triglyceride levels were measured to elucidate the etiology of adrenal hypoplasia and were above normal limits in both cases. Both patients required steroid and salt supplementation. They were both found to have Xp21.2 deletions (DMD, NR0B1, GK, IL1RAPL1). We conclude that AI in the context of other genetic abnormalities should prompt chromosomal investigations in the absence of another unifying explanation.

  2. An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis.

    PubMed

    Imrich, Richard; Vlcek, Miroslav; Aldag, Jean C; Kerlik, Jana; Radikova, Zofia; Rovensky, Jozef; Vigas, Milan; Masi, Alfonse T

    2010-04-01

    The concept of relative adrenal insufficiency (RAI) has been originally introduced to describe a situation in which critically ill patients, without any prior risk or evidence for adrenal insufficiency, have total serum cortisol levels inadequate for the severity of patients' illness. The concept provided a framework for other disease states, in which higher than normal adrenal function could be expected, such as in chronic inflammation. An intense research in RAI field highlighted some new methodological aspects that significantly improved assessment of adrenal function in chronic illness. Measurement of salivary cortisol may provide additional information on locally available cortisol in target tissues. Low levels of dehydroepiandrosterone (DHEAS) for given age and gender were confirmed as a simple and reliable indicator of decreased adrenal function, even in subjects with normal baseline cortisol or normal corticotropin-stimulated cortisol response. Combined lower DHEAS and lower baseline cortisol levels could be an example of hypocompetence of adrenocortical function, yet clinically not apparent.

  3. Actual 10-Year Survivors Following Resection of Adrenocortical Carcinoma

    PubMed Central

    Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Prescott, Jason D.; Wang, Tracy S.; Glenn, Jason; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Hatzaras, Ioannis; Shenoy, Rivfka; Pawlik, Timothy M.; Norton, Jeffrey A.; Poultsides, George A.

    2017-01-01

    Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long-term survivors following surgical resection for ACC have not been previously reported. Method Patients who underwent resection for ACC at one of 13 academic institutions participating in the US Adrenocortical Carcinoma Group from 1993 to 2014 were analyzed. Patients were stratified into four groups: early mortality (died within 2 years), late mortality (died within 2–5 years), actual 5-year survivor (survived at least 5 years), and actual 10-year survivor (survived at least 10 years). Patients with less than 5 years of follow-up were excluded. Results Among the 180 patients available for analysis, there were 49 actual 5-year survivors (27%) and 12 actual 10-year survivors (7%). Patients who experienced early mortality had higher rates of cortisol-secreting tumors, nodal metastasis, synchronous distant metastasis, and R1 or R2 resections (all P < 0.05). The need for multi-visceral resection, perioperative blood transfusion, and adjuvant therapy correlated with early mortality. However, nodal involvement, distant metastasis, and R1 resection did not preclude patients from becoming actual 10-year survivors. Ten of twelve actual 10-year survivors were women, and of the seven 10-year survivors who experienced disease recurrence, five had undergone repeat surgery to resect the recurrence. Conclusion Surgery for ACC can offer a 1 in 4 chance of actual 5-year survival and a 1 in 15 chance of actual 10-year survival. Long-term survival was often achieved with repeat resection for local or distant recurrence, further underscoring the important role of surgery in managing patients with ACC. PMID:27633419

  4. Lymphadenectomy for Adrenocortical Carcinoma: Is There a Therapeutic Benefit?

    PubMed Central

    Gerry, Jon M.; Tran, Thuy B.; Postlewait, Lauren M.; Maithel, Shishir K.; Prescott, Jason D.; Wang, Tracy S.; Glenn, Jason A.; Phay, John E.; Keplinger, Kara; Fields, Ryan C.; Jin, Linda X.; Weber, Sharon M.; Salem, Ahmed; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Hatzaras, Ioannis; Shenoy, Rivfka; Pawlik, Timothy M.; Norton, Jeffrey A.; Poultsides, George A.

    2017-01-01

    Background Lymph node metastasis is an established predictor of poor outcome for adrenocortical carcinoma (ACC); however, routine lymphadenectomy during surgical resection of ACC is not widely performed and its therapeutic role remains unclear. Methods Patients undergoing margin-negative resection for localized ACC were identified from a multi-institutional database. Patients were stratified into 2 groups based on the surgeon’s effort or not to perform a lymphadenectomy as documented in the operative note. Clinical, pathologic, and outcome data were compared between the 2 groups. Results Of 120 patients who met inclusion criteria from 1993 to 2014, 32 (27 %) underwent lymphadenectomy. Factors associated with lymphadenectomy were tumor size (12 vs. 9.5 cm; p = .007), palpable mass at presentation (26 vs. 12 %; p = .07), suspicious lymph nodes on preoperative imaging (44 vs. 7 %; p < .001), and need for multivisceral resection (78 vs. 36 %; p <.001). Median number of lymph nodes harvested was higher in the lymphadenectomy group (5.5 vs. 0; p < .001). In-hospital mortality (0 vs. 1.3 %; p =.72) and grade 3/4 complication rates (0 vs. 12 %; p = .061) were not significantly different. Patients who underwent lymphadenectomy had improved overall survival (5-year 76 vs. 59 %; p = .041). The benefit of lymphadenectomy on overall survival persisted on multivariate analysis (HR = 0.17; p = .006) controlling for adverse preoperative and intraoperative factors associated with lymphadenectomy, such as tumor size, palpable mass, irregular tumor edges, suspicious nodes on imaging, and multivisceral resection. Conclusions In this multicenter study of adrenocortical carcinoma patients undergoing R0 resection, the surgeon’s effort to dissect peritumoral lymph nodes was independently associated with improved overall survival. PMID:27590329

  5. Noninvasive monitoring of adrenocortical function in captive jaguars (Panthera onca).

    PubMed

    Conforti, Valéria A; Morato, Ronaldo G; Augusto, Anderson M; de Oliveira e Sousa, Lúcio; de Avila, David M; Brown, Janine L; Reeves, Jerry J

    2012-01-01

    Jaguars are threatened with extinction throughout their range. A sustainable captive population can serve as a hedge against extinction, but only if they are healthy and reproduce. Understanding how jaguars respond to stressors may help improve the captive environment and enhance their wellbeing. Thus, our objectives were to: (1) conduct an adrenocorticotrophic hormone (ACTH) challenge to validate a cortisol radioimmunoassay (RIA) for noninvasive monitoring of adrenocortical function in jaguars; (2) investigate the relationship between fecal corticoid (FCM) and androgen metabolite (FAM) concentrations in males during the ACTH challenge; and (3) establish a range of physiological concentrations of FCMs for the proposed protocol. Seven jaguars (3 M, 4 F) received 500 IU/animal of ACTH. Pre- and post-ACTH fecal samples were assayed for corticoid (M and F) and androgen metabolites (M) by RIA. Concentrations of FCMs increased (P80.01) after ACTH injection (pre-ACTH: 0.90 ± 0.12 µg/g dry feces; post-ACTH: 2.55 ± 0.25 µg/g). Considering pre- and post-ACTH samples, FCM concentrations were higher (P80.01) in males (2.15 ± 0.20 µg/g) than in females (1.30 ± 0.20 µg/g), but the magnitude of the response to ACTH was comparable (P>0.05) between genders. After ACTH injection, FAMs increased in two (of 3) males; in one male, FCMs and FAMs were positively correlated (0.60; P80.01). Excretion of FCMs was assessed in 16 jaguars (7 M, 9 F) and found to be highly variable (range, 80.11-1.56 µg/g). In conclusion, this study presents a cortisol RIA for monitoring adrenocortical function in jaguars noninvasively.

  6. Design and develop speed/pressure regulator

    SciTech Connect

    Hasanul Basher, A.M.

    1993-09-01

    The Physics Division at Oak Ridge National Laboratory has several recirculating water cooling systems. One of them supplies deionized water at 150 psi, which is mainly used for cooling magnet windings at the Oak Ridge Isochronous Cyclotron (ORIC). The system has three 125-hp water pumps, each of which is capable of supplying water at the rate of 1000 gpm. One of the major requirements of this water supply system is that the supply pressure must be kept constant. An adjustable-frequency speed controller was recently installed to control the speed of one of the pump motors. A servo-system was provided with the adjustable-frequency controller for regulating motor speed and, subsequently, the water pressure. After unsuccessful attempts to operate the servo, it was concluded that the regulator may not work for the existing system. Prior to installation of the variable-frequency controller, pressure regulation was accomplished with a pneumatically controlled load by-pass valve. To maintain constant pressure in the system, it is necessary to run always at full load, even if full load is not on the system. Hence, there is a waste of energy when full load is not connected to the system. So, designing and implementing one regulator that works at any load condition has become necessary. This report discusses the design of such a pressure regulator.

  7. GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

    PubMed Central

    Zolea, Fabiana; Rizza, Pietro; Avena, Paola; Malivindi, Rocco; De Luca, Arianna; Campana, Carmela; Martire, Emilia; Domanico, Francesco; Fallo, Francesco; Carpinelli, Giulia; Cerquetti, Lidia; Amendola, Donatella; Stigliano, Antonio; Pezzi, Vincenzo

    2015-01-01

    We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC. PMID:26131713

  8. Contributions of Steroidogenic Factor 1 to the Transcription Landscape of Y1 Mouse Adrenocortical Tumor Cells

    PubMed Central

    Schimmer, Bernard P.; Tsao, Jennivine; Cordova, Martha; Mostafavi, Sara; Morris, Quaid; Scheys, Joshua O.

    2011-01-01

    Summary The contribution of steroidogenic factor 1 (SF–1) to the gene expression profile of Y1 mouse adrenocortical cells was evaluated using short hairpin RNAs to knockdown SF–1. The reduced level of SF–1 RNA was associated with global changes that affected the accumulation of more than 2,000 transcripts. Among the down-regulated transcripts were several with functions in steroidogenesis that were affected to different degrees—i.e., Mc2r >Scarb1 > Star ≥ Hsd3b1 > Cyp11b1. For Star and Cyp11b1, the different levels of expression correlated with the amount of residual SF-1 bound to the proximal promoter regions. The knockdown of SF–1 did not affect the accumulation of Cyp11a1 transcripts even though the amount of SF–1 bound to the proximal promoter of the gene was reduced to background levels. Our results indicate that transcripts with functions in steroidogenesis vary in their dependence on SF–1 for constitutive expression. On a more global scale, SF–1 knockdown affects the accumulation of a large number of transcripts, most of which are not recognizably involved in steroid hormone biosynthesis. PMID:21111771

  9. StAR Protein Stability in Y1 and Kin-8 Mouse Adrenocortical Cells.

    PubMed

    Clark, Barbara J; Hudson, Elizabeth A

    2015-03-04

    The steroidogenic acute regulatory protein (STAR) protein expression is required for cholesterol transport into mitochondria to initiate steroidogenesis in the adrenal and gonads. STAR is synthesized as a 37 kDa precursor protein which is targeted to the mitochondria and imported and processed to an intra-mitochondrial 30 kDa protein. Tropic hormone stimulation of the cAMP-dependent protein kinase A (PKA) signaling pathway is the major contributor to the transcriptional and post-transcriptional regulation of STAR synthesis. Many studies have focused on the mechanisms of cAMP-PKA mediated control of STAR synthesis while there are few reports on STAR degradation pathways. The objective of this study was to determine the effect of cAMP-PKA-dependent signaling on STAR protein stability. We have used the cAMP-PKA responsive Y1 mouse adrenocortical cells and the PKA-deficient Kin-8 cells to measure STAR phosphorylation and protein half-life. Western blot analysis and standard radiolabeled pulse-chase experiments were used to determine STAR phosphorylation status and protein half-life, respectively. Our data demonstrate that PKA-dependent STAR phosphorylation does not contribute to 30 kDa STAR protein stability in the mitochondria. We further show that inhibition of the 26S proteasome does not block precursor STAR phosphorylation or steroid production in Y1 cells. These data suggest STAR can maintain function and promote steroidogenesis under conditions of proteasome inhibition.

  10. p53 Mutations in human adrenocortical neoplasms: Immunohistochemical and molecular studies

    SciTech Connect

    Reincke, M.; Allolio, B.; Travis, W.H.; Linehan, H.M.; Karl, M.; Mastorakos, G.; Chrousos, G.P.

    1994-03-01

    p53 is a recessive tumor suppressor gene located on chromosome 17p. Mutations in the p53 gene play an important role in the tumorigenesis of diverse types of human neoplasms including breast and colon cancers. More than 90% of all mutations discovered in such tumors have been detected in 4 hot spot areas that lie between exons 5 and 8. In contrast to wild-type p53, mutant p53 accumulates intracellularly and can be easily detected by immunohistochemistry. The authors therefore investigated the frequency of p53 mutations in human adrenocortical neoplasms using molecular biology and immunohistochemistry techniques. Five patients with adrenocortical adenomas (5 female; ages 39-72 yr), 11 patients with adrenocortical carcinomas (8 female, 3 male; ages 15-50 yr), and two adrenocortical tumor cell lines were studied. After DNA extraction from frozen tumor tissue or paraffin-embedded material, exons 5 through 8 were amplified using the polymerase chain reaction and directly sequenced by the dideoxy termination method. Immunohistochemistry was performed on paraffin-embedded tumor specimens obtained during adrenalectomy using a monoclonal antibody reacting with both wild-type and mutant p53. Prevalence of mutations was adenomas, 0/5, carcinomas, 3/11, and adrenocortical cell lines, 2/2. Single point mutations were detected in 3 cases (exons 5, 6, and 7, respectively), and rearrangements of exon 7/8 and 8 were found in 2 cases. Immunohistochemistry detected strong nuclear and/or cytoplasmic p53 immunoreactivity in all adrenocortical carcinomas with point mutations of the p53 gene but not in adenomas and carcinomas with the wild-type sequence or with deletion/rearrangement of the p53 gene. They conclude that p53 plays a role in the tumorigenesis of adrenocortical carcinomas but is of less importance to benign adenomas. 27 refs., 3 figs., 2 tabs.

  11. Developing Self-Regulated Learners in Secondary Schools

    ERIC Educational Resources Information Center

    Salter, Prue

    2012-01-01

    This paper draws on emerging data from a doctoral study exploring how schools approach the development of self-regulated learners in Years 7-12. The research is exploring stakeholders' attitudes, beliefs, experiences and perceptions around the development of self-regulated learning (SRL) in contemporary secondary schools and how new and emerging…

  12. Adiponectin (15-36) stimulates steroidogenic acute regulatory (StAR) protein expression and cortisol production in human adrenocortical cells: role of AMPK and MAPK kinase pathways.

    PubMed

    Ramanjaneya, Manjunath; Conner, Alex C; Brown, James E P; Chen, Jing; Digby, Janet E; Barber, Thomas M; Lehnert, Hendrik; Randeva, Harpal S

    2011-05-01

    Adiponectin is an abundantly circulating adipokine, orchestrating its effects through two 7-transmembrane receptors (AdipoR1 and AdipoR2). Steroidogenesis is regulated by a variety of neuropeptides and adipokines. Earlier studies have reported adipokine mediated steroid production. A key rate-limiting step in steroidogenesis is cholesterol transportation across the mitochondrial membrane by steroidogenic acute regulatory protein (StAR). Several signalling pathways regulate StAR expression. The actions of adiponectin and its role in human adrenocortical steroid biosynthesis are not fully understood. The aim of this study was to investigate the effects of adiponectin on StAR protein expression, steroidogenic genes, and cortisol production and to dissect the signalling cascades involved in the activation of StAR expression. Using qRT-PCR, Western blot analysis and ELISA, we have demonstrated that stimulation of human adrenocortical H295R cells with adiponectin results in increased cortisol secretion. This effect is accompanied by increased expression of key steroidogenic pathway genes including StAR protein expression via ERK1/2 and AMPK-dependent pathways. This has implications for our understanding of adiponectin receptor activation and peripheral steroidogenesis. Finally, our study aims to emphasise the key role of adipokines in the integration of metabolic activity and energy balance partly via the regulation of adrenal steroid production. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

  13. A rare case of Cushing's syndrome due to bilateral adrenocortical adenomas.

    PubMed

    Yasuda, Atsushi; Seki, Toshiro; Ito, Kazuko; Takagi, Atsushi; Watanabe, Daisuke; Nakamura, Naoya; Hanai, Kazuya; Terachi, Toshiro; Maekawa, Takashi; Sasano, Hironobu; Fukagawa, Masafumi

    2014-12-20

    We report a rare case of Cushing's syndrome caused by bilateral cortisol-secreting adenomas in a 63-year-old man. Our preoperative diagnosis was based on endocrinological results and imaging findings. Laparoscopic adrenalectomy has become a standard technique for adrenal tumors; however, bilateral adrenalectomy results in postoperative adrenal insufficiency, necessitating lifelong steroid replacement. To preserve adrenal function, the left adrenal gland was completely resected, whereas the right adrenal gland was partially resected laparoscopically. Hydrocortisone supplementation was initiated at a dose of 30 mg/day and was slowly tapered. However, symptoms of adrenal insufficiency developed, and adrenal steroid secretion did not respond to exogenous adrenocorticotropic hormone. Bilateral cortisol-secreting tumors rarely cause Cushing's syndrome. The present study comprised few patients, and the utilized surgical procedures (i.e., total/partial adrenalectomy or bilateral total adrenalectomy) were not uniform. Few cases of bilateral adrenal-preserving surgery have been reported. However, our patient developed adrenal insufficiency after the oral cortisone supplementation was tapered. This report demonstrates that partial adrenalectomy does not necessarily preserve normal adrenocortical function. Therefore, careful postoperative observation is necessary for patients undergoing a partial adrenalectomy.

  14. Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith–Wiedemann syndrome as a sporadic adrenocortical tumor

    PubMed Central

    H'mida Ben-Brahim, Dorra; Hammami, Sabeur; Haddaji Mastouri, Marwa; Trabelsi, Saoussen; Chourabi, Maroua; Sassi, Sihem; Mougou, Soumaya; Gribaa, Moez; Zakhama, Abdelfattah; Guédiche, Mohamed Neji; Saad, Ali

    2014-01-01

    Beckwith–Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith–Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith–Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith–Wiedemann syndrome presentation. PMID:26937341

  15. Network analysis reveals potential markers for pediatric adrenocortical carcinoma

    PubMed Central

    Kulshrestha, Anurag; Suman, Shikha; Ranjan, Rakesh

    2016-01-01

    Pediatric adrenocortical carcinoma (ACC) is a rare malignancy with a poor outcome. Molecular mechanisms of pediatric ACC oncogenesis and advancement are not well understood. Accurate and timely diagnosis of the disease requires identification of new markers for pediatric ACC. Differentially expressed genes (DEGs) were identified from the gene expression profile of pediatric ACC and obtained from Gene Expression Omnibus. Gene Ontology functional and pathway enrichment analysis was implemented to recognize the functions of DEGs. A protein–protein interaction (PPI) and gene–gene functional interaction (GGI) network of DEGs was constructed. Hub gene detection and enrichment analysis of functional modules were performed. Furthermore, a gene regulatory network incorporating DEGs–microRNAs–transcription factors was constructed and analyzed. A total of 431 DEGs including 228 upregulated and 203 downregulated DEGs were screened. These genes were largely involved in cell cycle, steroid biosynthesis, and p53 signaling pathways. Upregulated genes, CDK1, CCNB1, CDC20, and BUB1B, were identified as the common hubs of PPI and GGI networks. All the four common hub genes were also part of modules of the PPI network. Moreover, all the four genes were also present in the largest module of GGI network. A gene regulatory network consisting of 82 microRNAs and 100 transcription factors was also constructed. CDK1, CCNB1, CDC20, and BUB1B may serve as potential biomarker of pediatric ACC and as potential targets for therapeutic approach, although experimental studies are required to authenticate our findings. PMID:27555782

  16. Temperature and adrenocortical responses in rhesus monkeys exposed to microwaves

    SciTech Connect

    Lotz, W.G.; Podgorski, R.P.

    1982-12-01

    To determine if the endocrine response to microwave exposure was similar in a primate to that reported for other animals, rectal temperature and plasma levels of cortisol, thyroxine (T4), and growth hormone (GH) were measured in rhesus monkeys exposed to 1.29-GHz microwave radiation. Exposures were carried out under far-field conditions with the monkey restrained in a chair. Incident power densities of 0, 20, 28, and 38 mW/sq cm were used, with corresponding specific absorption rates of 0, 2.1, 3.0, and 4.1 W/kg. Blood samples were taken hourly via an indwelling jugular venous catheter over a 24-h period before, during, and after an 8-h exposure. Rectal temperature increased an average of 0.5, 0.7, and 1.7 C for the three intensities used. No changes in T4 or GH were observed. Cortisol levels were increased during exposure to 38 mW/sq cm. It was concluded that the temperature and adrenocortical responses to microwave exposure of the rhesus monkey are similar to the corresponding responses of other animals.

  17. Cell fate regulation in early mammalian development

    NASA Astrophysics Data System (ADS)

    Oron, Efrat; Ivanova, Natalia

    2012-08-01

    Preimplantation development in mammals encompasses a period from fertilization to implantation and results in formation of a blastocyst composed of three distinct cell lineages: epiblast, trophectoderm and primitive endoderm. The epiblast gives rise to the organism, while the trophectoderm and the primitive endoderm contribute to extraembryonic tissues that support embryo development after implantation. In many vertebrates, such as frog or fish, maternally supplied lineage determinants are partitioned within the egg. Cell cleavage that follows fertilization results in polarization of these factors between the individual blastomeres, which become restricted in their developmental fate. In contrast, the mouse oocyte and zygote lack clear polarity and, until the eight-cell stage, individual blastomeres retain the potential to form all lineages. How are cell lineages specified in the absence of a maternally supplied blueprint? This is a fundamental question in the field of developmental biology. The answer to this question lies in understanding the cell-cell interactions and gene networks involved in embryonic development prior to implantation and using this knowledge to create testable models of the developmental processes that govern cell fates. We provide an overview of classic and contemporary models of early lineage development in the mouse and discuss the emerging body of work that highlights similarities and differences between blastocyst development in the mouse and other mammalian species.

  18. Epigenetic and microRNA regulation during osteoarthritis development

    PubMed Central

    Chen, Di; Shen, Jie; Hui, Tianqian

    2015-01-01

    Osteoarthritis (OA) is a common degenerative joint disease, the pathological mechanism of which is currently unknown. Genetic alteration is one of the key contributing factors for OA pathology. Recent evidence suggests that epigenetic and microRNA regulation of critical genes may contribute to OA development. In this article, we review the epigenetic and microRNA regulations of genes related to OA development. Potential therapeutic strategies may be developed on the basis of novel findings. PMID:27508054

  19. Neuromuscular Development and Regulation of Myosin Expression

    NASA Technical Reports Server (NTRS)

    Bodine, Sue

    1997-01-01

    The proposed experiments were designed to determine whether the absence of gravity during embryogenesis influences the postnatal development of the neuromuscular system. Further, we examined the effects of reduced gravity on hindlimb muscles of the pregnant rats. Microgravity may have short and long-term effects on the development of muscle fiber type differentiation and force producing capabilities. Microgravity will reduce muscle fiber size and cause a shift in myosin heavy chain expression from slow to fast in hindlimb muscles of the adult pregnant rats.

  20. Effects of Neonicotinoids on Promoter-Specific Expression and Activity of Aromatase (CYP19) in Human Adrenocortical Carcinoma (H295R) and Primary Umbilical Vein Endothelial (HUVEC) Cells.

    PubMed

    Caron-Beaudoin, Élyse; Denison, Michael S; Sanderson, J Thomas

    2016-01-01

    The enzyme aromatase (CYP19; cytochrome P450 19) in humans undergoes highly tissue- and promoter-specific regulation. In hormone-dependent breast cancer, aromatase is over-expressed via several normally inactive promoters (PII, I.3, I.7). Aromatase biosynthesizes estrogens, which stimulate breast cancer cell proliferation. The placenta produces estrogens required for healthy pregnancy and the major placental CYP19 promoter is I.1. Exposure to certain pesticides, such as atrazine, is associated with increased CYP19 expression, but little is known about the effects of neonicotinoid insecticides on CYP19. We developed sensitive and robust RT-qPCR methods to detect the promoter-specific expression of CYP19 in human adrenocortical carcinoma (H295R) and primary umbilical vein endothelial (HUVEC) cells, and determined the potential promoter-specific disruption of CYP19 expression by atrazine and the commonly used neonicotinoids imidacloprid, thiacloprid, and thiamethoxam. In H295R cells, atrazine concentration-dependently increased PII- and I.3-mediated CYP19 expression and aromatase catalytic activity. Thiacloprid and thiamethoxam induced PII- and I.3-mediated CYP19 expression and aromatase activity at relatively low concentrations (0.1-1.0 µM), exhibiting non-monotonic concentration-response curves with a decline in gene induction and catalytic activity at higher concentrations. In HUVEC cells, atrazine slightly induced overall (promoter-indistinct) CYP19 expression (30 µM) and aromatase activity (≥ 3 µM), without increasing I.1 promoter activity. None of the neonicotinoids increased CYP19 expression or aromatase activity in HUVEC cells. Considering the importance of promoter-specific (over)expression of CYP19 in disease (breast cancer) or during sensitive developmental periods (pregnancy), our newly developed RT-qPCR methods will be helpful tools in assessing the risk that neonicotinoids and other chemicals may pose to exposed women.

  1. Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

    PubMed Central

    Hayashi, Yuichiro; Al-Eyd, Ghaith; Nakagawa, Ken; Morita, Shinya; Kosaka, Takeo; Oya, Mototsugu; Mitani, Fumiko; Suematsu, Makoto; Kabe, Yasuaki

    2016-01-01

    Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults. PMID:27721827

  2. Development of male-fertility-regulating agents.

    PubMed

    Ray, S; Verma, P; Kumar, A

    1991-09-01

    Steroidal, nonsteroidal, plant-derived, gonadotropin-related and immunological agents investigated for control of male fertility are reviewed with brief descriptions of their effects, and illustrations of their structures. The physiology of the male reproductive system is presented as an introduction: an ideal male antifertility agent would inhibit spermatogenesis at the level of the Sertoli cells, without affecting endogenous androgen production by Leydig cells, needed for libido and potency. Androgens down-regulate their own production at physiological levels, but few long-acting orally active derivatives are available. Anti-androgens with mixed androgen and progestin activity, combined with a pure androgen are potentially useful. Androgen-progestin combinations are being tested by WHO as implants. Dozens of miscellaneous nonsteroidal compounds have been discovered serendipitously to have antifertility activity in men or male animals, including alkylating agents antimetabolites, antibiotics, sulfa derivatives, fungicides, trichomonocides, amebicides, alpha blockers, antimalarials, coumarins, and carbohydrate derivatives. Various plant alkaloids have been screened. Those of Hibiscus, Vitex and Plumbago species, as well as Tripterygium wilfordii glycosides, which are being evaluated in combination with gossypol, are mentioned here. Gossypol has been thoroughly tested in China, but rejected because of its side effects, particularly hypokalemic paralysis, its low therapeutic index, and uncertain recovery of fertility. Gonadotropin-releasing hormone (GnRH) agonists and antagonists are being researched in combination with androgens with some success. The GnRH antagonists to date have low activity , or cause histamine-related side effects at higher doses; the androgens require a new route such as a long-acting implant to overcome the need for daily injections. Immunological contraception for males has not progressed beyond the research stage.

  3. Proteome Regulation during Olea europaea Fruit Development

    PubMed Central

    Bianco, Linda; Alagna, Fiammetta; Baldoni, Luciana; Finnie, Christine; Svensson, Birte; Perrotta, Gaetano

    2013-01-01

    Background Widespread in the Mediterranean basin, Olea europaea trees are gaining worldwide popularity for the nutritional and cancer-protective properties of the oil, mechanically extracted from ripe fruits. Fruit development is a physiological process with remarkable impact on the modulation of the biosynthesis of compounds affecting the quality of the drupes as well as the final composition of the olive oil. Proteomics offers the possibility to dig deeper into the major changes during fruit development, including the important phase of ripening, and to classify temporal patterns of protein accumulation occurring during these complex physiological processes. Methodology/Principal Findings In this work, we started monitoring the proteome variations associated with olive fruit development by using comparative proteomics coupled to mass spectrometry. Proteins extracted from drupes at three different developmental stages were separated on 2-DE and subjected to image analysis. 247 protein spots were revealed as differentially accumulated. Proteins were identified from a total of 121 spots and discussed in relation to olive drupe metabolic changes occurring during fruit development. In order to evaluate if changes observed at the protein level were consistent with changes of mRNAs, proteomic data produced in the present work were compared with transcriptomic data elaborated during previous studies. Conclusions/Significance This study identifies a number of proteins responsible for quality traits of cv. Coratina, with particular regard to proteins associated to the metabolism of fatty acids, phenolic and aroma compounds. Proteins involved in fruit photosynthesis have been also identified and their pivotal contribution in oleogenesis has been discussed. To date, this study represents the first characterization of the olive fruit proteome during development, providing new insights into fruit metabolism and oil accumulation process. PMID:23349718

  4. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors

    SciTech Connect

    Gicquel, C.; Schneid, H.; Le Bouc, Y.; Bertagna, X.; Francillard-Leblond, M.; Luton, J.P.; Girard, F.

    1994-06-01

    Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly in adrenocortical tumors associated with the Beckwith-Wiedemann syndrome, and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, the authors looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing`s syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing`s syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, a uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis. 58 refs., 6 figs., 4 tabs.

  5. Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation.

    PubMed

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Misiti, Silvia; Raza, Giorgio; De Paula, Ugo; Marchese, Rodolfo; Brunetti, Ercole; Toscano, Vincenzo; Stigliano, Antonio

    2010-08-01

    Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10(-5) M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability.

  6. BMP4 regulation of human trophoblast development

    PubMed Central

    Li, Yingchun; Parast, Mana M.

    2017-01-01

    Since derivation of human embryonic stem cells, and subsequent generation of induced pluripotent stem cells, there has been much excitement about the ability to model and evaluate human organ development in vitro. The finding that these cells, when treated with BMP4, are able to generate the extraembryonic cell type, trophoblast, which is the predominant functional epithelium in the placenta, has not been widely accepted. This review evaluates this model, providing comparison to early known events during placentation in both human and mouse and addressing specific challenges. Keeping in mind the ultimate goal of understanding human placental development and pregnancy disorders, our aim here is two-fold: 1) to distinguish gaps in knowledge from mis- or over-interpretation of data, and 2) to recognize the limitations of both mouse and human models, but work within those limitations towards the ultimate goal. PMID:25023690

  7. Adolescents' Self-Regulation Development via the Sensory Room System

    ERIC Educational Resources Information Center

    Kalimullin, Aydar M.; Kuvaldina, Elana A.; Koinova-Zoellner, Julia

    2016-01-01

    The urgency of the issue stated in this article is caused by the need for mastering skills and patterns of self-regulation when being an adolescent since this time is sensitive for developing processes of personal understanding and evolution. Thus, mastering skills and patterns of self-regulation as a necessary part of the whole ability of…

  8. Development of a Metaconceptual Awareness and Regulation Scale

    ERIC Educational Resources Information Center

    Kirbulut, Zubeyde Demet; Uzuntiryaki-Kondakci, Esen; Beeth, Michael Edward

    2016-01-01

    This study aimed to develop the Metaconceptual Awareness and Regulation Scale (MARS) -- a self-report instrument for measuring the extent to which students realise, monitor, and evaluate their ideas. MARS consists of 10 items scored on a six-point Likert scale for two factors: metaconceptual awareness and metaconceptual regulation. A pilot study…

  9. Coping, Regulation, and Development during Childhood and Adolescence

    ERIC Educational Resources Information Center

    Compas, Bruce E.

    2009-01-01

    This chapter identifies four challenges to the study of the development of coping and regulation and outlines specific theoretical and empirical strategies for addressing them. The challenges are (1) to integrate work on coping and processes of emotion regulation, (2) to use the integration of research on neuro-biology and context to inform the…

  10. Developing Self-Regulated Learners through an Intelligent Tutoring System

    ERIC Educational Resources Information Center

    Kelly, Kim; Heffernan, Neil

    2015-01-01

    Intelligent tutoring systems have been developed to help students learn independently. However, students who are poor self-regulated learners often struggle to use these systems because they lack the skills necessary to learn independently. The field of psychology has extensively studied self-regulated learning and can provide strategies to…

  11. Developing Young Children's Self-Regulation through Everyday Experiences

    ERIC Educational Resources Information Center

    Florez, Ida Rose

    2011-01-01

    Every child is different. Some have difficulty expressing their ideas verbally. Some struggle to get along with peers or follow classroom routines. In each case, however, one thing is the same: improved learning and behavior requires strong self-regulation skills. Children develop foundational skills for self-regulation in the first five years of…

  12. PEROXISOMES IN INNER ADRENOCORTICAL CELLS OF FETAL AND ADULT GUINEA PIGS

    PubMed Central

    Black, Virginia H.; Bogart, Bruce I.

    1973-01-01

    Abundant membrane-bounded granules, 0.1–0.45 µm in diameter, occur among the elements of the smooth-surfaced endoplasmic reticulum in zona fasciculata and zona reticularis adrenocortical cells of guinea pigs. Acid phosphatase cannot be cytochemically demonstrated in them, and they are therefore distinct from lysosomes. Incubation in medium containing 3,3'-diaminobenzidine results in dense staining of the granules, identifying them as peroxisomes. These small peroxisomes increase in number as fetal adrenocortical cells differentiate, and they appear to arise from dilated regions of endoplasmic reticulum. They maintain interconnections with the smooth endoplasmic reticulum and with one another. PMID:4633170

  13. Loss of sensitivity to ACTH of adrenocortical cells isolated from maturing domestic fowl.

    PubMed

    Carsia, R V; Scanes, C G; Malamed, S

    1985-07-01

    Maturation of domestic fowl corticosteroidogenesis was evaluated using purified adrenocortical cells. Basal corticosterone production decreased steadily from 2 days to 26 weeks after hatching. However, maximally stimulated corticosterone production was not changed. In contrast, the half-maximal steroidogenic concentrations (ED50 values or effective doses for 50% maximal effect) of ACTH analogs increased approximately 40 times by 26 weeks, but the ED50 values of 8-bromo-cyclic AMP and pregnenolone were not changed. This suggests that adrenocortical cell sensitivity to ACTH decreases with maturation of the domestic fowl.

  14. Ectopic Adrenocortical Tissue in the Spermatic Cord in a 44-Year-old Man☆

    PubMed Central

    Müllhaupt, Gautier; Mordasini, Livio; Gramann, Tobias; Ertel, Vera; Schmid, Hans-Peter; Abt, Dominik

    2014-01-01

    We report on a 44-year-old man who underwent microsurgical inguinal repair for symptomatic varicocele. As an incidental finding during surgery, a yellowish tumor (9 × 5 × 4 mm) was found in the spermatic cord. Histologic examination revealed ectopic adrenocortical tissue. Ectopic adrenocortical tissue in the spermatic cord is known to appear in children and adolescents but is extremely rare in adults. Surgical removal of the tissue is recommended, although malignant transformation or functional hormonal disorders are very unlikely. PMID:26958477

  15. Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways1 2

    PubMed Central

    Ronchi, Cristina L; Leich, Ellen; Sbiera, Silviu; Weismann, Dirk; Rosenwald, Andreas; Allolio, Bruno; Fassnacht, Martin

    2012-01-01

    The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≥20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors. PMID:22496620

  16. Neurocognitive bases of emotion regulation development in adolescence.

    PubMed

    Ahmed, Saz P; Bittencourt-Hewitt, Amanda; Sebastian, Catherine L

    2015-10-01

    Emotion regulation is the ability to recruit processes to influence emotion generation. In recent years there has been mounting interest in how emotions are regulated at behavioural and neural levels, as well as in the relevance of emotional dysregulation to psychopathology. During adolescence, brain regions involved in affect generation and regulation, including the limbic system and prefrontal cortex, undergo protracted structural and functional development. Adolescence is also a time of increasing vulnerability to internalising and externalising psychopathologies associated with poor emotion regulation, including depression, anxiety and antisocial behaviour. It is therefore of particular interest to understand how emotion regulation develops over this time, and how this relates to ongoing brain development. However, to date relatively little research has addressed these questions directly. This review will discuss existing research in these areas in both typical adolescence and in adolescent psychopathology, and will highlight opportunities for future research. In particular, it is important to consider the social context in which adolescent emotion regulation develops. It is possible that while adolescence may be a time of vulnerability to emotional dysregulation, scaffolding the development of emotion regulation during this time may be a fruitful preventative target for psychopathology.

  17. Regulation of CDPK isoforms during tuber development.

    PubMed

    Raíces, Marcela; Gargantini, Pablo Rubén; Chinchilla, Delphine; Crespi, Martín; Téllez-Iñón, María Teresa; Ulloa, Rita María

    2003-07-01

    CDPK activities present during tuber development were analysed. A high CDPK activity was detected in the soluble fraction of early stolons and a lower one was detected in soluble and particulate fractions of induced stolons. The early and late CDPK activities displayed diverse specificity for in vitro substrates and different subcellular distribution. Western blot analysis revealed two CDPKs of 55 and 60 kDa that follow a precise spatial and temporal profile of expression. The 55 kDa protein was only detected in early-elongating stolons and the 60 kDa one was induced upon stolon swelling, correlating with early and late CDPK activities. A new member of the potato CDPK family, StCDPK3, was identified from a stolon cDNA library. Gene specific RT-PCR demonstrated that this gene is only expressed in early stolons, while the previously identified StCDPK1 is expressed upon stolon swelling. This expression profile suggests that StCDPK3 could correspond to the 55 kDa isoform while StCDPK1 could encode the 60 kDa isoform present in swelling stolons. StCDPK1 has myristoylation and palmitoylation consensus possibly involved in its dual intracellular localization. Transient expression studies with wild-type and mutated forms of StCDPK1 fused to GFP were used to show that subcellular localization of this isoform is controlled by myristoylation and palmitoylation. Altogether, our data suggest that sequential activation of StCDPK3 and StCDPK1 and the subcellular localisation of StCDPK1 might be critical regulatory steps of calcium signalling during potato tuber development.

  18. Development of a Pressure Regulator to Conserve Energy Emitting in LP Gas Pressure Regulator

    NASA Astrophysics Data System (ADS)

    Kurihara, Yosuke; Misawa, Keigo; Watanabe, Kajiro; Kobayashi, Kazuyuki

    The development of electronics devices yields circuits which operates with low power consumption. This paper is aimed at describing a novel power supply system to such the devices. The energy levels diverged by mechanical vibration, pressure drops by regulators, thermal diverged, are low in the mechanical field but high enough to operate the electronics devices above. Here we describe a novel energy collecting method from pressure regulators in which high pressure is regulated to constant low pressure. In the regulation, energy is diverged. The method converts gas flow to rotation by a pneumatic motor and generates electric power by a generator connected with the motor. An LP gas regulator under normal use in a house, diverges about 30W energy. The devices developed here collected about 9W energy which is enough high for operating electronics devices around LP gas including intelligent gas meter.

  19. Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells.

    PubMed

    Sbiera, Silviu; Leich, Ellen; Liebisch, Gerhard; Sbiera, Iuliu; Schirbel, Andreas; Wiemer, Laura; Matysik, Silke; Eckhardt, Carolin; Gardill, Felix; Gehl, Annemarie; Kendl, Sabine; Weigand, Isabel; Bala, Margarita; Ronchi, Cristina L; Deutschbein, Timo; Schmitz, Gerd; Rosenwald, Andreas; Allolio, Bruno; Fassnacht, Martin; Kroiss, Matthias

    2015-11-01

    Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.

  20. The development of self-regulation across early childhood.

    PubMed

    Montroy, Janelle J; Bowles, Ryan P; Skibbe, Lori E; McClelland, Megan M; Morrison, Frederick J

    2016-11-01

    The development of early childhood self-regulation is often considered an early life marker for later life successes. Yet little longitudinal research has evaluated whether there are different trajectories of self-regulation development across children. This study investigates the development of behavioral self-regulation between the ages of 3 and 7 years, with a direct focus on possible heterogeneity in the developmental trajectories, and a set of potential indicators that distinguish unique behavioral self-regulation trajectories. Across 3 diverse samples, 1,386 children were assessed on behavioral self-regulation from preschool through first grade. Results indicated that majority of children develop self-regulation rapidly during early childhood, and that children follow 3 distinct developmental patterns of growth. These 3 trajectories were distinguishable based on timing of rapid gains, as well as child gender, early language skills, and maternal education levels. Findings highlight early developmental differences in how self-regulation unfolds, with implications for offering individualized support across children. (PsycINFO Database Record

  1. Adrenocortical adenoma and carcinoma: histopathological and molecular comparative analysis.

    PubMed

    Stojadinovic, Alexander; Brennan, Murray F; Hoos, Axel; Omeroglu, Atilla; Leung, Denis H Y; Dudas, Maria E; Nissan, Aviram; Cordon-Cardo, Carlos; Ghossein, Ronald A

    2003-08-01

    We compared histomorphological features and molecular expression profiles of adrenocortical adenomas (ACAd) and carcinomas (ACCa). A critical histopathological review (mean, 11 slides per patient) was conducted of 37 ACAd and 67 ACCa. Paraffin-embedded tissue cores of ACAd (n = 33) and ACCa (n = 38) were arrayed in triplicate on tissue microarrays. Expression profiles of p53, mdm-2, p21, Bcl-2, cyclin D1, p27, and Ki-67 were investigated by immunohistochemistry and correlated with histopathology and patient outcome using standard statistical methodology. Median follow-up period was 5 years. Tumor necrosis, atypical mitoses, and >1 mitosis per 50 high-power fields were factors that were highly specific for ACCa (P <.001). Number (0 to 4) of unfavorable markers [Ki-67 (+), p21 (+), p27 (+), mdm-2(-)] expressed was significantly associated with mitotic activity and morphologic index (i.e., number of adverse morphologic features) and highly predictive of malignancy (P <.001). Ki-67 overexpression occurred in 0 ACAd and 36% ACCa (P <.001) and was significantly associated with mitotic rate and unfavorable morphologic index (P <.001). Tumor necrosis, atypical mitoses, >5 mitoses per 50 high-power fields, sinusoidal invasion, histologic index of >5, and presence of more than two unfavorable molecular markers were associated significantly with metastasis in ACCa. Well-established histopathologic criteria and Ki-67 can specifically distinguish ACCAd from ACCa. Tumor cell proliferation (Ki-67) correlates with mitotic activity and morphologic index. Tumor morphology is a better predictor of metastatic risk in ACCa than current immunohistochemistry-detected cell cycle regulatory and proliferation-associated proteins.

  2. Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression

    PubMed Central

    Huang, Jiwei; Kong, Wen; Xue, Wei; Zhu, Yu; Zhang, Jin; Huang, Yiran

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC. PMID:26673009

  3. Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.

    PubMed

    Manenschijn, L; Quinkler, M; van Rossum, E F C

    2014-04-01

    The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mitotane is adrenolytic and therefore, hydrocortisone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Evaluation of hydrocortisone therapy in mitotane-treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydrocortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocortisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair segments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (β=0.03, p=0.93), hair cortisol levels were associated with BMI (β=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (β=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydrocortisone treatment in mitotane-treated ACC patients.

  4. RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

    PubMed Central

    Martin-Vilchez, Samuel; Whitmore, Leanna; Asmussen, Hannelore; Zareno, Jessica; Horwitz, Rick; Newell-Litwa, Karen

    2017-01-01

    Small RhoGTPases regulate changes in post-synaptic spine morphology and density that support learning and memory. They are also major targets of synaptic disorders, including Autism. Here we sought to determine whether upstream RhoGTPase regulators, including GEFs, GAPs, and GDIs, sculpt specific stages of synaptic development. The majority of examined molecules uniquely regulate either early spine precursor formation or later maturation. Specifically, an activator of actin polymerization, the Rac1 GEF β-PIX, drives spine precursor formation, whereas both FRABIN, a Cdc42 GEF, and OLIGOPHRENIN-1, a RhoA GAP, regulate spine precursor elongation. However, in later development, a novel Rac1 GAP, ARHGAP23, and RhoGDIs inactivate actomyosin dynamics to stabilize mature synapses. Our observations demonstrate that specific combinations of RhoGTPase regulatory proteins temporally balance RhoGTPase activity during post-synaptic spine development. PMID:28114311

  5. Thyroid hormone regulated genes in cerebral cortex development.

    PubMed

    Bernal, Juan

    2017-02-01

    The physiological and developmental effects of thyroid hormones are mainly due to the control of gene expression after interaction of T3 with the nuclear receptors. To understand the role of thyroid hormones on cerebral cortex development, knowledge of the genes regulated by T3 during specific stages of development is required. In our laboratory, we previously identified genes regulated by T3 in primary cerebrocortical cells in culture. By comparing these data with transcriptomics of purified cell types from the developing cortex, the cellular targets of T3 can be identified. In addition, many of the genes regulated transcriptionally by T3 have defined roles in cortex development, from which the role of T3 can be derived. This review analyzes the specific roles of T3-regulated genes in the different stages of cortex development within the physiological frame of the developmental changes of thyroid hormones and receptor concentrations in the human cerebral cortex during fetal development. These data indicate an increase in the sensitivity to T3 during the second trimester of fetal development. The main cellular targets of T3 appear to be the Cajal-Retzius and the subplate neurons. On the other hand, T3 regulates transcriptionally genes encoding extracellular matrix proteins, involved in cell migration and the control of diverse signaling pathways.

  6. miR-200 Regulates Endometrial Development During Early Pregnancy.

    PubMed

    Jimenez, Patricia T; Mainigi, Monica A; Word, R Ann; Kraus, W Lee; Mendelson, Carole R

    2016-09-01

    For successful embryo implantation, endometrial stromal cells must undergo functional and morphological changes, referred to as decidualization. However, the molecular mechanisms that regulate implantation and decidualization are not well defined. Here we demonstrate that the estradiol- and progesterone-regulated microRNA (miR)-200 family was markedly down-regulated in mouse endometrial stromal cells prior to implantation, whereas zinc finger E-box binding homeobox-1 and -2 and other known and predicted targets were up-regulated. Conversely, miR-200 was up-regulated during in vitro decidualization of human endometrial stromal cells. Knockdown of miR-200 negatively affected decidualization and prevented the mesenchymal-epithelial transition-like changes that accompanied decidual differentiation. Notably, superovulation of mice and humans altered miR-200 expression. Our findings suggest that hormonal alterations that accompany superovulation may negatively impact endometrial development and decidualization by causing aberrant miR-200 expression.

  7. Reciprocal Influences among Adrenocortical Activation, Psychosocial Processes, and the Behavioral Adjustment of Clinic-Referred Children.

    ERIC Educational Resources Information Center

    Granger, Douglas A.; And Others

    1996-01-01

    Assessed children's adjustment at clinic intake and six months later, and sampled children's saliva before and after a conflict-oriented parent-child interaction. Increases in salivary cortisol predicted children's internalizing problem behaviors and anxiety disorders at follow-up. High adrenocortical reactivity at intake and follow-up was…

  8. The Relations between Bullying Exposures in Middle Childhood, Anxiety, and Adrenocortical Activity

    ERIC Educational Resources Information Center

    Carney, JoLynn V.; Hazler, Richard J.; Oh, Insoo; Hibel, Leah C.; Granger, Douglas A.

    2010-01-01

    This exploratory study investigated how exposure to bullying at school in middle childhood is associated with student anxiety levels and adrenocortical activity at a time preceding lunch when anxiety about potential bullying would potentially be higher. Ninety-one sixth-grade students (55 female and 36 male) reported being exposed one or more…

  9. Drinking-induced changes in fowl adrenocortical activity: effect of visual and non-visual stimuli.

    PubMed

    Harvey, S; Klandorf, H; Lam, S K

    1985-02-01

    The deprivation of drinking water for 30 h resulted in increased corticosterone concentrations in the plasma of 8- to 10-week-old chickens. When water-deprived birds were allowed to drink ad libitum the corticosterone concentration declined within 45 min, to the level in hydrated controls, and remained suppressed thereafter. Similar reductions in the corticosterone concentrations were also observed in water-deprived chicks which were allowed to drink for only 5 min, 1 min or 5 s. The involvement of visual stimuli in mediating this adrenocortical response was demonstrated by a comparable decline in the corticosterone concentration in water-deprived birds which were presented with water but not allowed access to it. Non-visual stimuli also appeared to be causally involved in the adrenocortical suppression after drinking, since the intraperitoneal injection of tap water (40 ml per bird) also resulted in a lowering of the corticosterone level. However, in the absence of appropriate reinforcement from metabolic stimuli, a rebound in the corticosterone concentration was observed in birds prevented from drinking, in birds unable to satiate their thirst and in birds rehydrated (orally or intraperitoneally) without feeding. These results demonstrate adrenocortical suppression in water-deprived chickens after free access to food and water and the involvement of visual and non-visual stimuli in mediating this response. The maintenance of adrenocortical suppression is dependent upon metabolic stimuli associated with food and water intake.

  10. The Effects of Morning Naps, Car Trips, and Maternal Separation on Adrenocortical Activity in Human Infants.

    ERIC Educational Resources Information Center

    Larson, Mary C.; And Others

    1991-01-01

    Three studies examined adrenocortical activity in infants. Morning naps were associated with decreases in salivary cortisol. Riding for 40 minutes in a car lowered salivary cortisol concentrations. Thirty minutes of maternal separation in the laboratory resulted in higher salivary cortisol concentrations than did 30 minutes of play with the mother…

  11. Adrenocortical responses to repeated parachute jumping and subsequent h-CRH challenge in inexperienced healthy subjects.

    PubMed

    Deinzer, R; Kirschbaum, C; Gresele, C; Hellhammer, D H

    1997-04-01

    The present study examined the adrenocortical response to 3 consecutive parachute jumps and a poststress h-CRH challenge. Fifteen participants in a parachute-jumping course took saliva samples for later cortisol analysis every 20 min throughout the day, when they accomplished their very first 3 parachute jumps and throughout a control day. The effects of an h-CRH challenge on salivary cortisol were assessed in the evening of the jumping day and on a control day. Parachute jumping induced 3 distinct highly significant adrenocortical responses. The respective cortisol increases for the first, second, and third jump were 39.4 +/- 26.5 nmol/1, 31.4 +/- 21.4 nmol/l, and 16.5 +/- 11.9 nmol/l. Cortisol responses to the first and second jump did not differ but the response to the third jump was significantly reduced [t(13) = 3.11; p = 0.008]. Two groups of subjects were identified, "decreasers," whose response decreased from one to the other jump, and "increasers," whose response remained unchanged or increased. The magnitude of the preceding cortisol response of decreasers exceeded that of increasers significantly by about 30 nmol. The mean adrenocortical effects of the poststress h-CRH challenge and the time-matched challenge on a control day did not differ although, in 4 subjects, the poststress adrenocortical response to h-CRH was completely suppressed.

  12. Plk2 regulates mitotic spindle orientation and mammary gland development.

    PubMed

    Villegas, Elizabeth; Kabotyanski, Elena B; Shore, Amy N; Creighton, Chad J; Westbrook, Thomas F; Rosen, Jeffrey M

    2014-04-01

    Disruptions in polarity and mitotic spindle orientation contribute to the progression and evolution of tumorigenesis. However, little is known about the molecular mechanisms regulating these processes in vivo. Here, we demonstrate that Polo-like kinase 2 (Plk2) regulates mitotic spindle orientation in the mammary gland and that this might account for its suggested role as a tumor suppressor. Plk2 is highly expressed in the mammary gland and is required for proper mammary gland development. Loss of Plk2 leads to increased mammary epithelial cell proliferation and ductal hyperbranching. Additionally, a novel role for Plk2 in regulating the orientation of the mitotic spindle and maintaining proper cell polarity in the ductal epithelium was discovered. In support of a tumor suppressor function for Plk2, loss of Plk2 increased the formation of lesions in multiparous glands. Collectively, these results demonstrate a novel role for Plk2 in regulating mammary gland development.

  13. Human Cytochrome P450 2W1 Is Not Expressed in Adrenal Cortex and Is Only Rarely Expressed in Adrenocortical Carcinomas

    PubMed Central

    Nolé, Paola; Duijndam, Britt; Stenman, Adam; Juhlin, C. Christofer; Kozyra, Mikael; Larsson, Catharina; Ingelman-Sundberg, Magnus

    2016-01-01

    Human cytochome P450 2W1 (CYP2W1) enzyme is expressed in fetal colon and in colon tumors. The level of expression is higher in colon metastases than in the parent tumors and the enzyme is a possible drug target for treatment of colorectal cancer, as demonstrated in mouse xenograft studies. A previous study published in this journal reported that CYP2W1 is highly expressed in normal and transformed adrenal tissue. However, adrenal expression of CYP2W1 protein was not seen in previous studies in our research group. To clarify this inconsistency, we have used qRT-PCR and Western blotting with CYP2W1-specific antibodies to probe a panel of 27 adrenocortical carcinomas and 35 normal adrenal cortex samples. CYP2W1 mRNA expression is seen in all samples. However, significant CYP2W1 protein expression was found in only one tumor sample (a testosterone-producing adrenocortical carcinoma) and not in any normal tissue. Differences in the specificity of the CYP2W1 antibodies used in the two studies may explain the apparent discrepancy. We conclude that normal adrenal tissue lacks P450 2W1 enzyme expression; also, adrenocortical carcinomas generally do not express the enzyme. This information thus underline the colon cancer specificity of CYP2W1 enzyme expression and has implications for the development of anti-colon cancer therapies based on CYP2W1 as a drug target, since 2W1-dependent bioactivation of prodrugs for CYP2W1 will not take place in normal adrenal tissue or other non-transformed tissues. PMID:27598485

  14. Properties of calcium and potassium currents of clonal adrenocortical cells

    PubMed Central

    1989-01-01

    The ionic currents of clonal Y-1 adrenocortical cells were studied using the whole-cell variant of the patch-clamp technique. These cells had two major current components: a large outward current carried by K ions, and a small inward Ca current. The Ca current depended on the activity of two populations of Ca channels, slow (SD) and fast (FD) deactivating, that could be separated by their different closing time constants (at -80 mV, SD, 3.8 ms, and FD, 0.13 ms). These two kinds of channels also differed in (a) activation threshold (SD, approximately - 50 mV; FD, approximately -20 mV), (b) half-maximal activation (SD, between -15 and -10 mV; FD between +10 and +15 mV), and (c) inactivation time course (SD, fast; FD, slow). The total amplitude of the Ca current and the proportion of SD and FD channels varied from cell to cell. The amplitude of the K current was strongly dependent on the internal [Ca2+] and was almost abolished when internal [Ca2+] was less than 0.001 microM. The K current appeared to be independent, or only slightly dependent, of Ca influx. With an internal [Ca2+] of 0.1 microM, the activation threshold was -20 mV, and at +40 mV the half- time of activation was 9 ms. With 73 mM external K the closing time constant at -70 mV was approximately 3 ms. The outward current was also modulated by internal pH and Mg. At a constant pCa gamma a decrease of pH reduced the current amplitude, whereas the activation kinetics were not much altered. Removal of internal Mg produced a drastic decrease in the amplitude of the Ca-activated K current. It was also found that with internal [Ca2+] over 0.1 microM the K current underwent a time- dependent transformation characterized by a large increase in amplitude and in activation kinetics. PMID:2539432

  15. Targeting heterogeneity of adrenocortical carcinoma: Evaluation and extension of preclinical tumor models to improve clinical translation

    PubMed Central

    Hantel, Constanze; Shapiro, Igor; Poli, Giada; Chiapponi, Costanza; Bidlingmaier, Martin; Reincke, Martin; Luconi, Michaela; Jung, Sara; Beuschlein, Felix

    2016-01-01

    In recent years it has been recognized that clinical translation of novel therapeutic strategies for patients with adrenocortical carcinoma (ACC) often fails. These disappointing results indicate that the currently utilized tumor models only poorly reflect relevant pathophysiology and, thereby, do not predict clinical applicability of novel pharmacological approaches. However, also the development of new preclinical ACC models has remained a challenge with only one human cell line (NCI-H295R) and one recently established human pediatric xenograft model (SJ-ACC3) being available for this highly heterogeneous malignancy. Our current study furthermore reveals a poor reproducibility of therapeutic action between different clones of the most commonly used tumor model NCI-H295R. In an attempt to broaden the current preclinical armamentarium, we aimed at the development of patient-individual tumor models. During these studies, one xenograft (MUC-1) displayed marked engraftment and sustained tumor growth. MUC-1 tumor analysis revealed highly vascularized, proliferating and SF-1 positive xenografts. In a next step, we characterized all currently available human tumor models for ACC for Ki67, SF-1 and EGF-receptor status in comparison with MUC-1-xenografts. In addition, we established a primary culture, which is now viable over 31 passages with sustained nuclear SF-1 and cytoplasmic 3βHSD immuno-positivity. Subsequent investigation of therapeutic responsiveness upon treatment with the current systemic gold standard EDP-M (etoposide, doxorubicin, cisplatin and mitotane) demonstrated maintenance of the clinically observed drug resistance for MUC-1 exclusively. In summary, we provide evidence for a novel patient-derived tumor model with the potential to improve clinical prediction of novel therapeutic strategies for patients with ACC. PMID:27764813

  16. Epigenetic Regulation of BDNF Gene during Development and Diseases

    PubMed Central

    Chen, Kuan-Wei; Chen, Linyi

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) is required for the development of the nervous system, proper cognitive function and memory formation. While aberrant expression of BDNF has been implicated in neurological disorders, the transcriptional regulation of BDNF remains to be elucidated. In response to different stimuli, BDNF expression can be initiated from different promoters. Several studies have suggested that the expression of BDNF is regulated by promoter methylation. An emerging theme points to the possibility that histone modifications at the BDNF promoters may link to the neurological pathology. Thus, understanding the epigenetic regulation at the BDNF promoters will shed light on future therapies for neurological disorders. The present review summarizes the current knowledge of histone modifications of the BDNF gene in neuronal diseases, as well as the developmental regulation of the BDNF gene based on data from the Encyclopedia of DNA Elements (ENCODE). PMID:28272318

  17. Roles of cofilin in development and its mechanisms of regulation.

    PubMed

    Ohashi, Kazumasa

    2015-05-01

    Reorganization of the actin cytoskeleton is essential for cellular processes during animal development. Cofilin and actin depolymerizing factor (ADF) are potent actin-binding proteins that sever and depolymerize actin filaments, acting to generate the dynamics of the actin cytoskeleton. The activity of cofilin is spatially and temporally regulated by a variety of intracellular molecular mechanisms. Cofilin is regulated by cofilin binding molecules, is phosphorylated at Ser-3 (inactivation) by LIM-kinases (LIMKs) and testicular protein kinases (TESKs), and is dephosphorylated (reactivation) by slingshot protein phosphatases (SSHs). Although studies of the molecular mechanisms of cofilin-induced reorganization of the actin cytoskeleton have been ongoing for decades, the multicellular functions of cofilin and its regulation in development are just becoming apparent. This review describes the molecular mechanisms of generating actin dynamics by cofilin and the intracellular signaling pathways for regulating cofilin activity. Furthermore, recent findings of the roles of cofilin in the development of several tissues and organs, especially neural tissues and cells, in model animals are described. Recent developmental studies have indicated that cofilin and its regulatory mechanisms are involved in cellular proliferation and migration, the establishment of cellular polarity, and the dynamic regulation of organ morphology.

  18. Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence.

    PubMed

    Glover, A R; Zhao, J T; Ip, J C; Lee, J C; Robinson, B G; Gill, A J; Soon, P S H; Sidhu, S B

    2015-02-01

    Adrenocortical carcinoma (ACC) is an aggressive malignancy with high rates of recurrence following surgical resection. Long noncoding RNAs (lncRNAs) play an important role in cancer development. Pathogenesis of adrenal tumours have been characterised by mRNA, microRNA and methylation expression signatures, but it is unknown if this extends to lncRNAs. This study describes lncRNA expression signatures in ACC, adrenal cortical adenoma (ACA) and normal adrenal cortex (NAC) and presents lncRNAs associated with ACC recurrence to identify novel prognostic and therapeutic targets. RNA was extracted from freshly frozen tissue with confirmation of diagnosis by histopathology. Focused lncRNA and mRNA transcriptome analysis was performed using the ArrayStar Human LncRNA V3.0 microarray. Differentially expressed lncRNAs were validated using quantitative reverse transcriptase-PCR and correlated with clinical outcomes. Microarray of 21 samples (ten ACCs, five ACAs and six NACs) showed distinct patterns of lncRNA expression between each group. A total of 956 lncRNAs were differentially expressed between ACC and NAC, including known carcinogenesis-related lncRNAs such as H19, GAS5, MALAT1 and PRINS (P≤0.05); 85 lncRNAs were differentially expressed between ACC and ACA (P≤0.05). Hierarchical clustering and heat mapping showed ACC samples correctly grouped compared with NAC and ACA. Sixty-six differentially expressed lncRNAs were found to be associated with ACC recurrence (P≤0.05), one of which, PRINS, was validated in a group of 20 ACCs and also found to be associated with metastatic disease on presentation. The pathogenesis of adrenal tumours extends to lncRNA dysregulation and low expression of the lncRNA PRINS is associated with ACC recurrence.

  19. Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model.

    PubMed

    Hantel, Constanze; Jung, Sara; Mussack, Thomas; Reincke, Martin; Beuschlein, Felix

    2014-06-01

    Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

  20. Epigenetic regulation of cardiac myofibril gene expression during heart development.

    PubMed

    Zhao, Weian; Liu, Lingjuan; Pan, Bo; Xu, Yang; Zhu, Jing; Nan, Changlong; Huang, Xupei; Tian, Jie

    2015-07-01

    Cardiac gene expression regulation is controlled not only by genetic factors but also by environmental, i.e., epigenetic factors. Several environmental toxic effects such as oxidative stress and ischemia can result in abnormal myofibril gene expression during heart development. Troponin, one of the regulatory myofibril proteins in the heart, is a well-known model in study of cardiac gene regulation during the development. In our previous studies, we have demonstrated that fetal form troponin I (ssTnI) expression in the heart is partially regulated by hormones, such as thyroid hormone. In the present study, we have explored the epigenetic role of histone modification in the regulation of ssTnI expression. Mouse hearts were collected at different time of heart development, i.e., embryonic day 15.5, postnatal day 1, day 7, day 14 and day 21. Levels of histone H3 acetylation (acH3) and histone H3 lysine 9 trimethylation (H3K9me(3)) were detected using chromatin immunoprecipitation assays in slow upstream regulatory element (SURE) domain (TnI slow upstream regulatory element), 300-bp proximal upstream domain and the first intron of ssTnI gene, which are recognized as critical regions for ssTnI regulation. We found that the levels of acH3 on the SURE region were gradually decreased, corresponding to a similar decrease of ssTnI expression in the heart, whereas the levels of H3K9me(3) in the first intron of ssTnI gene were gradually increased. Our results indicate that both histone acetylation and methylation are involved in the epigenetic regulation of ssTnI expression in the heart during the development, which are the targets for environmental factors.

  1. Rac1 Regulates Endometrial Secretory Function to Control Placental Development.

    PubMed

    Davila, Juanmahel; Laws, Mary J; Kannan, Athilakshmi; Li, Quanxi; Taylor, Robert N; Bagchi, Milan K; Bagchi, Indrani C

    2015-08-01

    During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal

  2. Rac1 Regulates Endometrial Secretory Function to Control Placental Development

    PubMed Central

    Davila, Juanmahel; Laws, Mary J.; Kannan, Athilakshmi; Li, Quanxi; Taylor, Robert N.; Bagchi, Milan K.; Bagchi, Indrani C.

    2015-01-01

    During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal

  3. Brown adipocyte differentiation is regulated by hedgehog signaling during development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During development, brown fat tissue arises from mesenchymal precursor cells under the control of signaling networks that are not yet well understood. The Hedgehog (Hh) signaling pathway is one of the major signaling pathways that regulate mesenchymal cell fate. However, whether the Hh pathway contr...

  4. Career Development of Foreign Trained Immigrants from Regulated Professions

    ERIC Educational Resources Information Center

    Novak, Lydia; Chen, Charles P.

    2013-01-01

    In this article, we aim to examine and understand the career development experiences of foreign-trained immigrants from regulated professions (FTIRPs) in Canada. To provide some background on immigration in a Canadian context, we focus on a myriad of factors that affect the vocational well-being of FTIRPs. We apply key concepts from several major…

  5. MicroRNA-mediated regulation of flower development in grasses.

    PubMed

    Smoczynska, Aleksandra; Szweykowska-Kulinska, Zofia

    2016-01-01

    Flower structure in grasses is very unique. There are no petals or sepals like in eudicots but instead flowers develop bract-like structures - palea and lemma. Reproductive organs are enclosed by round lodicule that not only protects reproductive organs but also plays an important role during flower opening. The first genetic model for floral organ development was proposed 25 years ago and it was based on the research on model eudicots. Since then, studies have been carried out to answer the question whether this model could be applicable in the case of monocots. Genes from all classes found in eudicots have been also identified in genomes of such monocots like rice, maize or barley. What's more, it seems that miRNA-mediated regulation of floral organ genes that was observed in the case of Arabidopsis thaliana also takes place in monocots. MiRNA172, miRNA159, miRNA171 and miRNA396 regulate expression of floral organ identity genes in barley, rice and maize, affecting various features of the flower structure, ranging from formation of lemma and palea to the development of reproductive organs. A model of floral development in grasses and its genetic regulation is not yet fully characterized. Further studies on both, the model eudicots and grasses, are needed to unravel this topic. This review provides general overview of genetic model of flower organ identity specification in monocots and it's miRNA-mediated regulation.

  6. Development and regulation of pedicel abscission in tomato

    PubMed Central

    Ito, Yasuhiro; Nakano, Toshitsugu

    2015-01-01

    To shed unfertilized flowers or ripe fruits, many plant species develop a pedicel abscission zone (AZ), a specialized tissue that develops between the organ and the main body of the plant. Regulation of pedicel abscission is an important agricultural concern because pre-harvest abscission can reduce yields of fruit or grain crops, such as apples, rice, wheat, etc. Tomato has been studied as a model system for abscission, as tomato plants develop a distinct AZ at the midpoint of the pedicel and several tomato mutants, such as jointless, have pedicels that lack an AZ. This mini-review focuses on recent advances in research on the mechanisms regulating tomato pedicel abscission. Molecular genetic studies revealed that three MADS-box transcription factors interactively play a central role in pedicel AZ development. Transcriptome analyses identified activities involved in abscission and also found novel transcription factors that may regulate AZ activities. Another study identified transcription factors mediating abscission pathways from induction signals to activation of cell wall hydrolysis. These recent findings in tomato will enable significant advances in understanding the regulation of abscission in other key agronomic species. PMID:26124769

  7. Wnt2 regulates progenitor proliferation in the developing ventral midbrain.

    PubMed

    Sousa, Kyle M; Villaescusa, J Carlos; Cajanek, Lukas; Ondr, Jennifer K; Castelo-Branco, Goncalo; Hofstra, Wytske; Bryja, Vitezslav; Palmberg, Carina; Bergman, Tomas; Wainwright, Brandon; Lang, Richard A; Arenas, Ernest

    2010-03-05

    Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates beta-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development.

  8. Wnt2 Regulates Progenitor Proliferation in the Developing Ventral Midbrain*

    PubMed Central

    Sousa, Kyle M.; Villaescusa, J. Carlos; Cajanek, Lukas; Ondr, Jennifer K.; Castelo-Branco, Goncalo; Hofstra, Wytske; Bryja, Vitezslav; Palmberg, Carina; Bergman, Tomas; Wainwright, Brandon; Lang, Richard A.; Arenas, Ernest

    2010-01-01

    Wnts are secreted, lipidated proteins that regulate multiple aspects of brain development, including dopaminergic neuron development. In this study, we perform the first purification and signaling analysis of Wnt2 and define the function of Wnt2 in ventral midbrain precursor cultures, as well as in Wnt2-null mice in vivo. We found that purified Wnt2 induces the phosphorylation of both Lrp5/6 and Dvl-2/3, and activates β-catenin in SN4741 dopaminergic cells. Moreover, purified Wnt2 increases progenitor proliferation, and the number of dopaminergic neurons in ventral midbrain precursor cultures. In agreement with these findings, analysis of the ventral midbrain of developing Wnt2-null mice revealed a decrease in progenitor proliferation and neurogenesis that lead to a decrease in the number of postmitotic precursors and dopaminergic neurons. Collectively, our observations identify Wnt2 as a novel regulator of dopaminergic progenitors and dopaminergic neuron development. PMID:20018874

  9. Autocrine and Paracrine Hh Signaling Regulate Prostate Development

    DTIC Science & Technology

    2010-09-01

    development and tumorigenesis (13). The forkhead transcription factor Foxe1 was established as a downstream target of the Shh pathway in hair follicle morpho...in the epithelium of the developing prostate; activate Hh target genes expressed in the surrounding mesenchyme and influence prostate ductal growth...postanatally. We propose this temporal growth effects is mediated by the discordant regulation of a subset of target genes by Hh signaling in the prenatal and

  10. Regulation of Development and Nitrogen Fixation in Anabaena

    SciTech Connect

    James W. Golden

    2008-10-17

    The regulation of development and cellular differentiation is important for all multicellular organisms. The nitrogen-fixing filamentous cyanobacterium Anabaena (also Nostoc) sp. PCC 7120 (hereafter Anabaena) provides a model of multicellular microbial development and pattern formation. Anabaena reduces N2 to ammonia in specialized terminally differentiated cells called heterocysts. A one-dimensional developmental pattern of single heterocysts regularly spaced along filaments of photosynthetic vegetative cells is established to form a multicellular organism composed of these two interdependent cell types. This multicellular growth pattern, the distinct phylogeny of cyanobacteria, and the suspected antiquity of heterocyst development make this an important model system. Our long-term goal is to understand the regulatory network required for heterocyst development and nitrogen fixation. This project is focused on two key aspects of heterocyst regulation: one, the mechanism by which HetR controls the initiation of differentiation, and two, the cis and trans acting factors required for expression of the nitrogen-fixation (nif) genes. HetR is thought to be a central regulator of heterocyst development but the partners and mechanisms involved in this regulation are unknown. Our recent results indicate that PatS and other signals that regulate heterocyst pattern cannot interact, directly or indirectly, with a R223W mutant of HetR. We plan to use biochemical and genetic approaches to identify proteins that interact with the HetR protein, which will help reveal the mechanisms underlying its regulation of development. Our second goal is to determine how the nif genes are expressed. It is important to understand the mechanisms controlling nif genes since they represent the culmination of the differentiation process and the essence of heterocyst function. The Anabaena genome lacks the genes required for expression of nif genes present in other organisms such as rpoN (sigma 54

  11. Laminin regulates PDGFRβ+ cell stemness and muscle development

    PubMed Central

    Yao, Yao; Norris, Erin H.; E. Mason, Christopher; Strickland, Sidney

    2016-01-01

    Muscle-resident PDGFRβ+ cells, which include pericytes and PW1+ interstitial cells (PICs), play a dual role in muscular dystrophy. They can either undergo myogenesis to promote muscle regeneration or differentiate into adipocytes and other cells to compromise regeneration. How the differentiation and fate determination of PDGFRβ+ cells are regulated, however, remains unclear. Here, by utilizing a conditional knockout mouse line, we report that PDGFRβ+ cell-derived laminin inhibits their proliferation and adipogenesis, but is indispensable for their myogenesis. In addition, we show that laminin alone is able to partially reverse the muscle dystrophic phenotype in these mice at the molecular, structural and functional levels. Further RNAseq analysis reveals that laminin regulates PDGFRβ+ cell differentiation/fate determination via gpihbp1. These data support a critical role of laminin in the regulation of PDGFRβ+ cell stemness, identify an innovative target for future drug development and may provide an effective treatment for muscular dystrophy. PMID:27138650

  12. A morphometric analysis of adrenocortical actin localized by immunoelectron microscopy: the effect of adrenocorticotropin.

    PubMed

    Loesser, K E; Malamed, S

    1987-10-01

    The localization of actin and the effect of ACTH on its concentration was examined in freshly isolated rat adrenocortical cells. Lowicryl K4M-embedded cells were used for the immunoelectron localization of actin; gold was used as a label for immunoreactive sites. Actin was at least 4 times as concentrated at the cortical cytoplasm as in the lipid droplets and at least 5 times as concentrated in the microvilli as in the lipid droplets. ACTH stimulation approximately doubled the concentration of actin in the cortical cytoplasm and increased by 50% the concentration of actin in the microvilli. The microvillar contribution to the cell surface area was 40% higher in ACTH-stimulated cells than it was in unstimulated cells. These results provide quantitative evidence suggesting that actin and the microvilli participate in steroid secretion by the adrenocortical cell.

  13. A genetic and molecular update on adrenocortical causes of Cushing syndrome.

    PubMed

    Lodish, Maya; Stratakis, Constantine A

    2016-05-01

    Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP-PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP-PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder.

  14. Final Report for Regulation of Embryonic Development in Higher Plants

    SciTech Connect

    Harada, John J.

    2013-10-22

    The overall goal of the project was to define the cellular processes that underlie embryo development in plants at a mechanistic level. Our studies focused on a critical transcriptional regulator, Arabidopsis LEAFY COTYLEDON (LEC1), that is necessary and sufficient to induce processes required for embryo development. Because LEC1 regulates lipid accumulation during the maturation phase of embryo development, information about LEC1 may be useful in designing approaches to enhance biofuel production in plants. During the tenure of this project, we determined the molecular mechanisms by which LEC1 acts as a transcription factor in embryos. We also identified genes directly regulated by LEC1 and showed that many of these genes are involved in maturation processes. This information has been useful in dissecting the gene regulatory networks controlling embryo development. Finally, LEC1 is a novel isoform of a transcription factor that is conserved among eukaryotes, and LEC1 is active primarily in seeds. Therefore, we determined that the LEC1-type transcription factors first appeared in lycophytes during land plant evolution. Together, this study provides basic information that has implications for biofuel production.

  15. The regulation of Dkk1 expression during embryonic development.

    PubMed

    Lieven, Oliver; Knobloch, Jürgen; Rüther, Ulrich

    2010-04-15

    During embryogenesis, the Dkk1 mediated Wnt inhibition controls the spatiotemporal dynamics of cell fate determination, cell differentiation and cell death. Furthermore, the Dkk1 dose is critical for the normal Wnt homeostasis, as alteration of the Dkk1 activity is associated with various diseases. We investigated the regulation of Dkk1 expression during embryonic development. We identified nine conserved non-coding elements (CNEs), located 3' to the Dkk1 locus. Analyses of the regulatory potential revealed that four of these CNEs in combination drive reporter expression very similar to Dkk1 expression in several organs of transgenic embryos. We extended the knowledge of Dkk1 expression during hypophysis, external genitalia and kidney development, suggesting so far to unexplored functions of Dkk1 during the development of these organs. Characterization of the regulatory potential of four individual CNEs revealed that each of these promotes Dkk1 expression in brain and kidney. In combination, two enhancers are responsible for expression in the pituitary and the genital tubercle. Furthermore, individual CNEs mediates craniofacial, optic cup and limb specific Dkk1 regulation. Our study substantially improves the knowledge of Dkk1 regulation during embryonic development and thus might be of high relevance for therapeutic approaches.

  16. Cannabinoid receptor signaling regulates liver development and metabolism.

    PubMed

    Liu, Leah Y; Alexa, Kristen; Cortes, Mauricio; Schatzman-Bone, Stephanie; Kim, Andrew J; Mukhopadhyay, Bani; Cinar, Resat; Kunos, George; North, Trista E; Goessling, Wolfram

    2016-02-15

    Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function.

  17. Cannabinoid receptor signaling regulates liver development and metabolism

    PubMed Central

    Liu, Leah Y.; Alexa, Kristen; Cortes, Mauricio; Schatzman-Bone, Stephanie; Kim, Andrew J.; Mukhopadhyay, Bani; Cinar, Resat; Kunos, George; North, Trista E.; Goessling, Wolfram

    2016-01-01

    Endocannabinoid (EC) signaling mediates psychotropic effects and regulates appetite. By contrast, potential roles in organ development and embryonic energy consumption remain unknown. Here, we demonstrate that genetic or chemical inhibition of cannabinoid receptor (Cnr) activity disrupts liver development and metabolic function in zebrafish (Danio rerio), impacting hepatic differentiation, but not endodermal specification: loss of cannabinoid receptor 1 (cnr1) and cnr2 activity leads to smaller livers with fewer hepatocytes, reduced liver-specific gene expression and proliferation. Functional assays reveal abnormal biliary anatomy and lipid handling. Adult cnr2 mutants are susceptible to hepatic steatosis. Metabolomic analysis reveals reduced methionine content in Cnr mutants. Methionine supplementation rescues developmental and metabolic defects in Cnr mutant livers, suggesting a causal relationship between EC signaling, methionine deficiency and impaired liver development. The effect of Cnr on methionine metabolism is regulated by sterol regulatory element-binding transcription factors (Srebfs), as their overexpression rescues Cnr mutant liver phenotypes in a methionine-dependent manner. Our work describes a novel developmental role for EC signaling, whereby Cnr-mediated regulation of Srebfs and methionine metabolism impacts liver development and function. PMID:26884397

  18. Paediatric Nonfunctioning Adrenocortical Carcinoma with Extension up to Right-Side Heart: Cardiac Surgery Approach.

    PubMed

    Iezzi, Federica; Quarti, Andrea; Surace, Chiara; Pozzi, Marco

    2016-01-01

    Adrenocortical carcinoma is a rare malignancy. Due to late diagnosis and no adequate effective adjuvant treatment, prognosis remains poor. Only approximately 30% of these malignancies are confined to the adrenal gland when they are diagnosed, as these tumors tend to be found years after their genesis. Cardiac involvement of adrenal carcinoma is very rare. We report a rare case of a 7-year-old female with right adrenal cortical carcinoma, involving the right-side heart.

  19. Acanthosis Nigricans Associated with an Adrenocortical Tumor in a Pediatric Patient

    PubMed Central

    Dimitriadi, Filippina Filia; Barrows, Frank; Mostoufi-Moab, Sogol

    2013-01-01

    Malignant acanthosis nigricans (AN) is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis. This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor. PMID:23819073

  20. Acanthosis nigricans associated with an adrenocortical tumor in a pediatric patient.

    PubMed

    Isaacoff, Elizabeth; Dimitriadi, Filippina Filia; Barrows, Frank; Pawel, Bruce; Mattei, Peter; Mostoufi-Moab, Sogol

    2013-01-01

    Malignant acanthosis nigricans (AN) is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis. This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor.

  1. Paediatric Nonfunctioning Adrenocortical Carcinoma with Extension up to Right-Side Heart: Cardiac Surgery Approach

    PubMed Central

    Quarti, Andrea; Surace, Chiara; Pozzi, Marco

    2016-01-01

    Adrenocortical carcinoma is a rare malignancy. Due to late diagnosis and no adequate effective adjuvant treatment, prognosis remains poor. Only approximately 30% of these malignancies are confined to the adrenal gland when they are diagnosed, as these tumors tend to be found years after their genesis. Cardiac involvement of adrenal carcinoma is very rare. We report a rare case of a 7-year-old female with right adrenal cortical carcinoma, involving the right-side heart. PMID:27493811

  2. Classification and surgical treatment for 180 cases of adrenocortical hyperplastic disease

    PubMed Central

    Zhang, Yushi; Li, Hanzhong

    2015-01-01

    Objective: To review and discuss the diagnostic and surgical therapeutic methods of adrenocortical hyperplastic disease. Methods: A retrospective analysis was done to 180 adrenocortical hyperplasia patients (74 males, 109 females, aged 6~76 (average 40.1). Studies were done to the relationship between patients’ clinical characteristics, biochemical, endocrinological and imaging examination results, the therapeutic effects. Results: Among all 180 cases, there are 107 Cushing disease (CD), 19 ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 28 adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 4 primary pigmented nodular adrenocortical hyperplasia (PPNAH), and 28 Idiopathic Hyperaldosteronism (IHA). Twenty-four-hour urinary free cortisol (24 h UFC) excretion of CD, EAAH, AIMAH and PPNAH patients were 95.2~535.7 µg (average 287.6 µg), 24.8~808.2 µg (average 307.9 µg), 102.5~3127.0 µg (average 852.5 µg), and 243.8~1124.6 µg (average 564.3 µg). Both low and high-dose dexamethasone suppression tests (DDST) were not suppressed in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. CT thin scanning results of 180 patients all showed enlargements in the affected side adrenal gland. Unilateral adrenalectomies were performed in 102 hypercortisolism cases. Local lesion excisions were done to 21 IHA patients. 57 patients had surgeries in both sides of the adrenal glands (39 bilateral total adrenalectomies, 16 total adrenalectomy in one side andsubtotal adrenalectomy in the other, 2 bilateral subtotal adrenalectomies). 106 (59%) patients were followed up for 4~158 (average 32) months. Conclusion: Unilateral adrenalectomy was the first choice for operable adrenocortical hyperplasia patients. The operation mode for the other adrenal gland should be based on the type of hyperplasia and clinical observation. PMID:26770569

  3. Low DICER1 expression is associated with poor clinical outcome in adrenocortical carcinoma.

    PubMed

    de Sousa, Gabriela Resende Vieira; Ribeiro, Tamaya C; Faria, Andre M; Mariani, Beatriz M P; Lerario, Antonio M; Zerbini, Maria Claudia N; Soares, Iberê C; Wakamatsu, Alda; Alves, Venancio A F; Mendonca, Berenice B; Fragoso, Maria Candida B V; Latronico, Ana Claudia; Almeida, Madson Q

    2015-09-08

    Low DICER1 expression was associated with poor outcome in several cancers. Recently, hot-spot DICER1 mutations were found in ovarian tumors, and TARBP2 truncating mutations in tumor cell lines with microsatellite instability. In this study, we assessed DICER1 e TRBP protein expression in 154 adult adrenocortical tumors (75 adenomas and 79 carcinomas). Expression of DICER1 and TARBP2 gene was assessed in a subgroup of 61 tumors. Additionally, we investigated mutations in metal biding sites located at the RNase IIIb domain of DICER1 and in the exon 5 of TARBP2 in 61 tumors. A strong DICER1 expression was demonstrated in 32% of adenomas and in 51% of carcinomas (p = 0.028). Similarly, DICER1 gene overexpression was more frequent in carcinomas (60%) than in adenomas (23%, p = 0.006). But, among adrenocortical carcinomas, a weak DICER1 expression was significantly more frequent in metastatic than in non-metastatic adrenocortical carcinomas (66% vs. 31%; p = 0.002). Additionally, a weak DICER1 expression was significantly correlated with a reduced overall (p = 0.004) and disease-free (p = 0.005) survival. In the multivariate analysis, a weak DICER1 expression (p = 0.048) remained as independent predictor of recurrence. Regarding TARBP2 gene, its protein and gene expression did not correlate with histopathological and clinical parameters. No variant was identified in hot spot areas of DICER1 and TARBP2. In conclusion, a weak DICER1 protein expression was associated with reduced disease-free and overall survival and was a predictor of recurrence in adrenocortical carcinomas.

  4. ACTH-Independent Cushing’s Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

    PubMed Central

    Louiset, Estelle; Gobet, Françoise; Libé, Rossella; Horvath, Anelia; Renouf, Sylvie; Cariou, Juliette; Rothenbuhler, Anya; Bertherat, Jérôme; Clauser, Eric; Grise, Philippe; Stratakis, Constantine A.; Kuhn, Jean-Marc; Lefebvre, Hervé

    2010-01-01

    Context: Bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushing’s syndrome. Objective: The aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma. Design and Setting: In vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories. Intervention: Mutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies. Main Outcome Measure: Detection of 17α-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes. Results: Histological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17α-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway. Conclusion: This case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushing’s syndrome. PMID:19915020

  5. Developing medical device software in compliance with regulations.

    PubMed

    Zema, M; Rosati, S; Gioia, V; Knaflitz, M; Balestra, G

    2015-08-01

    In the last decade, the use of information technology (IT) in healthcare has taken a growing role. In fact, the adoption of an increasing number of computer tools has led to several benefits related to the process of patient care and allowed easier access to social and health care resources. At the same time this trend gave rise to new challenges related to the implementation of these new technologies. Software used in healthcare can be classified as medical devices depending on the way they are used and on their functional characteristics. If they are classified as medical devices they must satisfy specific regulations. The aim of this work is to present a software development framework that can allow the production of safe and high quality medical device software and to highlight the correspondence between each software development phase and the appropriate standard and/or regulation.

  6. Identification of a Novel TP53 Germline Mutation E285V in a Rare Case of Pediatric Adrenocortical Carcinoma and Choroid Plexus Carcinoma

    PubMed Central

    Russell-Swetek, Aubrey; West, Alina N.; Mintern, Jane E.; Jenkins, Jesse; Rodriguez-Galindo, Carlos; Ribeiro, Raul; Zambetti, Gerard P.

    2012-01-01

    Pediatric choroid plexus carcinomas (CPC) and adrenocortical carcinomas (ACC) are exceedingly rare tumors, each occurring at an annual rate of 0.3 cases per million children or less. Although both tumor types are associated with Li-Fraumeni Syndrome (LFS), the penetrance of germline TP53 mutations in CPC remains to be established. We report here a young boy without a family history of cancer who presented with CPC and subsequently ACC. Genetic testing revealed a novel de novo germline TP53 mutation (E285V). Neither tumor underwent loss of heterozygosity. Consistent with this observation, functional analyses demonstrated that E285V acts as a dominant-negative mutant that is defective in regulating target gene expression, growth suppression and apoptosis. These results further strengthen the association between germline TP53 mutations and childhood CPC, even when occurring in the absence of familial tumor susceptibility. PMID:18762572

  7. Functional Enhancers As Master Regulators of Tissue-Specific Gene Regulation and Cancer Development

    PubMed Central

    Ko, Je Yeong; Oh, Sumin; Yoo, Kyung Hyun

    2017-01-01

    Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells. In addition, noncoding RNAs, named eRNAs, are synthesized at super-enhancer regions before their target genes are transcribed. Many functional studies revealed that super-enhancers and eRNAs are essential for the regulation of tissue-specific gene expression. In this review, we summarize recent findings concerning enhancer function in tissue-specific gene regulation and cancer development. PMID:28359147

  8. Morphological changes in the pituitary-adrenocortical axis in natives of La Paz

    NASA Astrophysics Data System (ADS)

    Gosney, John; Heath, Donald; Williams, David; Rios-Dalenz, Jaime

    1991-03-01

    Increased activity of the hypothalamic-pituitary-adrenocortical axis is part of the response to the stress of initial exposure to hypoxia, but there is evidence to suggest that it persists after homeostatic stability has been regained and acclimatization achieved. The adrenal glands of five lifelong residents of La Paz, Bolivia, who had lived at altitudes in the range 3600 3800 m, were significantly larger than those in age-matched controls from sea level (15.3g vs 10.4g; P<0.001) and appeared hyperplastic. The pituitary glands of the highlanders were not significantly different in size from those of the controls (0.67 g vs 0.51 g), but contained larger populations of corticotrophs expressed in terms of the total cell population of their anterior lobes (25.6% vs 19.4%; P<0.001). In conjunction with other studies of this endocrine axis in man and animals exposed to a hypoxic environment, these data suggest that greater amounts of adrenocorticotrophic hormone (ACTH) are required to maintain normal adrenocortical function under such circumstances, probably as a result of hypoxic inhibition of adrenocortical sensitivity to stimulation. Physiological hyperplasia of the adrenal cortex may be common in people living at high altitude.

  9. Visual and metabolic stimuli cause adrenocortical suppression in fasted chickens during refeeding.

    PubMed

    Harvey, S; Klandorf, H; Pinchasov, Y

    1983-07-01

    Concentrations of corticosterone were determined in the plasma of fasted domestic fowl before and at intervals after refeeding. The deprivation of food markedly increased (p less than 0.001) the level of plasma corticosterone. When refed ad libitum the corticosterone concentration declined (by 70%) within 45 min to the level in fed birds and remained at this concentration thereafter. A similar depression in the corticosterone concentration was observed when fasted birds were merely given the sight of the same diet, although the concentration returned to the fasting level within 60 min of food presentation. Refeeding diets with different metabolic energy contents demonstrated that the duration of the feeding-induced adrenocortical suppression was energy related. In fasted birds the presentation of an inert cellulose diet caused a temporary decline in the corticosterone level. In the absence of visual stimuli the administration (by force feeding) of the inert diet had no effect on the corticosterone concentration, whereas force feeding of metabolizable diets still induced adrenocortical suppression. These results demonstrate that adrenocortical suppression occurs in fasted refed birds and both visual and metabolic stimuli are involved in this response.

  10. Multimodal imaging of the self-regulating developing brain

    PubMed Central

    Fjell, Anders M.; Walhovd, Kristine Beate; Brown, Timothy T.; Kuperman, Joshua M.; Chung, Yoonho; Hagler, Donald J.; Venkatraman, Vijay; Roddey, J. Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G.; Bloss, Cinnamon S.; Libiger, Ondrej; Darst, Burcu F.; Schork, Nicholas J.; Casey, B. J.; Chang, Linda; Ernst, Thomas M.; Gruen, Jeffrey R.; Kaufmann, Walter E.; Kenet, Tal; Frazier, Jean; Murray, Sarah S.; Sowell, Elizabeth R.; van Zijl, Peter; Mostofsky, Stewart; Jernigan, Terry L.; Dale, Anders M.; Jernigan, Terry L.; McCabe, Connor; Chang, Linda; Akshoomoff, Natacha; Newman, Erik; Dale, Anders M.; Ernst, Thomas; Dale, Anders M.; Van Zijl, Peter; Kuperman, Joshua; Murray, Sarah; Bloss, Cinnamon; Schork, Nicholas J.; Appelbaum, Mark; Gamst, Anthony; Thompson, Wesley; Bartsch, Hauke; Jernigan, Terry L.; Dale, Anders M.; Akshoomoff, Natacha; Chang, Linda; Ernst, Thomas; Keating, Brian; Amaral, David; Sowell, Elizabeth; Kaufmann, Walter; Van Zijl, Peter; Mostofsky, Stewart; Casey, B.J.; Ruberry, Erika J.; Powers, Alisa; Rosen, Bruce; Kenet, Tal; Frazier, Jean; Kennedy, David; Gruen, Jeffrey

    2012-01-01

    Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4–21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development. PMID:23150548

  11. Multimodal imaging of the self-regulating developing brain.

    PubMed

    Fjell, Anders M; Walhovd, Kristine Beate; Brown, Timothy T; Kuperman, Joshua M; Chung, Yoonho; Hagler, Donald J; Venkatraman, Vijay; Roddey, J Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Libiger, Ondrej; Darst, Burcu F; Schork, Nicholas J; Casey, B J; Chang, Linda; Ernst, Thomas M; Gruen, Jeffrey R; Kaufmann, Walter E; Kenet, Tal; Frazier, Jean; Murray, Sarah S; Sowell, Elizabeth R; van Zijl, Peter; Mostofsky, Stewart; Jernigan, Terry L; Dale, Anders M

    2012-11-27

    Self-regulation refers to the ability to control behavior, cognition, and emotions, and self-regulation failure is related to a range of neuropsychiatric problems. It is poorly understood how structural maturation of the brain brings about the gradual improvement in self-regulation during childhood. In a large-scale multicenter effort, 735 children (4-21 y) underwent structural MRI for quantification of cortical thickness and surface area and diffusion tensor imaging for quantification of the quality of major fiber connections. Brain development was related to a standardized measure of cognitive control (the flanker task from the National Institutes of Health Toolbox), a critical component of self-regulation. Ability to inhibit responses and impose cognitive control increased rapidly during preteen years. Surface area of the anterior cingulate cortex accounted for a significant proportion of the variance in cognitive performance. This finding is intriguing, because characteristics of the anterior cingulum are shown to be related to impulse, attention, and executive problems in neurodevelopmental disorders, indicating a neural foundation for self-regulation abilities along a continuum from normality to pathology. The relationship was strongest in the younger children. Properties of large-fiber connections added to the picture by explaining additional variance in cognitive control. Although cognitive control was related to surface area of the anterior cingulate independently of basic processes of mental speed, the relationship between white matter quality and cognitive control could be fully accounted for by speed. The results underscore the need for integration of different aspects of brain maturation to understand the foundations of cognitive development.

  12. Regulation of bone morphogenetic proteins in early embryonic development

    NASA Astrophysics Data System (ADS)

    Yamamoto, Yukiyo; Oelgeschläger, Michael

    2004-11-01

    Bone morphogenetic proteins (BMPs), a large subgroup of the TGF-β family of secreted growth factors, control fundamental events in early embryonic development, organogenesis and adult tissue homeostasis. The plethora of dose-dependent cellular processes regulated by BMP signalling demand a tight regulation of BMP activity. Over the last decade, a number of proteins have been identified that bind BMPs in the extracellular space and regulate the interaction of BMPs with their cognate receptors, including the secreted BMP antagonist Chordin. In the early vertebrate embryo, the localized secretion of BMP antagonists from the dorsal blastopore lip establishes a functional BMP signalling gradient that is required for the determination of the dorsoventral or back to belly body axis. In particular, inhibition of BMP activity is essential for the formation of neural tissue in the development of vertebrate and invertebrate embryos. Here we review recent studies that have provided new insight into the regulation of BMP signalling in the extracellular space. In particular, we discuss the recently identified Twisted gastrulation protein that modulates, in concert with metalloproteinases of the Tolloid family, the interaction of Chordin with BMP and a family of proteins that share structural similarities with Chordin in the respective BMP binding domains. In addition, genetic and functional studies in zebrafish and frog provide compelling evidence that the secreted protein Sizzled functionally interacts with the Chd BMP pathway, despite being expressed ventrally in the early gastrula-stage embryo. These intriguing discoveries may have important implications, not only for our current concept of early embryonic patterning, but also for the regulation of BMP activity at later developmental stages and tissue homeostasis in the adult.

  13. Caenorhabditis elegans flamingo cadherin fmi-1 regulates GABAergic neuronal development.

    PubMed

    Najarro, Elvis Huarcaya; Wong, Lianna; Zhen, Mei; Carpio, Edgar Pinedo; Goncharov, Alexandr; Garriga, Gian; Lundquist, Erik A; Jin, Yishi; Ackley, Brian D

    2012-03-21

    In a genetic screen for regulators of synaptic morphology, we identified the single Caenorhabditis elegans flamingo-like cadherin fmi-1. The fmi-1 mutants exhibit defective axon pathfinding, reduced synapse number, aberrant synapse size and morphology, as well as an abnormal accumulation of synaptic vesicles at nonsynaptic regions. Although FMI-1 is primarily expressed in the nervous system, it is not expressed in the ventral D-type (VD) GABAergic motorneurons, which are defective in fmi-1 mutants. The axon and synaptic defects of VD neurons could be rescued when fmi-1 was expressed exclusively in non-VD neighboring neurons, suggesting a cell nonautonomous action of FMI-1. FMI-1 protein that lacked its intracellular domain still retained its ability to rescue the vesicle accumulation defects of GABAergic motorneurons, indicating that the extracellular domain was sufficient for this function of FMI-1 in GABAergic neuromuscular junction development. Mutations in cdh-4, a Fat-like cadherin, cause similar defects in GABAergic motorneurons. The cdh-4 is expressed by the VD neurons and seems to function in the same genetic pathway as fmi-1 to regulate GABAergic neuron development. Thus, fmi-1 and cdh-4 cadherins might act together to regulate synapse development and axon pathfinding.

  14. Thrombospondins selectively activate one of the two latent forms of transforming growth factor-beta present in adrenocortical cell-conditioned medium.

    PubMed

    Souchelnitskiy, S; Chambaz, E M; Feige, J J

    1995-11-01

    Transforming growth factor-beta (TGF beta) has been shown previously to be a potent inhibitor of bovine adrenocortical cell steroidogenic functions. However, it is present in the culture medium of these cells in a latent form. In this study, we analyzed in detail the biochemical composition of this latent TGF beta. Two distinct complexes could be separated chromatographically by gel filtration on Sephacryl S-300, and their composition was studied using immunochemical methods. The results indicate that one form (peak I) is a complex between alpha 2-macroglobulin (alpha 2M) and either the unprocessed TGF beta precursor or the mature form of TGF beta. In a major fraction of this complex, TGF beta is covalently linked to alpha 2 M, whereas in a minor fraction, it is noncovalently bound and, therefore, activatable. The second form of latent TGF beta (peak II) is a complex among latent TGF beta-binding protein (LTBP), latency-associated protein, and mature TGF beta and a complex between LTBP and unprocessed TGF beta. We investigated the ability of thrombospondins (TSP1 and TSP2) to activate these latent forms of TGF beta. TSP1 and TSP2 were equally potent at activating the LTBP-latency-associated protein-TGF beta complex in the absence of cell contact, but were ineffective on the alpha 2M-TGF beta complex. Therefore, TGF beta may act as an autocrine regulator of adrenocortical steroidogenic functions. Its activity appears to be controlled by TSPs, the local production of which is regulated by systemic ACTH.

  15. Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development

    PubMed Central

    Akbergenova, Yulia; Cho, Richard W.; Baas-Thomas, Maximilien S.; Littleton, J. Troy

    2016-01-01

    Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo. Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development. SIGNIFICANCE STATEMENT Haploinsufficiency for SHANK3 is one of the most prevalent monogenic causes of autism spectrum disorder, making it imperative to understand how the Shank family regulates neurodevelopment and synapse function. We created the first animal model lacking all Shank proteins and used the Drosophila neuromuscular junction, a model glutamatergic synapse, to characterize the role of Shank at synapses. We identified a novel function of Shank in synapse maturation via regulation of Wnt signaling in the postsynaptic cell. PMID:27225771

  16. Visual experience regulates gene expression in the developing striate cortex.

    PubMed

    Neve, R L; Bear, M F

    1989-06-01

    We have examined the regulation of expression of the genes for the neuronal growth-associated protein GAP43, the type II calcium/calmodulin-dependent protein kinase, and glutamic acid decarboxylase in the kitten visual cortex during normal postnatal development and after a period of visual deprivation. We find that the mRNA transcripts of these genes display very different patterns of normal development but are all increased in the visual cortex of animals reared in the dark. Upon exposure to light, the transcript of the GAP43 gene drops to near-normal levels within 12 hr.

  17. Crim1 regulates integrin signaling in murine lens development.

    PubMed

    Zhang, Ying; Fan, Jieqing; Ho, Joshua W K; Hu, Tommy; Kneeland, Stephen C; Fan, Xueping; Xi, Qiongchao; Sellarole, Michael A; de Vries, Wilhelmine N; Lu, Weining; Lachke, Salil A; Lang, Richard A; John, Simon W M; Maas, Richard L

    2016-01-15

    The developing lens is a powerful system for investigating the molecular basis of inductive tissue interactions and for studying cataract, the leading cause of blindness. The formation of tightly controlled cell-cell adhesions and cell-matrix junctions between lens epithelial (LE) cells, between lens fiber (LF) cells, and between these two cell populations enables the vertebrate lens to adopt a highly ordered structure and acquire optical transparency. Adhesion molecules are thought to maintain this ordered structure, but little is known about their identity or interactions. Cysteine-rich motor neuron 1 (Crim1), a type I transmembrane protein, is strongly expressed in the developing lens and its mutation causes ocular disease in both mice and humans. How Crim1 regulates lens morphogenesis is not understood. We identified a novel ENU-induced hypomorphic allele of Crim1, Crim1(glcr11), which in the homozygous state causes cataract and microphthalmia. Using this and two other mutant alleles, Crim1(null) and Crim1(cko), we show that the lens defects in Crim1 mouse mutants originate from defective LE cell polarity, proliferation and cell adhesion. Crim1 adhesive function is likely to be required for interactions both between LE cells and between LE and LF cells. We show that Crim1 acts in LE cells, where it colocalizes with and regulates the levels of active β1 integrin and of phosphorylated FAK and ERK. The RGD and transmembrane motifs of Crim1 are required for regulating FAK phosphorylation. These results identify an important function for Crim1 in the regulation of integrin- and FAK-mediated LE cell adhesion during lens development.

  18. An unusual presentation of Carney complex with diffuse primary pigmented nodular adrenocortical disease on one adrenal gland and a nonpigmented adrenocortical adenoma and focal primary pigmented nodular adrenocortical disease on the other.

    PubMed

    Tung, Shih-Chen; Hwang, Daw-Yang; Yang, Joseph W; Chen, Wei-Jen; Lee, Chien-Te

    2012-01-01

    A 24-year-old female patient with cushingoid appearance was admitted in May 2000. The endocrine studies showed ACTH-independent Cushing's syndrome. A 2-day high-dose dexamethasone suppression test (HDDST) revealed paradoxical increase of 24 h urinary free cortisol (UFC). Abdominal computed tomography demonstrated a left adrenal nodule (3 x 2 cm in diameter). An adrenal scintigram with ¹³¹I-6β-iodomethyl-19-norcholesterol showed uptake of the isotope in the left adrenal gland and non-visualization in the right adrenal gland throughout the examination course. A retroperitoneoscopic left total adrenalectomy was performed in July 2000. The cut surface of the left adrenal was yellow-tan grossly. Microscopically, the left adrenal nodule contained a nonpigmented adrenocortical adenoma (NP) and another focal primary pigmented nodular adrenocortical disease (PPNAD, FP) mixed lesion. The immunohistochemical studies of CYP17 demonstrate positive in NP and FP of the left adrenal gland. Very low baseline morning plasma cortisol (0.97 μg/dL) and subnormal ACTH (8.16 pg/mL) levels were measured 1.5 months after left adrenalectomy. Right adrenal gland recovered its function 6 months after left adrenalectomy. Plasma cortisol could be suppressed to 3.47 μg/dL by overnight low-dose dexamethasone suppression test 65 months after left adrenalectomy. Cushingoid features still did not appear 122 months after left adrenalectomy. In May 2011, this patient was readmitted due to cushingoid characteristics. Paradoxical rise of 24-h UFC to 2-day HDDST was demonstrated. Ultrasonography of thyroid showed bilateral thyroid cysts. Subtotal right adrenalectomy about 80% of right adrenal was performed. Diffuse PPNAD of the right adrenal was proved pathologically. Immunohischemical stain for CYP17 is positive in the right adrenal gland but weaker positive than that in the left adrenal gland. The genetic study of the peripheral blood, left adrenocortical nodule, and right PPNAD all showed p.R16X

  19. Ihh signaling regulates mandibular symphysis development and growth.

    PubMed

    Sugito, H; Shibukawa, Y; Kinumatsu, T; Yasuda, T; Nagayama, M; Yamada, S; Minugh-Purvis, N; Pacifici, M; Koyama, E

    2011-05-01

    Symphyseal secondary cartilage is important for mandibular development, but the molecular mechanisms underlying its formation remain largely unknown. Here we asked whether Indian hedgehog (Ihh) regulates symphyseal cartilage development and growth. By embryonic days 16.5 to 18.5, Sox9-expressing chondrocytes formed within condensed Tgfβ-1/Runx2-expressing mesenchymal cells at the prospective symphyseal joint site, and established a growth-plate-like structure with distinct Ihh, collagen X, and osteopontin expression patterns. In post-natal life, mesenchymal cells expressing the Ihh receptor Patched1 were present anterior to the Ihh-expressing secondary cartilage, proliferated, differentiated into chondrocytes, and contributed to anterior growth of alveolar bone. In Ihh-null mice, however, symphyseal development was defective, mainly because of enhanced chondrocyte maturation and reduced proliferation of chondroprogenitor cells. Proliferation was partially restored in dual Ihh;Gli3 mutants, suggesting that Gli3 is normally a negative regulator of symphyseal development. Thus, Ihh signaling is essential for symphyseal cartilage development and anterior mandibular growth.

  20. Profilin1 Regulates Sternum Development and Endochondral Bone Formation

    PubMed Central

    Miyajima, Daisuke; Hayata, Tadayoshi; Suzuki, Takafumi; Hemmi, Hiroaki; Nakamoto, Tetsuya; Notomi, Takuya; Amagasa, Teruo; Böttcher, Ralph T.; Costell, Mercedes; Fässler, Reinhard; Ezura, Yoichi; Noda, Masaki

    2012-01-01

    Bone development is a dynamic process that requires cell motility and morphological adaptation under the control of actin cytoskeleton. This actin cytoskeleton system is regulated by critical modulators including actin-binding proteins. Among them, profilin1 (Pfn1) is a key player to control actin fiber structure, and it is involved in a number of cellular activities such as migration. During the early phase of body development, skeletal stem cells and osteoblastic progenitor cells migrate to form initial rudiments for future skeletons. During this migration, these cells extend their process based on actin cytoskeletal rearrangement to locate themselves in an appropriate location within microenvironment. However, the role of Pfn1 in regulation of mesenchymal progenitor cells (MPCs) during skeletal development is incompletely understood. Here we examined the role of Pfn1 in skeletal development using a genetic ablation of Pfn1 in MPCs by using Prx1-Cre recombinase. We found that Pfn1 deficiency in MPCs caused complete cleft sternum. Notably, Pfn1-deficient mice exhibited an absence of trabecular bone in the marrow space of appendicular long bone. This phenotype is location-specific, as Pfn1 deficiency did not largely affect osteoblasts in cortical bone. Pfn1 deficiency also suppressed longitudinal growth of long bone. In vitro, Pfn1 deficiency induced retardation of osteoblastic cell migration. These observations revealed that Pfn1 is a critical molecule for the skeletal development, and this could be at least in part associated with the retardation of cell migration PMID:22773831

  1. Subplate Neurons: Crucial Regulators of Cortical Development and Plasticity

    PubMed Central

    Kanold, Patrick O.

    2009-01-01

    The developing cerebral cortex contains a distinct class of cells, subplate neurons, which form one of the first functional cortical circuits. Subplate neurons reside in the cortical white matter, receive thalamic inputs and project into the developing cortical plate, mostly to layer 4. Subplate neurons are present at key time points during development. Removal of subplate neurons profoundly affects cortical development. Subplate removal in visual cortex prevents the maturation of thalamocortical synapse, the maturation of inhibition in layer 4, the development of orientation selective responses in individual cortical neurons, and the formation of ocular dominance columns. In addition, monocular deprivation during development reveals that ocular dominance plasticity is paradoxical in the absence of subplate neurons. Because subplate neurons projecting to layer 4 are glutamatergic, these diverse deficits following subplate removal were hypothesized to be due to lack of feed-forward thalamic driven cortical excitation. A computational model of the developing thalamocortical pathway incorporating feed-forward excitatory subplate projections replicates both normal development and plasticity of ocular dominance as well as the effects of subplate removal. Therefore, we postulate that feed-forward excitatory projections from subplate neurons into the developing cortical plate enhance correlated activity between thalamus and layer 4 and, in concert with Hebbian learning rules in layer 4, allow maturational and plastic processes in layer 4 to commence. Thus subplate neurons are a crucial regulator of cortical development and plasticity, and damage to these neurons might play a role in the pathology of many neurodevelopmental disorders. PMID:19738926

  2. Amine oxidase activity regulates the development of pulmonary fibrosis.

    PubMed

    Marttila-Ichihara, Fumiko; Elima, Kati; Auvinen, Kaisa; Veres, Tibor Z; Rantakari, Pia; Weston, Christopher; Miyasaka, Masayuki; Adams, David; Jalkanen, Sirpa; Salmi, Marko

    2017-03-01

    In pulmonary fibrosis, an inflammatory reaction and differentiation of myofibroblasts culminate in pathologic deposition of collagen. Amine oxidase copper containing-3 (AOC3) is a cell-surface expressed oxidase that regulates leukocyte extravasation. Here we analyzed the potential role of AOC3 using gene-modified and inhibitor-treated mice in a bleomycin-induced pulmonary fibrosis model. Inflammation and fibrosis of lungs were assessed by histologic, flow cytometric, and quantitative PCR analysis. AOC3-deficient mice showed a 30-50% reduction in fibrosis, collagen synthesis, numbers of myofibroblasts, and accumulation of CD4(+) lymphocytes, NK T cells, macrophages, and type 2 innate lymphoid cells compared with wild-type control mice. AOC3 knock-in mice, which express a catalytically inactive form of AOC3, were also protected from lung fibrosis. In wild-type mice, a small-molecule AOC3 inhibitor treatment reduced leukocyte infiltration, myofibroblast differentiation, and fibrotic injury both in prophylactic and early therapeutic settings by about 50% but was unable to reverse the established fibrosis. AOC3 was also induced in myofibroblasts in human idiopathic pulmonary fibrosis. Thus, the oxidase activity of AOC3 contributes to the development of lung fibrosis mainly by regulating the accumulation of pathogenic leukocyte subtypes, which drive the fibrotic response.-Marttila-Ichihara, F., Elima, K., Auvinen, K., Veres, T. Z., Rantakari, P., Weston, C., Miyasaka, M., Adams, D., Jalkanen, S., Salmi, M. Amine oxidase activity regulates the development of pulmonary fibrosis.

  3. GLK gene pairs regulate chloroplast development in diverse plant species.

    PubMed

    Fitter, David W; Martin, David J; Copley, Martin J; Scotland, Robert W; Langdale, Jane A

    2002-09-01

    Chloroplast biogenesis is a complex process that requires close co-ordination between two genomes. Many of the proteins that accumulate in the chloroplast are encoded by the nuclear genome, and the developmental transition from proplastid to chloroplast is regulated by nuclear genes. Here we show that a pair of Golden 2-like (GLK) genes regulates chloroplast development in Arabidopsis. The GLK proteins are members of the GARP superfamily of transcription factors, and phylogenetic analysis demonstrates that the maize, rice and Arabidopsis GLK gene pairs comprise a distinct group within the GARP superfamily. Further phylogenetic analysis suggests that the gene pairs arose through separate duplication events in the monocot and dicot lineages. As in rice, AtGLK1 and AtGLK2 are expressed in partially overlapping domains in photosynthetic tissue. Insertion mutants demonstrate that this expression pattern reflects a degree of functional redundancy as single mutants display normal phenotypes in most photosynthetic tissues. However, double mutants are pale green in all photosynthetic tissues and chloroplasts exhibit a reduction in granal thylakoids. Products of several genes involved in light harvesting also accumulate at reduced levels in double mutant chloroplasts. GLK genes therefore regulate chloroplast development in diverse plant species.

  4. Hormonal regulation of early follicle development in the rat ovary.

    PubMed

    Hsueh, A J; McGee, E A; Hayashi, M; Hsu, S Y

    2000-05-25

    Although earlier studies focused on the hormonal regulation of antral and preovulatory follicles, recent studies indicate the importance of the hormonal control mechanism for preantral follicles. The endocrine hormone FSH is not only a survival factor for early antral follicles but also a potent growth and differentiation factor for preantral follicles. In addition, KGF secreted by theca cells and c-kit ligand secreted by granulosa cells play paracrine roles in the regulation of preantral follicle growth and development. Furthermore oocyte-derived GDF-9 promotes the growth and differentiation of early follicles by acting on somatic cells in the follicle. It is likely that the genetic makeup of an oocyte could determine the secretion of oocyte hormones which would, in turn, regulate the growth and differentiation of the surrounding somatic cells of that follicle. A better understanding of the hormonal mechanisms underlying early follicle development could provide a refined culture system for the in vitro maturation of fertilizable oocytes and future design of fertility and contraceptive agents.

  5. Glutamate dehydrogenase 1 and SIRT4 regulate glial development.

    PubMed

    Komlos, Daniel; Mann, Kara D; Zhuo, Yue; Ricupero, Christopher L; Hart, Ronald P; Liu, Alice Y-C; Firestein, Bonnie L

    2013-03-01

    Congenital hyperinsulinism/hyperammonemia (HI/HA) syndrome is caused by an activation mutation of glutamate dehydrogenase 1 (GDH1), a mitochondrial enzyme responsible for the reversible interconversion between glutamate and α-ketoglutarate. The syndrome presents clinically with hyperammonemia, significant episodic hypoglycemia, seizures, and frequent incidences of developmental and learning defects. Clinical research has implicated that although some of the developmental and neurological defects may be attributed to hypoglycemia, some characteristics cannot be ascribed to low glucose and as hyperammonemia is generally mild and asymptomatic, there exists the possibility that altered GDH1 activity within the brain leads to some clinical changes. GDH1 is allosterically regulated by many factors, and has been shown to be inhibited by the ADP-ribosyltransferase sirtuin 4 (SIRT4), a mitochondrially localized sirtuin. Here we show that SIRT4 is localized to mitochondria within the brain. SIRT4 is highly expressed in glial cells, specifically astrocytes, in the postnatal brain and in radial glia during embryogenesis. Furthermore, SIRT4 protein decreases in expression during development. We show that factors known to allosterically regulate GDH1 alter gliogenesis in CTX8 cells, a novel radial glial cell line. We find that SIRT4 and GDH1 overexpression play antagonistic roles in regulating gliogenesis and that a mutant variant of GDH1 found in HI/HA patients accelerates the development of glia from cultured radial glia cells.

  6. ROLE OF CENTRAL GLUCAGON-LIKE PEPTIDE-1 IN HYPOTHALAMO-PITUITARY-ADRENOCORTICAL FACILITATION FOLLOWING CHRONIC STRESS

    PubMed Central

    Tauchi, Miyuki; Zhang, Rong; D’Alessio, David A.; Seeley, Randy J; Herman, James P

    2008-01-01

    Central glucagon-like peptide-1 (GLP-1) regulates food intake, glucose homeostasis, and behavioral and neuroendocrine responses to acute stress. Given its pronounced role in acute stress regulation, the GLP-1 system is a prime candidate for mediating the prolonged drive of the hypothalamo-pituitary-adrenocortical axis by chronic stress. To test this hypothesis, we evaluated the necessity and sufficiency of GLP-1 for production of chronic stress-induced changes in HPA axis function. Exogenous GLP-1 or the GLP-1 receptor antagonist, dHG-exendin, were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress (CVS) for 7 days. Animals in the CVS groups received GLP-1 or dHG-exendin immediately prior to each stress exposure. Prior to and at the end of the 7-day trial, chronically stressed animals were subjected to a novel stressor to test for HPA axis facilitation. Neither GLP-1 nor dHG-exendin affected CVS-associated increases in adrenal weight or decreases in basal plasma glucose levels. In addition, neither exogenous GLP-1 nor dHG-exendin altered any index of HPA axis activity in unstressed rats. However, GLP-1 enhanced CVS-induced facilitation of corticosterone (but not ACTH) response to an acute stress, whereas dHG-exendin inhibited facilitation. In addition, GLP-1 decreased body weight in chronically-stressed animals. dHG-exendin increased food intake and body weight in unstressed animals, consistent with a tonic role for GLP-1 in body weight regulation. Overall, our data suggest that brain GLP-1 modulates HPA axis activity within the context of chronic stress, perhaps at the level of the adrenal gland. PMID:18177641

  7. Interactions among Genes Regulating Ovule Development in Arabidopsis Thaliana

    PubMed Central

    Baker, S. C.; Robinson-Beers, K.; Villanueva, J. M.; Gaiser, J. C.; Gasser, C. S.

    1997-01-01

    The INNER NO OUTER (INO) and AINTEGUMENTA (ANT) genes are essential for ovule integument development in Arabidopsis thaliana. Ovules of ino mutants initiate two integument primordia, but the outer integument primordium forms on the opposite side of the ovule from the normal location and undergoes no further development. The inner integument appears to develop normally, resulting in erect, unitegmic ovules that resemble those of gymnosperms. ino plants are partially fertile and produce seeds with altered surface topography, demonstrating a lineage dependence in development of the testa. ant mutations affect initiation of both integuments. The strongest of five new ant alleles we have isolated produces ovules that lack integuments and fail to complete megasporogenesis. ant mutations also affect flower development, resulting in narrow petals and the absence of one or both lateral stamens. Characterization of double mutants between ant, ino and other mutations affecting ovule development has enabled the construction of a model for genetic control of ovule development. This model proposes parallel independent regulatory pathways for a number of aspects of this process, a dependence on the presence of an inner integument for development of the embryo sac, and the existence of additional genes regulating ovule development. PMID:9093862

  8. CCN1 Regulates Chondrocyte Maturation and Cartilage Development.

    PubMed

    Zhang, Yongchun; Sheu, Tzong-jen; Hoak, Donna; Shen, Jie; Hilton, Matthew J; Zuscik, Michael J; Jonason, Jennifer H; O'Keefe, Regis J

    2016-03-01

    WNT/β-CATENIN signaling is involved in multiple aspects of skeletal development, including chondrocyte differentiation and maturation. Although the functions of β-CATENIN in chondrocytes have been extensively investigated through gain-of-function and loss-of-function mouse models, the precise downstream effectors through which β-CATENIN regulates these processes are not well defined. Here, we report that the matricellular protein, CCN1, is induced by WNT/β-CATENIN signaling in chondrocytes. Specifically, we found that β-CATENIN signaling promotes CCN1 expression in isolated primary sternal chondrocytes and both embryonic and postnatal cartilage. Additionally, we show that, in vitro, CCN1 overexpression promotes chondrocyte maturation, whereas inhibition of endogenous CCN1 function inhibits maturation. To explore the role of CCN1 on cartilage development and homeostasis in vivo, we generated a novel transgenic mouse model for conditional Ccn1 overexpression and show that cartilage-specific CCN1 overexpression leads to chondrodysplasia during development and cartilage degeneration in adult mice. Finally, we demonstrate that CCN1 expression increases in mouse knee joint tissues after meniscal/ligamentous injury (MLI) and in human cartilage after meniscal tear. Collectively, our data suggest that CCN1 is an important regulator of chondrocyte maturation during cartilage development and homeostasis.

  9. CCN1 Regulates Chondrocyte Maturation and Cartilage Development

    PubMed Central

    Zhang, Yongchun; Sheu, Tzong-jen; Hoak, Donna; Shen, Jie; Hilton, Matthew J; Zuscik, Michael J; Jonason, Jennifer H; O’Keefe, Regis J

    2016-01-01

    WNT/β-CATENIN signaling is involved in multiple aspects of skeletal development, including chondrocyte differentiation and maturation. Although the functions of β-CATENIN in chondrocytes have been extensively investigated through gain-of-function and loss-of-function mouse models, the precise downstream effectors through which β-CATENIN regulates these processes are not well defined. Here, we report that the matricellular protein, CCN1, is induced by WNT/β-CATENIN signaling in chondrocytes. Specifically, we found that β-CATENIN signaling promotes CCN1 expression in isolated primary sternal chondrocytes and both embryonic and postnatal cartilage. Additionally, we show that, in vitro, CCN1 overexpression promotes chondrocyte maturation, whereas inhibition of endogenous CCN1 function inhibits maturation. To explore the role of CCN1 on cartilage development and homeostasis in vivo, we generated a novel transgenic mouse model for conditional Ccn1 overexpression and show that cartilage-specific CCN1 overexpression leads to chondrodysplasia during development and cartilage degeneration in adult mice. Finally, we demonstrate that CCN1 expression increases in mouse knee joint tissues after meniscal/ligamentous injury (MLI) and in human cartilage after meniscal tear. Collectively, our data suggest that CCN1 is an important regulator of chondrocyte maturation during cartilage development and homeostasis. PMID:26363286

  10. Pharmaceuticals in Australia: developments in regulation and governance.

    PubMed

    Lofgren, Hans; Boer, Rebecca de

    2004-06-01

    The pharmaceutical domain represents a type of internationalised policy network theorised in recent writings on neo-liberalism, neo-corporatism and governance. This article presents an analysis of developments in prescription drug regulation in Australia. A relatively stable, state-managed pattern of interaction has been superseded by less closed exchange, and the government itself has fragmented into agencies pursuing different objectives. Developments in the three core regulatory areas are described: safety and efficacy controls, social policy (access and equity), and state support for industry (economic) development. Consensus-building occurs within the context of the National Medicines Policy. The pharmaceutical industry, represented by Medicines Australia, has a stake in all aspects of pharmaceutical policy and regulation, and draws upon unique resources (expertise and lobbying capacity). The context for the developments described is Australia's abandonment of a protectionist version of the Keynesian welfare national state in favour of the model of the competition state, which is oriented towards support for the growth of high technology industries such as pharmaceuticals, premised on partnerships with business.

  11. Noninvasive monitoring of adrenocortical activity in carnivores by fecal glucocorticoid analyses.

    PubMed

    Young, K M; Walker, S L; Lanthier, C; Waddell, W T; Monfort, S L; Brown, J L

    2004-06-01

    Measurement of glucocorticoid metabolites in feces has become an accepted method for the noninvasive evaluation of adrenocortical activity. The objective of this study was to determine if a simple cortisol enzyme immunoassay (EIA) was suitable for monitoring adrenocortical activity in a variety of carnivore species. Performance of the cortisol EIA was gauged by comparison to a corticosterone radioimmunoassay (RIA) that has been used for measuring glucocorticoid metabolites in feces of numerous species. Tests for parallelism and extraction efficiency were used to compare the cortisol EIA and corticosterone RIA across eight species of carnivores (Himalayan black bear, sloth bear, domestic cat, cheetah, clouded leopard, black-footed ferret, slender-tailed meerkat, and red wolf). The biological relevance of immunoreactive glucocorticoid metabolites in feces was established for at least one species of each Carnivora family studied with an adrenocorticotropic hormone (ACTH) challenge. High performance liquid chromatography (HPLC) analysis of fecal extracts for each species revealed (1) the presence of multiple immunoreactive glucocorticoid metabolites in feces, but (2) the two immunoassays measured different metabolites, and (3) there were differences across species in the number and polarities of metabolites identified between assay systems. ACTH challenge studies revealed increases in fecal metabolite concentrations measured by the cortisol EIA and corticosterone RIA of approximately 228-1145% and approximately 231-4150% above pre-treatment baseline, respectively, within 1-2 days of injection. Concentrations of fecal glucocorticoid metabolites measured by the cortisol EIA and corticosterone RIA during longitudinal evaluation (i.e., >50 days) of several species were significantly correlated (P<0.0025, correlation coefficient range 0.383-0.975). Adrenocortical responses to physical and psychological stressors during longitudinal evaluations varied with the type of

  12. Regulation of flower development in Arabidopsis by SCF complexes.

    PubMed

    Ni, Weimin; Xie, Daoxin; Hobbie, Lawrence; Feng, Baomin; Zhao, Dazhong; Akkara, Joseph; Ma, Hong

    2004-04-01

    SCF complexes are the largest and best studied family of E3 ubiquitin protein ligases that facilitate the ubiquitylation of proteins targeted for degradation. The SCF core components Skp1, Cul1, and Rbx1 serve in multiple SCF complexes involving different substrate-specific F-box proteins that are involved in diverse processes including cell cycle and development. In Arabidopsis, mutations in the F-box gene UNUSUAL FLORAL ORGANS (UFO) result in a number of defects in flower development. However, functions of the core components Cul1 and Rbx1 in flower development are poorly understood. In this study we analyzed floral phenotypes caused by altering function of Cul1 or Rbx1, as well as the effects of mutations in ASK1 and ASK2. Plants homozygous for a point mutation in the AtCUL1 gene showed reduced floral organ number and several defects in each of the four whorls. Similarly, plants with reduced AtRbx1 expression due to RNA interference also exhibited floral morphological defects. In addition, compared to the ask1 mutant, plants homozygous for ask1 and heterozygous for ask2 displayed enhanced reduction of B function, as well as other novel defects of flower development, including carpelloid sepals and an inhibition of petal development. Genetic analyses demonstrate that AGAMOUS (AG) is required for the novel phenotypes observed in the first and second whorls. Furthermore, the genetic interaction between UFO and AtCUL1 supports the idea that UFO regulates multiple aspects of flower development as a part of SCF complexes. These results suggest that SCF complexes regulate several aspects of floral development in Arabidopsis.

  13. Individual development and evolution: experiential canalization of self-regulation.

    PubMed

    Blair, Clancy; Raver, C Cybele

    2012-05-01

    In this article, we contrast evolutionary and psychobiological models of individual development to address the idea that individual development occurring in prototypically risky and unsupportive environments can be understood as adaptation. We question traditional evolutionary explanations of individual development, calling on the principle of probabilistic epigenesis to suggest that individual development resulting from the combined activity of genes and environments is best understood to precede rather than follow from evolutionary change. Specifically, we focus on the ways in which experience shapes the development of stress response physiology, with implications for individual development and intergenerational transmission of reactive, as opposed to reflective, phenotypes. In doing so, we describe results from several analyses conducted with a longitudinal data set of 1,292 children and their primary caregivers followed from birth. Our results indicate that the effects of poverty on stress response physiology and on the development of the self-regulation of behavior represent instances of the experiential canalization of development with implications for understanding the genesis and "adaptiveness" of risk behavior.

  14. Regulated Noise in the Epigenetic Landscape of Development and Disease

    PubMed Central

    Pujadas, Elisabet; Feinberg, Andrew

    2012-01-01

    In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and mediates robustness during cell fate commitment. After grounding our argument in a discussion of stochastic noise and non-genetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach the unraveling of disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, which leads to tumor cell heterogeneity. PMID:22424224

  15. scaRNAs regulate splicing and vertebrate heart development.

    PubMed

    Patil, Prakash; Kibiryeva, Nataliya; Uechi, Tamayo; Marshall, Jennifer; O'Brien, James E; Artman, Michael; Kenmochi, Naoya; Bittel, Douglas C

    2015-08-01

    Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several genes that regulate heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and MBNL2). In addition, we used antisense morpholinos to knock down the expression of two scaRNAs (scarna1 and snord94) in zebrafish and saw a corresponding disruption of heart development with an accompanying alteration in splice isoforms of cardiac regulatory genes. Based on these combined results, we hypothesize that scaRNA modification of spliceosomal RNAs assists in fine tuning the spliceosome for dynamic selection of mRNA splice isoforms. Our results are consistent with disruption of splicing patterns during early embryonic development leading to insufficient communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for determining the mechanisms underlying congenital cardiac malformations.

  16. Roles and regulation of cytokinins in tomato fruit development.

    PubMed

    Matsuo, Satoshi; Kikuchi, Kaori; Fukuda, Machiko; Honda, Ichiro; Imanishi, Shunsuke

    2012-09-01

    Cytokinins (CKs) are thought to play important roles in fruit development, especially cell division. However, the mechanisms and regulation of CK activity have not been well investigated. This study analysed CK concentrations and expression of genes involved in CK metabolism in developing tomato (Solanum lycopersicum) ovaries. The concentrations of CK ribosides and isopentenyladenine and the transcript levels of the CK biosynthetic genes SlIPT3, SlIPT4, SlLOG6, and SlLOG8 were high at anthesis and decreased immediately afterward. In contrast, trans-zeatin concentration and the transcript levels of the CK biosynthetic genes SlIPT1, SlIPT2, SlCYP735A1, SlCYP735A2, and SlLOG2 increased after anthesis. The expression of type-A response regulator genes was high in tomato ovaries from pre-anthesis to early post-anthesis stages. These results suggest that the CK signal transduction pathway is active in the cell division phase of fruit development. This study also investigated the effect of CK application on fruit set and development. Application of a synthetic CK, N-(2-chloro-pyridin-4-yl)-N'-phenylurea (CPPU), to unpollinated tomato ovaries induced parthenocarpic fruit development. The CPPU-induced parthenocarpic fruits were smaller than pollinated fruits, because of reduction of pericarp cell size rather than reduced cell number. Thus, CPPU-induced parthenocarpy was attributable to the promotion of cell division, not cell expansion. Overall, the results provide evidence that CKs are involved in cell division during development of tomato fruit.

  17. Epigenetic regulation of development and pathogenesis in fungal plant pathogens.

    PubMed

    Dubey, Akanksha; Jeon, Junhyun

    2016-10-17

    Evidently, epigenetics is at forefront in explaining the mechanisms underlying the success of human pathogens and in the identification of pathogen-induced modifications within host plants. However, there is a lack of studies highlighting the role of epigenetics in the modulation of the growth and pathogenicity of fungal plant pathogens. In this review, we attempt to highlight and discuss the role of epigenetics in the regulation of the growth and pathogenicity of fungal phytopathogens using Magnaporthe oryzae, a devastating fungal plant pathogen, as a model system. With the perspective of wide application in the understanding of the development, pathogenesis and control of other fungal pathogens, we attempt to provide a synthesized view of the epigenetic studies conducted on M. oryzae to date. First, we discuss the mechanisms of epigenetic modifications in M. oryzae and their impact on fungal development and pathogenicity. Second, we highlight the unexplored epigenetic mechanisms and areas of research that should be considered in the near future to construct a holistic view of epigenetic functioning in M. oryzae and other fungal plant pathogens. Importantly, the development of a complete understanding of the modulation of epigenetic regulation in fungal pathogens can help in the identification of target points to combat fungal pathogenesis.

  18. Steroids as Central Regulators of Organismal Development and Lifespan

    PubMed Central

    Lee, Siu Sylvia; Schroeder, Frank C.

    2012-01-01

    Larvae of the nematode Caenorhabditis elegans must choose between reproductive development and dauer diapause. This decision is based on sensing of environmental inputs and dauer pheromone, a small molecule signal that serves to monitor population density. These signals are integrated via conserved neuroendocrine pathways that converge on steroidal ligands of the nuclear receptor DAF-12, a homolog of the mammalian vitamin D receptor and liver X receptor. DAF-12 acts as the main switch between gene expression programs that drive either reproductive development or dauer entry. Extensive studies in the past two decades demonstrated that biosynthesis of two bile acid-like DAF-12 ligands, named dafachronic acids (DA), controls developmental fate. In this issue of PLoS Biology, Wollam et al. showed that a conserved steroid-modifying enzyme, DHS-16, introduces a key feature in the structures of the DAF-12 ligands, closing a major gap in the DA biosynthesis pathway. The emerging picture of DA biosynthesis in C. elegans enables us to address a key question in the field: how are complex environmental signals integrated to enforce binary, organism-wide decisions on developmental fate? Schaedel et al. demonstrated that pheromone and DA serve as competing signals, and that a positive feedback loop based on regulation of DA biosynthesis ensures organism-wide commitment to reproductive development. Considering that many components of DA signaling are highly conserved, ongoing studies in C. elegans may reveal new aspects of bile acid function and lifespan regulation in mammals. PMID:22505849

  19. A Case of Oncocytic Adrenocortical Neoplasm of Borderline (Uncertain) Malignant Potential

    PubMed Central

    Brown, Linda G; Denning, Krista L; Pacioles, Toni

    2016-01-01

    Oncocytic neoplasms are tumors composed predominantly or exclusively of oncocytes (large polygonal cells with granular eosinophilic cytoplasm due to abnormal mitochondrial accumulation). These tumors are frequently reported in the thyroid, kidneys, and salivary glands. However, they are distinctly rare in the adrenal cortex. Oncocytic adrenocortical neoplasms (OAN) are classified regarding their biological behavior by their histological features according to the Lin-Weiss-Bisceglia system (LWB). Here, we report a case of OAN of borderline or uncertain malignant potential (BMP) with subsequently identified papillary thyroid carcinoma (PTC). A 34-year-old female with a nine-month history of fatigue presented with chest pain. A right adrenal mass was incidentally found while ruling out pulmonary embolism. A CT-guided adrenal biopsy, although not routinely indicated, was performed and interpreted as malignant with no definitive origin. Hormonal workup was unremarkable. PET-scan showed hypermetabolic adrenal mass with peak standardized uptake value of 15, suspicious of malignancy. A hypermetabolic thyroid nodule was also identified, but there was no evidence of metastatic disease. The patient underwent adrenalectomy, and the initial pathology report was interpreted as atypical pink cell tumor. A second pathology report from another laboratory favored OAN based on the morphology and immunohistochemical staining. While the histologic criteria of malignancy were not met, the large tumor size makes it compatible with BMP according to LWB criteria. A follow-up thyroid ultrasound revealed a complex thyroid nodule. A total thyroidectomy was performed, and pathology was consistent with PTC. Of interest, PTC frequently shows an increase in mitochondrial content, which is characteristic of oncocytic tumors. This case illustrates that OAN, although rare, should be considered in the differential diagnosis of adrenal masses. When OAN is identified, it should be classified

  20. A Case of Oncocytic Adrenocortical Neoplasm of Borderline (Uncertain) Malignant Potential.

    PubMed

    Shenouda, Mina; Brown, Linda G; Denning, Krista L; Pacioles, Toni

    2016-06-13

    Oncocytic neoplasms are tumors composed predominantly or exclusively of oncocytes (large polygonal cells with granular eosinophilic cytoplasm due to abnormal mitochondrial accumulation). These tumors are frequently reported in the thyroid, kidneys, and salivary glands. However, they are distinctly rare in the adrenal cortex. Oncocytic adrenocortical neoplasms (OAN) are classified regarding their biological behavior by their histological features according to the Lin-Weiss-Bisceglia system (LWB). Here, we report a case of OAN of borderline or uncertain malignant potential (BMP) with subsequently identified papillary thyroid carcinoma (PTC). A 34-year-old female with a nine-month history of fatigue presented with chest pain. A right adrenal mass was incidentally found while ruling out pulmonary embolism. A CT-guided adrenal biopsy, although not routinely indicated, was performed and interpreted as malignant with no definitive origin. Hormonal workup was unremarkable. PET-scan showed hypermetabolic adrenal mass with peak standardized uptake value of 15, suspicious of malignancy. A hypermetabolic thyroid nodule was also identified, but there was no evidence of metastatic disease. The patient underwent adrenalectomy, and the initial pathology report was interpreted as atypical pink cell tumor. A second pathology report from another laboratory favored OAN based on the morphology and immunohistochemical staining. While the histologic criteria of malignancy were not met, the large tumor size makes it compatible with BMP according to LWB criteria. A follow-up thyroid ultrasound revealed a complex thyroid nodule. A total thyroidectomy was performed, and pathology was consistent with PTC. Of interest, PTC frequently shows an increase in mitochondrial content, which is characteristic of oncocytic tumors. This case illustrates that OAN, although rare, should be considered in the differential diagnosis of adrenal masses. When OAN is identified, it should be classified

  1. Strigolactone regulates shoot development through a core signalling pathway

    PubMed Central

    Müller, Dörte

    2016-01-01

    ABSTRACT Strigolactones are a recently identified class of hormone that regulate multiple aspects of plant development. The DWARF14 (D14) α/β fold protein has been identified as a strigolactone receptor, which can act through the SCFMAX2 ubiquitin ligase, but the universality of this mechanism is not clear. Multiple proteins have been suggested as targets for strigolactone signalling, including both direct proteolytic targets of SCFMAX2, and downstream targets. However, the relevance and importance of these proteins to strigolactone signalling in many cases has not been fully established. Here we assess the contribution of these targets to strigolactone signalling in adult shoot developmental responses. We find that all examined strigolactone responses are regulated by SCFMAX2 and D14, and not by other D14-like proteins. We further show that all examined strigolactone responses likely depend on degradation of SMXL proteins in the SMXL6 clade, and not on the other proposed proteolytic targets BES1 or DELLAs. Taken together, our results suggest that in the adult shoot, the dominant mode of strigolactone signalling is D14-initiated, MAX2-mediated degradation of SMXL6-related proteins. We confirm that the BRANCHED1 transcription factor and the PIN-FORMED1 auxin efflux carrier are plausible downstream targets of this pathway in the regulation of shoot branching, and show that BRC1 likely acts in parallel to PIN1. PMID:27793831

  2. The role of abscisic acid in regulating cucumber fruit development and ripening and its transcriptional regulation.

    PubMed

    Wang, Yanping; Wang, Ya; Ji, Kai; Dai, Shengjie; Hu, Ying; Sun, Liang; Li, Qian; Chen, Pei; Sun, Yufei; Duan, Chaorui; Wu, Yan; Luo, Hao; Zhang, Dian; Guo, Yangdong; Leng, Ping

    2013-03-01

    Cucumber (Cucumis sativus L.), a kind of fruit usually harvested at the immature green stage, belongs to non-climacteric fruit. To investigate the contribution of abscisic acid (ABA) to cucumber fruit development and ripening, variation in ABA level was investigated and a peak in ABA level was found in pulp before fruit get fully ripe. To clarify this point further, exogenous ABA was applied to cucumber fruits at two different development stages. Results showed that ABA application at the turning stage promotes cucumber fruit ripening, while application at the immature green stage had inconspicuous effects. In addition, with the purpose of understanding the transcriptional regulation of ABA, two partial cDNAs of CsNCED1 and CsNCED2 encoding 9-cis-epoxycarotenoid dioxygenase (NCED), a key enzyme in ABA biosynthetic pathway; one partial cDNA of CsCYP707A1 for 8'-hydroxylase, a key enzyme in the oxidative catabolism of ABA and two partial cDNAs of CsBG1 and CsBG2 for β-glucosidase (BG) that hydrolyzes ABA glucose ester (ABA-GE) to release active ABA were cloned from cucumber. The DNA and deduced amino acid sequences of these obtained genes respectively showed high similarities to their homologous genes in other plants. Real-time PCR analysis revealed that ABA content may be regulated by its biosynthesis (CsNCEDs), catabolism (CsCYP707A1) and reactivation genes (CsBGs) at the transcriptional level during cucumber fruit development and ripening, in response to ABA application, dehydration and pollination, among which CsNCED1, CsCYP707A1 and CsBG1 were highly expressed in pulp and may play more important roles in regulating ABA metabolism.

  3. Reactive oxygen species in regulation of fungal development.

    PubMed

    Gessler, N N; Aver'yanov, A A; Belozerskaya, T A

    2007-10-01

    Reactive oxygen species (ROS) are formed by fungi in the course of metabolic activity. ROS production increases in fungi due to various stress agents such as starvation, light, mechanical damage, and interactions with some other living organisms. Regulation of ROS level appears to be very important during development of the fungal organism. ROS sources in fungal cells, their sensors, and ROS signal transduction pathways are discussed in this review. Antioxidant defense systems in different classes of fungi are characterized in detail. Particular emphasis is placed on ROS functions in interactions of phytopathogenic fungi with plant cells.

  4. Mechanical stress regulation of plant growth and development

    NASA Technical Reports Server (NTRS)

    Mitchell, C. A.; Myers, P. N.

    1995-01-01

    The authors introduce the chapter with a discussion of lessons from nature, agriculture, and landscapes; terms and definitions; and an historical perspective of mechanical stress regulation of plant growth and development. Topics include developmental responses to mechanical stress; mechanical stress-environment interactions; metabolic, productivity, and compositional changes; hormonal involvement; mechanoperception and early transduction mechanisms; applications in agriculture; and research implications. The discussion of hormonal involvement in mechanical stress physiology includes ethylene, auxin, gibberellins, and other phytohormones. The discussion of applications in agriculture examines windbreaks, nursery practices, height control and conditioning, and enhancement of growth and productivity. Implications for research are related to handling plant materials, space biology, and future research needs.

  5. The Chromatin Regulator Brpf1 Regulates Embryo Development and Cell Proliferation*

    PubMed Central

    You, Linya; Yan, Kezhi; Zou, Jinfeng; Zhao, Hong; Bertos, Nicholas R.; Park, Morag; Wang, Edwin; Yang, Xiang-Jiao

    2015-01-01

    With hundreds of chromatin regulators identified in mammals, an emerging issue is how they modulate biological and pathological processes. BRPF1 (bromodomain- and PHD finger-containing protein 1) is a unique chromatin regulator possessing two PHD fingers, one bromodomain and a PWWP domain for recognizing multiple histone modifications. In addition, it binds to the acetyltransferases MOZ, MORF, and HBO1 (also known as KAT6A, KAT6B, and KAT7, respectively) to promote complex formation, restrict substrate specificity, and enhance enzymatic activity. We have recently showed that ablation of the mouse Brpf1 gene causes embryonic lethality at E9.5. Here we present systematic analyses of the mutant animals and demonstrate that the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure. At the cellular level, Brpf1 loss inhibits proliferation of embryonic fibroblasts and hematopoietic progenitors. Molecularly, the loss reduces transcription of a ribosomal protein L10 (Rpl10)-like gene and the cell cycle inhibitor p27, and increases expression of the cell-cycle inhibitor p16 and a novel protein homologous to Scp3, a synaptonemal complex protein critical for chromosome association and embryo survival. These results uncover a crucial role of Brpf1 in controlling mouse embryo development and regulating cellular and gene expression programs. PMID:25773539

  6. Mitochondrial Atpif1 regulates heme synthesis in developing erythroblasts

    PubMed Central

    Shah, Dhvanit I.; Takahashi-Makise, Naoko; Cooney, Jeffrey D.; Li, Liangtao; Schultz, Iman J.; Pierce, Eric L.; Narla, Anupama; Seguin, Alexandra; Hattangadi, Shilpa M.; Medlock, Amy E.; Langer, Nathaniel B.; Dailey, Tamara A.; Hurst, Slater N.; Faccenda, Danilo; Wiwczar, Jessica M.; Heggers, Spencer K.; Vogin, Guillaume; Chen, Wen; Chen, Caiyong; Campagna, Dean R.; Brugnara, Carlo; Zhou, Yi; Ebert, Benjamin L.; Danial, Nika N.; Fleming, Mark D.; Ward, Diane M.; Campanella, Michelangelo; Dailey, Harry A.; Kaplan, Jerry; Paw, Barry H.

    2012-01-01

    SUMMARY Defects in the availability of heme substrates or the catalytic activity of the terminal enzyme in heme biosynthesis, ferrochelatase (Fech), impair heme synthesis, and thus cause human congenital anemias1,2. The inter-dependent functions of regulators of mitochondrial homeostasis and enzymes responsible for heme synthesis are largely unknown. To uncover this unmet need, we utilized zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anemia, pinotage (pnt tq209). We now report a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize heme. The loss of Atpif1 impairs hemoglobin synthesis in zebrafish, mouse, and human hematopoietic models as a consequence of diminished Fech activity, and elevated mitochondrial pH. To understand the relationship among mitochondrial pH, redox potential, [2Fe-2S] clusters, and Fech activity, we used (1) genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, and (2) pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to Atpif1-regulated mitochondrial pH and redox potential perturbations. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize heme, resulting in anemia. The novel mechanism of Atpif1 as a regulator of heme synthesis advances the understanding of mitochondrial heme homeostasis and red blood cell development. A deficiency of Atpif1 may contribute to important human diseases, such as congenital sideroblastic anemias and mitochondriopathies. PMID:23135403

  7. Developing recreational harvest regulations for an unexploited lake trout population

    USGS Publications Warehouse

    Lenker, Melissa A; Weidel, Brian C.; Jensen, Olaf P.; Solomon, Christopher T.

    2016-01-01

    Developing fishing regulations for previously unexploited populations presents numerous challenges, many of which stem from a scarcity of baseline information about abundance, population productivity, and expected angling pressure. We used simulation models to test the effect of six management strategies (catch and release; trophy, minimum, and maximum length limits; and protected and exploited slot length limits) on an unexploited population of Lake Trout Salvelinus namaycush in Follensby Pond, a 393-ha lake located in New York State’s Adirondack Park. We combined field and literature data and mark–recapture abundance estimates to parameterize an age-structured population model and used the model to assess the effects of each management strategy on abundance, catch per unit effort (CPUE), and harvest over a range of angler effort (0–2,000 angler-days/year). Lake Trout density (3.5 fish/ha for fish ≥ age 13, the estimated age at maturity) was similar to densities observed in other unexploited systems, but growth rate was relatively slow. Maximum harvest occurred at levels of effort ≤ 1,000 angler-days/year in all the scenarios considered. Regulations that permitted harvest of large postmaturation fish, such as New York’s standard Lake Trout minimum size limit or a trophy size limit, resulted in low harvest and high angler CPUE. Regulations that permitted harvest of small and sometimes immature fish, such as a protected slot or maximum size limit, allowed high harvest but resulted in low angler CPUE and produced rapid declines in harvest with increases in effort beyond the effort consistent with maximum yield. Management agencies can use these results to match regulations to management goals and to assess the risks of different management options for unexploited Lake Trout populations and other fish species with similar life history traits.

  8. Sphingolipid metabolism regulates development and lifespan in Caenorhabditis elegans

    PubMed Central

    Cutler, Roy G.; Thompson, Kenneth W.; Camandola, Simonetta; Mack, Kendra T.; Mattson, Mark P.

    2015-01-01

    Sphingolipids are a highly conserved lipid component of cell membranes involved in the formation of lipid raft domains that house many of the receptors and cell-to-cell signaling factors involved in regulating cell division, maturation, and terminal differentiation. By measuring and manipulating sphingolipid metabolism using pharmacological and genetic tools in Caenorhabditis elegans, we provide evidence that the synthesis and remodeling of specific ceramides (e.g., dC18:1–C24:1), gangliosides (e.g., GM1–C24:1), and sphingomyelins (e.g., dC18:1–C18:1) influence development rate and lifespan. We found that the levels of fatty acid chain desaturation and elongation in many sphingolipid species increased during development and aging, with no such changes in developmentally-arrested dauer larvae or normal adults after food withdrawal (an anti-aging intervention). Pharmacological inhibitors and small interfering RNAs directed against serine palmitoyl transferase and glucosylceramide synthase acted to slow development rate, extend the reproductive period, and increase lifespan. In contrast, worms fed an egg yolk diet rich in sphingolipids exhibited accelerated development and reduced lifespan. Our findings demonstrate that sphingolipid accumulation and remodeling are critical events that determine development rate and lifespan in the nematode model, with both development rate and aging being accelerated by the synthesis of sphingomyelin, and its metabolism to ceramides and gangliosides. PMID:25437839

  9. An Nfic-hedgehog signaling cascade regulates tooth root development

    PubMed Central

    Liu, Yang; Feng, Jifan; Li, Jingyuan; Zhao, Hu; Ho, Thach-Vu; Chai, Yang

    2015-01-01

    Coordination between the Hertwig's epithelial root sheath (HERS) and apical papilla (AP) is crucial for proper tooth root development. The hedgehog (Hh) signaling pathway and Nfic are both involved in tooth root development; however, their relationship has yet to be elucidated. Here, we establish a timecourse of mouse molar root development by histological staining of sections, and we demonstrate that Hh signaling is active before and during root development in the AP and HERS using Gli1 reporter mice. The proper pattern of Hh signaling activity in the AP is crucial for the proliferation of dental mesenchymal cells, because either inhibition with Hh inhibitors or constitutive activation of Hh signaling activity in transgenic mice leads to decreased proliferation in the AP and shorter roots. Moreover, Hh activity is elevated in Nfic−/− mice, a root defect model, whereas RNA sequencing and in situ hybridization show that the Hh attenuator Hhip is downregulated. ChIP and RNAscope analyses suggest that Nfic binds to the promoter region of Hhip. Treatment of Nfic−/− mice with Hh inhibitor partially restores cell proliferation, AP growth and root development. Taken together, our results demonstrate that an Nfic-Hhip-Hh signaling pathway is crucial for apical papilla growth and proper root formation. This discovery provides insight into the molecular mechanisms regulating tooth root development. PMID:26293299

  10. Regulation of lung development and regeneration by the vascular system.

    PubMed

    Woik, Nicole; Kroll, Jens

    2015-07-01

    Blood vessels have been described a long time ago as passive circuits providing sufficient blood supply to ensure proper distribution of oxygen and nutrition. Blood vessels are mainly formed during embryonic development and in the early postnatal period. In the adult, blood vessels are quiescent, but can be activated and subsequently induced under pathophysiological conditions, such as ischemia and tumor growth. Surprisingly, recent data have suggested an active function for blood vessels, named angiocrine signaling, releasing trophogens which regulate organ development and organ regeneration including in the pancreas, lung, tumor cells, liver and bone. Lung development is driven by hypoxia as well as an intense endothelial-epithelial interaction, and important mechanisms contributing to these processes have recently been identified. This review aims to summarize recent developments and concepts about embryonic pulmonary vascular development and lung regeneration. We discuss hypoxia-inducible factor HIF-2α and vascular endothelial growth factor VEGF as important mediators in lung development and focus on endothelial-epithelial interactions and angiocrine signaling mechanisms.

  11. Development and regulation of biosimilars: current status and future challenges.

    PubMed

    Tsiftsoglou, Asterios S; Ruiz, Sol; Schneider, Christian K

    2013-06-01

    Biologic medicinal products developed via rDNA technology as recombinant protein-based medicines that have been in clinical use since the early 1980s as original biopharmaceuticals have greatly contributed to the therapy of severe metabolic and degenerative diseases. The recent expiration of the data protection or patents for most of them created opportunities for the development of copy versions of original biopharmaceuticals with similar biologic activity (termed biosimilars). Production of these new products is expected to meet worldwide demand, promote market competition, maintain the incentives for innovation, and sustain the healthcare systems. The licencing of these products, however, relies on the experience gained with the original biopharmaceuticals. Critical issues related to this class of medicinal products include their terminology (to avoid confusion with generics and non-innovator copy versions that have not been tested according to the biosimilar guidelines), manufacturing, and regulation. The European Union (EU) has been the first to establish a regulatory framework for marketing authorization application (MAA) and has named these products biosimilars, a term also recently adopted by the US FDA. Unlike the conventional, more common small molecular weight human medicines and chemical generics, protein-based medicines exhibit higher molecular weight, complexity in structure and function that can be affected by changes in the manufacturing process. Therefore, biosimilars represent a relatively heterogeneous class of medicinal products that make their regulation quite challenging. According to the current understanding in the EU, a biosimilar is a copy version of an already authorized biopharmaceutical (or reference product) with similar biologic activity, physicochemical characteristics, efficacy, and safety, based on a full comparability exercise at quality, preclinical and clinical level to ensure similar efficacy and safety. Guidance has been

  12. Radial glia regulate vascular patterning around the developing spinal cord

    PubMed Central

    Matsuoka, Ryota L; Marass, Michele; Avdesh, Avdesh; Helker, Christian SM; Maischein, Hans-Martin; Grosse, Ann S; Kaur, Harmandeep; Lawson, Nathan D; Herzog, Wiebke; Stainier, Didier YR

    2016-01-01

    Vascular networks surrounding individual organs are important for their development, maintenance, and function; however, how these networks are assembled remains poorly understood. Here we show that CNS progenitors, referred to as radial glia, modulate vascular patterning around the spinal cord by acting as negative regulators. We found that radial glia ablation in zebrafish embryos leads to excessive sprouting of the trunk vessels around the spinal cord, and exclusively those of venous identity. Mechanistically, we determined that radial glia control this process via the Vegf decoy receptor sFlt1: sflt1 mutants exhibit the venous over-sprouting observed in radial glia-ablated larvae, and sFlt1 overexpression rescues it. Genetic mosaic analyses show that sFlt1 function in trunk endothelial cells can limit their over-sprouting. Together, our findings identify CNS-resident progenitors as critical angiogenic regulators that determine the precise patterning of the vasculature around the spinal cord, providing novel insights into vascular network formation around developing organs. DOI: http://dx.doi.org/10.7554/eLife.20253.001 PMID:27852438

  13. Activins and inhibins: Novel regulators of thymocyte development

    SciTech Connect

    Licona-Limon, Paula; Aleman-Muench, German; Macias-Silva, Marina; Garcia-Zepeda, Eduardo A.; Fortoul, Teresa I.; Soldevila, Gloria

    2009-04-03

    Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A and inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.

  14. Linking metabolism and epigenetic regulation in development of hepatocellular carcinoma.

    PubMed

    Puszyk, William Matthew; Trinh, Thu Le; Chapple, Sarah J; Liu, Chen

    2013-09-01

    Hepatocellular carcinoma (HCC) is the fifth most common form of cancer globally and is rarely curable once detected. The 5-year survival rate of patients diagnosed with late-stage HCC may be as low as 27%. HCC is a cancer largely driven by epigenetic changes that arise from exposure to exogenous environmental factors rather than coding sequence mutations. The liver is susceptible to effects from Hepatitis C and Hepatitis B viruses, exposure to aflatoxin and continuous excessive consumption of alcohol. The liver is a highly metabolic organ balancing many vital biochemical processes; exposure to any of the above environmental factors is associated with loss of liver function and is a major risk factor for the development of HCC. Emerging studies aim to examine the underlying metabolic processes that are abrogated in cancer and lead to the altered flux and availability of key metabolites important for epigenetic processes. Metabolites have been shown to act as substrates for many canonical epigenetic regulators. These enzymes are responsible for regulating histone modification, DNA methylation and micro RNA expression. By studying the impact of altered liver metabolism, we may better understand the long-term epigenetic processes, which lead to the development and progression of HCC.

  15. Regulation of basophil and mast cell development by transcription factors.

    PubMed

    Sasaki, Haruka; Kurotaki, Daisuke; Tamura, Tomohiko

    2016-04-01

    Basophils and mast cells play important roles in host defense against parasitic infections and allergic responses. Several progenitor populations, either shared or specific, for basophils and/or mast cells have been identified, thus elucidating the developmental pathways of these cells. Multiple transcription factors essential for their development and the relationships between them have been also revealed. For example, IRF8 induces GATA2 expression to promote the generation of both basophils and mast cells. The STAT5-GATA2 axis induces C/EBPα and MITF expression, facilitating the differentiation into basophils and mast cells, respectively. In addition, C/EBPα and MITF mutually suppress each other's expression. This review provides an overview of recent advances in our understanding of how transcription factors regulate the development of basophils and mast cells.

  16. MicroRNA networks regulate development of brown adipocytes.

    PubMed

    Trajkovski, Mirko; Lodish, Harvey

    2013-09-01

    Brown adipose tissue (BAT) is specialized for heat generation and energy expenditure as a defense against cold and obesity; in both humans and mice increased amounts of BAT are associated with a lean phenotype and resistance to development of the metabolic syndrome and its complications. Here we summarize recent research showing that several BAT-expressed microRNAs (miRNAs) play important roles in regulating differentiation and metabolism of brown and beige adipocytes; we discuss the key mRNA targets downregulated by these miRNAs and show how these miRNAs affect directly or indirectly transcription factors important for BAT development. We suggest that these miRNAs could be part of novel therapeutics to increase BAT in humans.

  17. A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients.

    PubMed

    Garg, Madhu B; Sakoff, Jennette A; Ackland, Stephen P

    2011-08-01

    Mitotane (o,p'-DDD or (1,1-dichloro-2-[o-chlorophenyl]-2-[p-chlorophenyl]ethane, DDD) is the drug of choice for non-resectable and metastatic adrenocortical carcinomas (ACC). Measurement of mitotane and metabolites, o,p'-DDE (1,1-dichloro-2-[p-chlorophenyl]-2-[o-chlorophenyl]ethene, DDE) and o,p'-DDA (1,1-[o,p'-dichlorodiphenyl] acetic acid, DDA) provides a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed a simple, robust and efficient high performance liquid chromatography (HPLC) method to measure mitotane and its two main metabolites, DDE and DDA. The method involves a single ethanol extraction of mitotane, DDE, DDA, and an internal standard (int std) p,p'-DDD (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane) with an extraction efficiency of 77-88%. All compounds are measured simultaneously using a reversed-phase phenyl HPLC column with an isocratic elution of mobile phase at a flow rate of 0.6 ml/min followed by UV detection at λ 226 nm. Inter and intra-day validation demonstrates good reproducibility and accuracy. Limits of quantitation are 0.2 μg/ml for mitotane and DDE, and 0.5 μg/ml for DDA. The method has been evaluated in plasma from 23 patients on mitotane therapy, revealing DDA concentrations 1-18 times higher than the parent compound.

  18. Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats

    PubMed Central

    Wulsin, Aynara C.; Wick-Carlson, Dayna; Packard, Benjamin A.; Morano, Rachel; Herman, James P.

    2016-01-01

    Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45–58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood. PMID:26751968

  19. Adolescent chronic stress causes hypothalamo-pituitary-adrenocortical hypo-responsiveness and depression-like behavior in adult female rats.

    PubMed

    Wulsin, Aynara C; Wick-Carlson, Dayna; Packard, Benjamin A; Morano, Rachel; Herman, James P

    2016-03-01

    Adolescence is a period of substantial neuroplasticity in stress regulatory neurocircuits. Chronic stress exposure during this period leads to long-lasting changes in neuroendocrine function and emotional behaviors, suggesting adolescence may be a critical period for development of stress vulnerability. This study investigated the effects of exposure to 14 days of chronic variable stress (CVS) in late-adolescent (pnd 45-58) female rats on neuroendocrine function, neuropeptide mRNA expression and depressive-like behavior in adolescence (pnd 59) and in adulthood (pnd 101). Adult females exposed to CVS in adolescence have a blunted hypothalamo-pituitary-adrenocortical (HPA) axis in response to a novel stressor and increased immobility in the forced swim test. Blunted HPA axis responses were accompanied by reduced vasopressin mRNA expression in the paraventricular nucleus of the hypothalamus (PVN), suggesting decreased central drive. Adolescent females tested immediately after CVS did not exhibit differences in stress reactivity or immobility in the forced swim test, despite evidence for enhanced central HPA axis drive (increased CRH mRNA expression in PVN). Overall, our study demonstrates that exposure to chronic stress in adolescence is sufficient to induce lasting changes in neuroendocrine drive and behavior, potentially altering the developmental trajectory of stress circuits as female rats age into adulthood.

  20. Low SGK1 Expression in Human Adrenocortical Tumors Is Associated with ACTH-Independent Glucocorticoid Secretion and Poor Prognosis

    PubMed Central

    Sbiera, Silviu; Leich, Ellen; Tissier, Frédérique; Steinhauer, Sonja; Deutschbein, Timo; Fassnacht, Martin; Allolio, Bruno

    2012-01-01

    Context: Using single-nucleotide polymorphism analysis, we observed allelic loss of the gene for serum glucocorticoid (GC) kinase 1 (SGK1), a GC-responsive kinase involved in multiple cellular functions, in a subset of cortisol-secreting adenomas. Objective: Our objective was to analyze SGK1 expression in adrenocortical tumors and to further characterize its role in ACTH-independent cortisol secretion, tumor progression, and prognosis. Design and Setting: Gene expression levels of SGK1, SGK3, and CTNNB1 (coding for β-catenin) and protein expression levels of SGK1, nuclear β-catenin, and phosphorylated AKT were determined in adrenocortical tumors and normal adrenal glands. Patients: A total of 227 adrenocortical tumors (40 adenomas and 187 carcinomas) and 25 normal adrenal tissues were included. Among them, 62 frozen tumor samples were used for mRNA analysis and 203 tumors were investigated on tissue microarrays or full standard slides by immunohistochemistry. Main Outcome Measures: We evaluated the relationship between SGK1 mRNA and/or protein levels and clinical parameters. Results: SGK1 mRNA levels were lower in cortisol-secreting than in nonsecreting tumors (P < 0.005). Nonsecreting neoplasias showed a significant correlation between SGK1 and CTNNB1 mRNA levels (P < 0.001; r = 0.57). Low SGK1 protein levels, but not nuclear β-catenin and phosphorylated AKT, were associated with poor overall survival in patients with adrenocortical carcinoma (P < 0.005; hazard ratio = 2.0; 95% confidence interval = 1.24–3.24), independent of tumor stage and GC secretion. Conclusion: Low SGK1 expression is related to ACTH-independent cortisol secretion in adrenocortical tumors and is a new prognostic factor in adrenocortical carcinoma. PMID:23055545

  1. Regulation of Development and Nitrogen Fixation in Anabaena

    SciTech Connect

    James W Golden

    2004-08-05

    The nitrogen-fixing filamentous cyanobacterium Anabaena sp. strain PCC 7120 is being used as a simple model of microbial development and pattern formation in a multicellular prokaryotic organism. Anabaena reduces atmospheric nitrogen to ammonia in highly specialized, terminally differentiated cells called heterocysts. Anabaena is an important model system because of the multicellular growth pattern, the suspected antiquity of heterocyst development, and the contribution of fixed nitrogen to the environment. We are especially interested in understanding the molecular signaling pathways and genetic regulation that control heterocyst development. In the presence of an external source of reduced nitrogen, the differentiation of heterocysts is inhibited. When Anabaena is grown on dinitrogen, a one-dimensional developmental pattern of single heterocysts separated by approximately ten vegetative cells is established to form a multicellular organism composed of two interdependent cell types. The goal of this project is to understand the signaling and regulatory pathways that commit a vegetative cell to terminally differentiate into a nitrogen-fixing heterocyst. Several genes identified by us and by others were chosen as entry points into the regulatory network. Our research, which was initially focused on transcriptional regulation by group 2 sigma factors, was expanded to include group 3 sigma factors and their regulators after the complete Anabaena genome sequence became available. Surprisingly, no individual sigma factor is essential for heterocyst development. We have used the isolation of extragenic suppressors to study genetic interactions between key regulatory genes such as patS, hetR, and hetC in signaling and developmental pathways. We identified a hetR R223W mutation as a bypass suppressor of patS overexpression. Strains containing the hetR R223W allele fail to respond to pattern formation signals and overexpression of this allele results in a lethal phenotype

  2. Regulation of miR-34 Family in Neuronal Development.

    PubMed

    Jauhari, Abhishek; Singh, Tanisha; Singh, Parul; Parmar, Devendra; Yadav, Sanjay

    2017-01-13

    Differentiation of neural stem cells (NSC's) to mature and functional neurons requires coordinated expression of mRNA, microRNAs (miRNAs) and regulatory proteins. Our earlier unbiased miRNA profiling studies have identified miR-200, miR-34 and miR-221/222 as maximally up-regulated miRNA families in differentiating PC12 cells and demonstrated the capability of miR-200 family in inducing neuronal differentiation (J. Neurochem, 2015, 133, 640-652). In present study, we have investigated role of miR-34 family in neuronal differentiation and identified P53 as mediator of nerve growth factor (NGF) induced miR-34a expression in differentiating PC12 cells. Our studies have shown that NGF induced miR-34a, arrests proliferating PC12 cells to G1 phase, which is pre-requisite for neuronal differentiation. Our studies have also shown that increased expression of miR-34a controls the P53 level in differentiated PC12 cells in feedback inhibition manner, which probably prevents differentiated cells from P53 induced apoptosis. Expression profiling of miR-34 family in different neuronal, non-neuronal and developing cells have identified differentiated and aged brain cells as richest source of miR-34, which also indicates that higher expression of miR-34 family helps in maintaining the mature neurons in non-proliferative stage. In conclusion, our studies have shown that miR-34 is brain enriched miRNA family, which up-regulates with neuronal maturation and brain ageing and co-operative regulation of P53 and miR-34a helps in neuronal differentiation by arresting cells in G1 phase.

  3. Development of polymer concrete vaults for natural gas regulator stations

    SciTech Connect

    Fontana, J.J.; Miller, C.A.; Reams, W.; Elling, D.

    1990-08-01

    Vaults for natural gas regulator stations have traditionally been fabricated with steel-reinforced portland cement concrete. Since these vaults are installed below ground level, they are usually coated with a water-proofing material to prevent the ingress of moisture into the vault. In some cases, penetrations for piping that are normally cast into the vault do not line up with the gas lines in the streets. This necessitates off-setting the lines to line up with the penetrations in the vault or breaking out new penetrations which could weaken the structure and/or allow water ingress. By casting the vaults using a new material of construction such as polymer concrete, a longer maintenance free service life is possible because the physical and durability properties of polymer concrete composites are much superior to those of portland cement concrete. The higher strengths of polymer concrete allow the design engineer to reduce the wall, floor, and ceiling thicknesses making the vaults lighter for easier transportation and installation. Penetrations can be cut after casting to match existing street lines, thus making the vault more universal and reducing the number of vaults that are normally in stock. The authors developed a steel-fiber reinforced polymer concrete composite that could be used for regulator vaults. Based on the physical properties of his new composite, vaults were designed to replace the BUG PV-008 and Con Ed GR-6 regulator vaults made of reinforced portland cement concrete. Quarter-scale models of the polymer concrete vaults were tested and the results reaffirmed the reduced wall thickness design. Two sets of vaults, cast by Hardinge Bros., were inspected by representatives of the utilities and BNL (Brookhaven National Laboratory), and were accepted for delivery. 6 refs., 5 figs., 12 tabs.

  4. ACAT-selective and nonselective DGAT1 inhibition: adrenocortical effects--a cross-species comparison.

    PubMed

    Floettmann, Jan Eike; Buckett, Linda K; Turnbull, Andrew V; Smith, Tim; Hallberg, Carina; Birch, Alan; Lees, David; Jones, Huw B

    2013-01-01

    Acyl-coenzyme A: cholesterol O-Acyltransferase (ACAT) and Acyl-coenzyme A: diacylglycerol O-acyltransferase (DGAT) enzymes play important roles in synthesizing neutral lipids, and inhibitors of these enzymes have been investigated as potential treatments for diabetes and other metabolic diseases. Administration of a Acyl-coenzyme A: diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor with very limited cellular selectivity over ACAT resulted in significant adrenocortical degenerative changes in dogs. These changes included macrosteatotic vacuolation associated with adrenocyte cell death in the zonae glomerulosa and fasciculata and minimal to substantial mixed inflammatory cell infiltration and were similar to those described previously for some ACAT inhibitors in dogs. In the mouse, similar but only transient adrenocortical degenerative changes were seen as well as a distinctive nondegenerative reduction in cortical fine vacuolation. In the marmoset, only the distinctive nondegenerative reduction in cortical fine vacuolation was observed, suggesting that the dog, followed by the mouse, is the most sensitive species for cortical degeneration. Biochemical analysis of adrenal cholesterol and cholesteryl ester indicated that the distinctive reduction in cortical fine vacuolation correlated with a significant reduction in cholesteryl ester in the mouse and marmoset, whereas no significant reduction in cholestryl ester, but an increase in free cholesterol was observed in dogs. Administration of a DGAT1 inhibitor with markedly improved selectivity over ACAT to the marmoset and the mouse resulted in no adrenal pathology at exposures sufficient to cause substantial DGAT1 but not ACAT inhibition, thereby implicating ACAT rather than DGAT1 inhibition as the probable cause of the observed adrenal changes. Recognizing that the distinctive nondegenerative reduction in cortical fine vacuolation in the mouse could be used as a histopathological biomarker for an in vivo model of

  5. Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells.

    PubMed

    Hescot, Ségolène; Slama, Abdelhamid; Lombès, Anne; Paci, Angelo; Remy, Hervé; Leboulleux, Sophie; Chadarevian, Rita; Trabado, Séverine; Amazit, Larbi; Young, Jacques; Baudin, Eric; Lombès, Marc

    2013-06-01

    Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.

  6. Mitotane effects in a H295R xenograft model of adjuvant treatment of adrenocortical cancer.

    PubMed

    Lindhe, O; Skogseid, B

    2010-09-01

    Adrenocortical cancer is one of the most aggressive endocrine malignancies. Growth through the capsule or accidental release of cancer cells during surgery frequently results in metastatic disease. We investigated the antitumoral effect of 2 adrenocorticolytic compounds, O, P'-DDD and MeSO2-DDE, in the adrenocortical cell line H295R both in vitro and as a xenograft model in vivo. H295R cells were injected s. c. in nude mice. O, P'-DDD, MeSO2-DDE, or oil (control) was administered i. p., either simultaneously with cell injection at day 0 (mimicking adjuvant treatment), or at day 48 (established tumors). Accumulation of PET tracers [ (11)C]methionine (MET), [ (11)C] metomidate (MTO), 2-deoxy-2-[ (18)F]fluoro-d-glucose (FDG), and [ (18)F]-l-tyrosine (FLT) in the aggregates were assessed +/- drug treatment in vitro. Tumor growth was significantly inhibited when O, P'-DDD was given at the same time as injection of tumor cells. No significant growth inhibition was observed after treatment with O, P'-DDD at day 48. A significant reduction in FLT uptake and an increased FDG uptake, compared to control, were observed following treatment with 15 microM O, P'-DDD (p<0.01) in vitro. MeSO2-DDE (15 microM) treatment gave rise to a reduced MET and an increased FLT uptake (p<0.01). Both compounds reduced the uptake of MTO compared to control (p<0.01). Treatment with O, P'-DDD simultaneously to inoculation of H295R cells in mice, imitating release of cells during surgery, gave a markedly better effect than treatment of established H295R tumors. We suggest that FLT may be a potential PET biomarker when assessing adrenocortical cancer treatment with O,P'-DDD. Further studies in humans are needed to investigate this.

  7. microRNAs as Potential Biomarkers in Adrenocortical Cancer: Progress and Challenges

    PubMed Central

    Cherradi, Nadia

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecular pathways in adrenocortical tumors, such as the IGF2 pathway, the Wnt pathway, and TP53, high-throughput technologies enabled a more comprehensive genomic characterization of adrenocortical cancer. Integration of expression profile data with exome sequencing, SNP array analysis, methylation, and microRNA (miRNA) profiling led to the identification of subgroups of malignant tumors with distinct molecular alterations and clinical outcomes. miRNAs post-transcriptionally silence their target gene expression either by degrading mRNA or by inhibiting translation. Although our knowledge of the contribution of deregulated miRNAs to the pathogenesis of ACC is still in its infancy, recent studies support their relevance in gene expression alterations in these tumors. Some miRNAs have been shown to carry potential diagnostic and prognostic values, while others may be good candidates for therapeutic interventions. With the emergence of disease-specific blood-borne miRNAs signatures, analyses of small cohorts of patients with ACC suggest that circulating miRNAs represent promising non-invasive biomarkers of malignancy or recurrence. However, some technical challenges still remain, and most of the miRNAs reported in the literature have not yet been validated in sufficiently powered and longitudinal studies. In this review, we discuss the current knowledge regarding the deregulation of tumor-associated and circulating miRNAs in ACC patients, while emphasizing their potential significance in pathogenic pathways in light of recent insights into the role of miRNAs in shaping the tumor microenvironment. PMID:26834703

  8. Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer

    PubMed Central

    Grolmusz, Vince Kornél; Karászi, Katalin; Micsik, Tamás; Tóth, Eszter Angéla; Mészáros, Katalin; Karvaly, Gellért; Barna, Gábor; Szabó, Péter Márton; Baghy, Kornélia; Matkó, János; Kovalszky, Ilona; Tóth, Miklós; Rácz, Károly; Igaz, Péter; Patócs, Attila

    2016-01-01

    Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications. PMID:27725909

  9. The reticulin algorithm for adrenocortical tumor diagnosis: a multicentric validation study on 245 unpublished cases.

    PubMed

    Duregon, Eleonora; Fassina, Ambrogio; Volante, Marco; Nesi, Gabriella; Santi, Raffaella; Gatti, Gaia; Cappellesso, Rocco; Dalino Ciaramella, Paolo; Ventura, Laura; Gambacorta, Marcello; Dei Tos, Angelo Paolo; Loli, Paola; Mannelli, Massimo; Mantero, Franco; Berruti, Alfredo; Terzolo, Massimo; Papotti, Mauro

    2013-09-01

    The pathologic diagnosis of adrenocortical carcinoma (ACC) still needs to be improved, because the renowned Weiss Score (WS) system has a poor reproducibility of some parameters and is difficult to apply in borderline cases and in ACC variants. The "reticulin algorithm" (RA) defines malignancy through an altered reticulin framework associated with 1 of the 3 following parameter: necrosis, high mitotic rate, and vascular invasion. This study aimed at validating the interobserver reproducibility of reticulin stain evaluation in an unpublished series of 245 adrenocortical tumors (61 adenomas and 184 carcinomas) from 5 Italian centers, classified according to the WS. Eight pathologists reviewed all reticulin-stained slides. After training, a second round of evaluation on discordant cases was performed 10 weeks later. The RA reclassified 67 cases (27%) as adenomas, including 44 with no reticulin alterations and 23 with an altered reticulin framework but lacking the subsequent parameters of the triad. The other 178 cases (73%) were carcinomas according to the above-mentioned criteria. A complete (8/8 pathologists) interobserver agreement was reached in 75% of cases (κ=0.702), irrespective of case derivation, pathologists' experience, and histologic variants, and was further improved when only those cases with high WS and clinically malignant behavior were considered. After the training, the overall agreement increased to 86%. We conclude that reticulin staining is a reliable technique and an easy-to-interpret system in adrenocortical tumors; moreover, it has a high interobserver reproducibility, which supports the notion of using such a method in the proposed 2-step RA approach for ACC diagnosis.

  10. The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia

    PubMed Central

    Correa, Ricardo; Zilbermint, Mihail; Berthon, Annabel; Espiard, Stephanie; Batsis, Maria; Papadakis, Georgios Z.; Xekouki, Paraskevi; Lodish, Maya B.; Bertherat, Jerome; Faucz, Fabio R.; Stratakis, Constantine A.

    2015-01-01

    Objective Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing’s syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor-suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes. Design All of the nodules where obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocols and the ARMC5 sequence was determined by the Sanger method. Results Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: 6 were frame shift, 4 were missense, 3 were nonsense, and 1 was a splice site variation. Allelic losses were confirmed in 2 of the nodules. Conclusion This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, “private”, and -in most cases- completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery. PMID:26162405

  11. Early development of Moniliophthora perniciosa basidiomata and developmentally regulated genes

    PubMed Central

    2009-01-01

    Background The hemibiotrophic fungus Moniliophthora perniciosa is the causal agent of Witches' broom, a disease of Theobroma cacao. The pathogen life cycle ends with the production of basidiocarps in dead tissues of the infected host. This structure generates millions of basidiospores that reinfect young tissues of the same or other plants. A deeper understanding of the mechanisms underlying the sexual phase of this fungus may help develop chemical, biological or genetic strategies to control the disease. Results Mycelium was morphologically analyzed prior to emergence of basidiomata by stereomicroscopy, light microscopy and scanning electron microscopy. The morphological changes in the mycelium before fructification show a pattern similar to other members of the order Agaricales. Changes and appearance of hyphae forming a surface layer by fusion were correlated with primordia emergence. The stages of hyphal nodules, aggregation, initial primordium and differentiated primordium were detected. The morphological analysis also allowed conclusions on morphogenetic aspects. To analyze the genes involved in basidiomata development, the expression of some selected EST genes from a non-normalized cDNA library, representative of the fruiting stage of M. perniciosa, was evaluated. A macroarray analysis was performed with 192 selected clones and hybridized with two distinct RNA pools extracted from mycelium in different phases of basidiomata formation. This analysis showed two groups of up and down-regulated genes in primordial phases of mycelia. Hydrophobin coding, glucose transporter, Rho-GEF, Rheb, extensin precursor and cytochrome p450 monooxygenase genes were grouped among the up-regulated. In the down-regulated group relevant genes clustered coding calmodulin, lanosterol 14 alpha demethylase and PIM1. In addition, 12 genes with more detailed expression profiles were analyzed by RT-qPCR. One aegerolysin gene had a peak of expression in mycelium with primordia and a

  12. FoxP2 regulates neurogenesis during embryonic cortical development.

    PubMed

    Tsui, David; Vessey, John P; Tomita, Hideaki; Kaplan, David R; Miller, Freda D

    2013-01-02

    The transcription factor FoxP2 has been associated with the development of human speech but the underlying cellular function of FoxP2 is still unclear. Here we provide evidence that FoxP2 regulates genesis of some intermediate progenitors and neurons in the mammalian cortex, one of the key centers for human speech. Specifically, knockdown of FoxP2 in embryonic cortical precursors inhibits neurogenesis, at least in part by inhibiting the transition from radial glial precursors to neurogenic intermediate progenitors. Moreover, overexpression of human, but not mouse, FoxP2 enhances the genesis of intermediate progenitors and neurons. In contrast, expression of a human FoxP2 mutant that causes vocalization deficits decreases neurogenesis, suggesting that in the murine system human FoxP2 acts as a gain-of-function protein, while a human FoxP2 mutant acts as a dominant-inhibitory protein. These results support the idea that FoxP2 regulates the transition from neural precursors to transit-amplifying progenitors and ultimately neurons, and shed light upon the molecular changes that might contribute to evolution of the mammalian cortex.

  13. Multi-organ resection for locally advanced adrenocortical cancer: surgical strategy and literature review

    PubMed Central

    GUIDA, F.; CLEMENTE, M.; VALVANO, L.; NAPOLITANO, C.

    2015-01-01

    Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with an estimated worldwide incidence of 0.5–2 per million/year. Complete surgical removal of ACC represents the current treatment of choice for this tumor. A disease-free resection margin (R0) is an important predictor of long-term survival: surgery is demanding and must be performed by a highly experienced surgical team. We report the surgical strategy adopted in a patient with locally advanced ACC and virilization to obtain a R0 resection. PMID:26712261

  14. Globalisation reaches gene regulation: the case for vertebrate limb development.

    PubMed

    Zuniga, Aimée

    2005-08-01

    Analysis of key regulators of vertebrate limb development has revealed that the cis-regulatory regions controlling their expression are often located several hundred kilobases upstream of the transcription units. These far up- or down-stream cis-regulatory regions tend to reside within rather large, functionally and structurally unrelated genes. Molecular analysis is beginning to reveal the complexity of these large genomic landscapes, which control the co-expression of clusters of diverse genes by this novel type of long-range and globally acting cis-regulatory region. An increasing number of spontaneous mutations in vertebrates, including humans, are being discovered inactivating or altering such global control regions. Thereby, the functions of a seemingly distant but essential gene are disrupted rather than the closest.

  15. Matrix Metalloproteinase-9 Regulates Neuronal Circuit Development and Excitability.

    PubMed

    Murase, Sachiko; Lantz, Crystal L; Kim, Eunyoung; Gupta, Nitin; Higgins, Richard; Stopfer, Mark; Hoffman, Dax A; Quinlan, Elizabeth M

    2016-07-01

    In early postnatal development, naturally occurring cell death, dendritic outgrowth, and synaptogenesis sculpt neuronal ensembles into functional neuronal circuits. Here, we demonstrate that deletion of the extracellular proteinase matrix metalloproteinase-9 (MMP-9) affects each of these processes, resulting in maladapted neuronal circuitry. MMP-9 deletion increases the number of CA1 pyramidal neurons but decreases dendritic length and complexity. Parallel changes in neuronal morphology are observed in primary visual cortex and persist into adulthood. Individual CA1 neurons in MMP-9(-/-) mice have enhanced input resistance and a significant increase in the frequency, but not amplitude, of miniature excitatory postsynaptic currents (mEPSCs). Additionally, deletion of MMP-9 significantly increases spontaneous neuronal activity in awake MMP-9(-/-) mice and enhances response to acute challenge by the excitotoxin kainate. Our data document a novel role for MMP-9-dependent proteolysis: the regulation of several aspects of circuit maturation to constrain excitability throughout life.

  16. Six3 regulates optic nerve development via multiple mechanisms.

    PubMed

    Samuel, Anat; Rubinstein, Ariel M; Azar, Tehila T; Ben-Moshe Livne, Zohar; Kim, Seok-Hyung; Inbal, Adi

    2016-01-29

    Malformations of the optic nerve lead to reduced vision or even blindness. During optic nerve development, retinal ganglion cell (RGC) axons navigate across the retina, exit the eye to the optic stalk (OS), and cross the diencephalon midline at the optic chiasm en route to their brain targets. Many signalling molecules have been implicated in guiding various steps of optic nerve pathfinding, however much less is known about transcription factors regulating this process. Here we show that in zebrafish, reduced function of transcription factor Six3 results in optic nerve hypoplasia and a wide repertoire of RGC axon pathfinding errors. These abnormalities are caused by multiple mechanisms, including abnormal eye and OS patterning and morphogenesis, abnormal expression of signalling molecules both in RGCs and in their environment and anatomical deficiency in the diencephalic preoptic area, where the optic chiasm normally forms. Our findings reveal new roles for Six3 in eye development and are consistent with known phenotypes of reduced SIX3 function in humans. Hence, the new zebrafish model for Six3 loss of function furthers our understanding of the mechanisms governing optic nerve development and Six3-mediated eye and forebrain malformations.

  17. Localized JNK signaling regulates organ size during development

    PubMed Central

    Willsey, Helen Rankin; Zheng, Xiaoyan; Carlos Pastor-Pareja, José; Willsey, A Jeremy; Beachy, Philip A; Xu, Tian

    2016-01-01

    A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control. DOI: http://dx.doi.org/10.7554/eLife.11491.001 PMID:26974344

  18. Ethylene Signaling Influences Light-Regulated Development in Pea.

    PubMed

    Weller, James L; Foo, Eloise M; Hecht, Valérie; Ridge, Stephen; Vander Schoor, Jacqueline K; Reid, James B

    2015-09-01

    Plant responses to light involve a complex network of interactions among multiple plant hormones. In a screen for mutants showing altered photomorphogenesis under red light, we identified a mutant with dramatically enhanced leaf expansion and delayed petal senescence. We show that this mutant exhibits reduced sensitivity to ethylene and carries a nonsense mutation in the single pea (Pisum sativum) ortholog of the ethylene signaling gene ETHYLENE INSENSITIVE2 (EIN2). Consistent with this observation, the ein2 mutation rescues the previously described effects of ethylene overproduction in mature phytochrome-deficient plants. In seedlings, ein2 confers a marked increase in leaf expansion under monochromatic red, far-red, or blue light, and interaction with phytochromeA, phytochromeB, and long1 mutants confirms that ein2 enhances both phytochrome- and cryptochrome-dependent responses in a LONG1-dependent manner. In contrast, minimal effects of ein2 on seedling development in darkness or high-irradiance white light show that ethylene is not limiting for development under these conditions. These results indicate that ethylene signaling constrains leaf expansion during deetiolation in pea and provide further evidence that down-regulation of ethylene production may be an important component mechanism in the broader control of photomorphogenic development by phytochrome and cryptochrome.

  19. Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells.

    PubMed

    Robitaille, Christina N; Rivest, Patricia; Sanderson, J Thomas

    2015-01-01

    Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1.

  20. [The peculiarities of calcium metabolism regulation in different periods of growth and development].

    PubMed

    Moĭsa, S S; Nozdrachev, A D

    2014-01-01

    The review contains literature data about calcium metabolism regulation in different periods of growth and development. The analyses of retrospective and current sources of information about the regulation of calcium homeostasis under the theory of functional systems, the regulation of calcium metabolism in prenatal and postnatal periods of the development, the significance of calcium metabolism disturbances in the development of pathological conditions were showed.

  1. Regulating social interactions: Developing a functional theory of collaboration

    NASA Astrophysics Data System (ADS)

    Borge, Marcela

    A role-playing intervention was developed and implemented in a fifth grade classroom. The goal of the intervention was to address serious problems that researchers have connected to dysfunctional collaborative interactions. These problems include an inability to: engage in important aspects of argumentation and communication, monitor and regulate group processes, and ensure equity in participation. To this end, a comprehensive theory of collaboration was presented to students through the use of four sociocognitive roles: mediation manager, collaboration manager, communication manager, and productivity manager. Each role came with a written guide that included specific goals and strategies related to the role. Metacognitive activities, including planning and reflection, were also used during class sessions to support students' understanding and role-use. Each of the students in the class was assigned one of the roles to manage during a two part collaborative science project. Students took quizzes on the roles and provided verbal and written feedback about their role-use and metacognitive activities. Students from one of the video-recorded groups were also interviewed after the intervention. Analyses of data from video sessions, quizzes, and interviews supported three important findings: (1) students were able to learn goals, and strategies for all of the roles, even though they only managed a single role, (2) students demonstrated the ability to take the information they learned and put it into practice, and (3) when students employed the roles while their group was working, members of the group accepted the role-use. These findings related to the learning and utilization of the roles are important because they: (1) imply that the intervention was successful at developing students' knowledge of the theory of collaboration that the roles represented, (2) indicate that students used this knowledge to monitor and regulate behaviors in an authentic context, and (3

  2. Different regulation of limb development by p63 transcript variants

    PubMed Central

    Kawata, Manabu; Taniguchi, Yuki; Mori, Daisuke; Yano, Fumiko; Ohba, Shinsuke; Chung, Ung-il; Shimogori, Tomomi; Mills, Alea A.; Tanaka, Sakae

    2017-01-01

    The apical ectodermal ridge (AER), located at the distal end of each limb bud, is a key signaling center which controls outgrowth and patterning of the proximal-distal axis of the limb through secretion of various molecules. Fibroblast growth factors (FGFs), particularly Fgf8 and Fgf4, are representative molecules produced by AER cells, and essential to maintain the AER and cell proliferation in the underlying mesenchyme, meanwhile Jag2-Notch pathway negatively regulates the AER and limb development. p63, a transcription factor of the p53 family, is expressed in the AER and indispensable for limb formation. However, the underlying mechanisms and specific roles of p63 variants are unknown. Here, we quantified the expression of p63 variants in mouse limbs from embryonic day (E) 10.5 to E12.5, and found that ΔNp63γ was strongly expressed in limbs at all stages, while TAp63γ expression was rapidly increased in the later stages. Fluorescence-activated cell sorting analysis of limb bud cells from reporter mouse embryos at E11.5 revealed that all variants were abundantly expressed in AER cells, and their expression was very low in mesenchymal cells. We then generated AER-specific p63 knockout mice by mating mice with a null and a flox allele of p63, and Msx2-Cre mice (Msx2-Cre;p63Δ/fl). Msx2-Cre;p63Δ/fl neonates showed limb malformation that was more obvious in distal elements. Expression of various AER-related genes was decreased in Msx2-Cre;p63Δ/fl limb buds and embryoid bodies formed by p63-knockdown induced pluripotent stem cells. Promoter analyses and chromatin immunoprecipitation assays demonstrated Fgf8 and Fgf4 as transcriptional targets of ΔNp63γ, and Jag2 as that of TAp63γ. Furthermore, TAp63γ overexpression exacerbated the phenotype of Msx2-Cre;p63Δ/fl mice. These data indicate that ΔNp63 and TAp63 control limb development through transcriptional regulation of different target molecules with different roles in the AER. Our findings contribute to

  3. Trim69 regulates zebrafish brain development by ap-1 pathway

    PubMed Central

    Han, Ruiqin; Wang, Renxian; Zhao, Qing; Han, Yongqing; Zong, Shudong; Miao, Shiying; Song, Wei; Wang, Linfang

    2016-01-01

    Proteins belonging to the TRIM family have been implicated in a variety of cellular processes such as apoptosis, differentiation, neurogenesis, muscular physiology and innate immune responses. Trim69, previously identified as a novel gene cloned from a human testis cDNA library, has a homologous gene in zebrafish and this study focused on investigating the function of trim69 in zebrafish neurogenesis. Trim69 was found to be expressed in zebrafish embryo brain at the early stages. Knockdown of trim69 led to deformed brain development, obvious signs of apoptosis present in the head, and decreased expression of neuronal differentiation and stem cell markers. This phenotype was rescued upon co-injection of human mRNA together along with the trim69 knockdown. Results of this study also showed an interaction between TRIM69 and c-Jun in human cells, and upon TRIM69 knock down c-Jun expression subsequently increased, whereas the over-expression of TRIM69 led to the down-regulation of c-Jun. Additionally, knockdown both c-Jun and trim69 can rescue the deformed brain, evident cellular apoptosis in the head and decreased expression of neuronal differentiation and stem cell markers. Overall, our results support a role for trim69 in the development of the zebrafish brain through ap-1 pathway. PMID:27050765

  4. Neuralized functions cell autonomously to regulate Drosophila sense organ development.

    PubMed

    Yeh, E; Zhou, L; Rudzik, N; Boulianne, G L

    2000-09-01

    Neurogenic genes, including Notch and Delta, are thought to play important roles in regulating cell-cell interactions required for Drosophila sense organ development. To define the requirement of the neurogenic gene neuralized (neu) in this process, two independent neu alleles were used to generate mutant clones. We find that neu is required for determination of cell fates within the proneural cluster and that cells mutant for neu autonomously adopt neural fates when adjacent to wild-type cells. Furthermore, neu is required within the sense organ lineage to determine the fates of daughter cells and accessory cells. To gain insight into the mechanism by which neu functions, we used the GAL4/UAS system to express wild-type and epitope-tagged neu constructs. We show that Neu protein is localized primarily at the plasma membrane. We propose that the function of neu in sense organ development is to affect the ability of cells to receive Notch-Delta signals and thus modulate neurogenic activity that allows for the specification of non-neuronal cell fates in the sense organ.

  5. A Signaling-Regulated, Short-Chain Dehydrogenase of Stagonospora nodorum Regulates Asexual Development ▿ ‡

    PubMed Central

    Tan, Kar-Chun; Heazlewood, Joshua L.; Millar, A. Harvey; Thomson, Gordon; Oliver, Richard P.; Solomon, Peter S.

    2008-01-01

    The fungus Stagonospora nodorum is a causal agent of leaf and glume blotch disease of wheat. It has been previously shown that inactivation of heterotrimeric G protein signaling in Stagonospora nodorum caused development defects and reduced pathogenicity [P. S. Solomon et al., Mol. Plant-Microbe Interact. 17:456-466, 2004]. In this study, we sought to identify targets of the signaling pathway that may have contributed to phenotypic defects of the signaling mutants. A comparative analysis of Stagonospora nodorum wild-type and Gα-defective mutant (gna1) intracellular proteomes was performed via two-dimensional polyacrylamide gel electrophoresis. Several proteins showed significantly altered abundances when comparing the two strains. One such protein, the short-chain dehydrogenase Sch1, was 18-fold less abundant in the gna1 strain, implying that it is positively regulated by Gα signaling. Gene expression and transcriptional enhanced green fluorescent protein fusion analyses of Sch1 indicates strong expression during asexual development. Mutant strains of Stagonospora nodorum lacking Sch1 demonstrated poor growth on minimal media and exhibited a significant reduction in asexual sporulation on all growth media examined. Detailed histological experiments on sch1 pycnidia revealed that the gene is required for the differentiation of the subparietal layers of asexual pycnidia resulting in a significant reduction in both pycnidiospore size and numbers. PMID:18776038

  6. Adrenocortical function of Arctic-breeding glaucous gulls in relation to persistent organic pollutants.

    PubMed

    Verboven, Nanette; Verreault, Jonathan; Letcher, Robert J; Gabrielsen, Geir W; Evans, Neil P

    2010-03-01

    Unpredictable changes in the environment stimulate the avian hypothalamo-pituitary-adrenal axis to produce corticosterone, which induces behavioural and metabolic changes that enhance survival in the face of adverse environmental conditions. In addition to profound environmental perturbations, such as severe weather conditions and unpredictable food shortages, many Arctic-breeding birds are also confronted with chronic exposure to persistent organic pollutants (POPs), some of which are known to disrupt endocrine processes. This study investigated the adrenocortical function of a top predator in the Arctic marine environment, the glaucous gull (Larus hyperboreus). High concentrations of organochlorines, brominated flame retardants and metabolically-derived products in blood plasma of incubating glaucous gulls were associated with high baseline corticosterone concentrations in both sexes and a reduced stress response in males. Contaminant-related changes in corticosterone concentration occurred over and above differences in body condition and seasonal variation. Chronically high corticosterone concentrations and/or a compromised adrenocortical response to stress can have negative effects on the health of an individual. The results of the present study suggest that exposure to POPs may increase the vulnerability of glaucous gulls to environmental stressors and thus could potentially compromise their ability to adapt to the rapidly changing environmental conditions associated with climate change that are currently seen in the Arctic.

  7. Isolated adrenocortical cells of the domestic fowl (Gallus domesticus): steroidogenic and ultrastructural properties.

    PubMed

    Carsia, R V; Scanes, C G; Malamed, S

    1985-02-01

    Isolated adrenocortical cells from White Leghorn chickens (Gallus domesticus) were compared to those from rats (Rattus norvegicus). Cells were prepared from collagenase-dispersed adrenal glands of sexually mature male animals. Corticosterone was measured by radioimmunoassay after incubation for 2 h with steroidogenic agents. Of the four ACTH analogues used, three were 6-17 times more potent with rat cells than with fowl cells (potencies were indicated by half-maximal steroidogenic concentrations). However, 9-tryptophan (O-nitrophenylsulfenyl) ACTH was 8 times more potent with fowl cells than with rat cells, thus suggesting that ACTH receptor differences exist between the two cell types. In addition, cAMP analogues were 10 times more potent with rat cells than with fowl cells suggesting that fowl corticosteroidogenesis is less dependent on cAMP than is rat corticosteroidogenesis. At equal cell concentrations, rat cells secreted 20-40 times more corticosterone than did chicken cells when they were maximally stimulated. Although rat cells converted 8 times more pregnenolone to corticosterone than did fowl cells, the half-maximal steroidogenic concentration for pregnenolone-supported corticosterone synthesis was the same for both cell types (about 5 microM). This suggests that fowl cells have lower steroidogenic enzyme content rather than lower steroidogenic enzyme activity. An unusual feature seen in the isolated fowl adrenocortical cells was an abundance of intracellular filaments.

  8. Steroid control of steroidogenesis in isolated adrenocortical cells: molecular and species specificity.

    PubMed

    Carsia, R V; Macdonald, G J; Malamed, S

    1983-06-01

    The molecular and species specificity of glucocorticoid suppression of corticosteroidogenesis was investigated in isolated adrenocortical cells. Trypsin-isolated cells from male rat, domestic fowl and bovine adrenal glands were incubated with or without steroidogenic agents and with or without steroids. Glucocorticoids were measured by radioimmunoassay or fluorometric assay after 1-2 h incubation. Glucocorticoids suppressed ACTH-induced steroidogenesis of isolated rat cells with the following relative potencies: corticosterone greater than cortisol = cortisone greater than dexamethasone. The mineralocorticoid, aldosterone did not affect steroidogenesis. Suppression by glucocorticoids was acute (within 1-2 h), and varied directly with the glucocorticoid concentration. Testosterone also suppressed ACTH-induced steroidogenesis. Glucocorticoid-type steroids have equivalent suppressive potencies, thus suggesting that these steroids may induce suppression at least partly by a common mechanism. Although corticosterone caused the greatest suppression, testosterone was more potent. The steroid specificity of suppression of cyclic AMP (cAMP)-induced and ACTH-induced steroidogenesis were similar, suggesting that suppression is not solely the result of interference with ACTH receptor function or the induction of adenylate cyclase activity. Exogenous glucocorticoids also suppressed ACTH-induced steroidogenesis of cells isolated from domestic fowl and beef adrenal glands, thus suggesting that this observed suppression may be a general mechanism of adrenocortical cell autoregulation.

  9. Acute effects of ACTH on dissociated adrenocortical cells: quantitative changes in mitochondria and lipid droplets.

    PubMed

    Zoller, L C; Malamed, S

    1975-08-01

    To study the role of certain organelles in steroidogenesis, dissociated rat adrenocortical cells were incubated for two hours with ACTH at a concentration that induces a high level of steroid production. Sections of ACTH treated and untreated cells were photographed in the electron microscope, and morphometric analysis was undertaken to assess possible ACTH-induced changes in total cell volume, volume density and numerical denisty of lipid droplets and mitochondria. There was no change in total cell volume. Lipid droplet volume density and numerical density decreased. Mitochondrial volume density did not change, but numerical density increased. The decrease in lipid droplet volume density indicates a rapid depletion of cholesterol for steroid production. This depletion is almost entirely due to the disappearance of lipid droplets, rather than to an overall diminution in their size, as shown by the decrease in lipid droplet numerical density. The mitochondrial data suggest that the adrenocortical cell has an adedquate mitochondrial apparatus to respond to acute ACTH stimulation with increased steroid output without an increase inmitochondrial volume.

  10. An unusual case of adrenocortical carcinoma with liver metastasis that occurred at 23 years after surgery

    PubMed Central

    Rayar, Michel; Beuzit, Luc; Levi Sandri, Giovanni Battista; Dagher, Julien; Merdrignac, Aude; Tanguy, Laetitia; Boudjema, Karim; Sulpice, Laurent; Meunier, Bernard

    2016-01-01

    Adrenocortical carcinoma (ACC) is an uncommon and aggressive cancer occurring more frequently in women; local or distant recurrences occur in 80% of cases, typically within 1 year after curative resection. Liver is the preferred metastatic site. Herein, we report the case of a unique liver metastasis from ACC occurring 23 years after the curative prior tumor surgery. A 45-year-old woman was operated in 1991 for adrenocortical stage II without microvascular involvement or capsular infiltration. At that time, no adjuvant treatment was indicated. The initial surgery consisted on a left adrenalectomy with contemporaneous left nephrectomy and regional lymphadenectomy. Five years after surgery, the patient was considered cured. However, 23 years later, the patient presented an atypical right subcostal pain. A 4 cm liver ACC metastasis involving the segment 4 and initially diagnosed as a hemangioma was discovered. A curative resection of the segment 4 was performed. Final pathological examination confirmed the diagnosis of ACC metastasis with a complete R0 resection; no lymph node metastases were observed. This case is the latest metachronous ACC metastasis ever reported in literature. To date, the patient is alive with no signs of recurrence after a post-surgical follow-up of 13 months. PMID:27275470

  11. Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells.

    PubMed

    Poli, Giada; Guasti, Daniele; Rapizzi, Elena; Fucci, Rossella; Canu, Letizia; Bandini, Alessandra; Cini, Nicoletta; Bani, Daniele; Mannelli, Massimo; Luconi, Michaela

    2013-08-01

    At present, mitotane (MTT) represents the first-line pharmacological approach for the treatment of advanced adrenocortical carcinoma (ACC). Despite clear evidence that the drug can reduce the clinical signs of steroid excess in secreting ACC, the mechanism mediating the possible toxic effect of MTT on tumor cells still remains obscure. This study investigated the intracellular events underlying the toxic effect of MTT by studying qualitative and quantitative alterations in mitochondrial morphology and functions in human adrenocortical cancer cell lines, H295R and SW13. Increasing concentrations of MTT resulted in rapid intracellular accumulation and conversion of the drug. Cytostatic and cytotoxic effects were evident at doses corresponding to the therapeutic window (30-50 μM) through an apoptotic mechanism involving caspase 3/7. Electron microscopic analysis of cell mitochondria displayed MTT-induced dose- and time-dependent alterations in the morphology of the organelle. These alterations were characterized by a marked swelling and a decrease in the number of respiratory cristae, accompanied by a significant depolarization of the mitochondrial membrane potential, finally leading to the disruption of the organelle. A drastic reduction of oxygen consumption was observed due to mitochondrial membrane damage, which was accompanied by a decrease in the levels of VDAC1 integral membrane channel. These findings contribute to better understand the intracellular mechanism of action of MTT in ACC cells, showing that its cytotoxic effect seems to be mainly mediated by an apoptotic process activated by the disruption of mitochondria.

  12. Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells.

    PubMed

    Gagliano, Teresa; Gentilin, Erica; Benfini, Katiuscia; Di Pasquale, Carmelina; Tassinari, Martina; Falletta, Simona; Feo, Carlo; Tagliati, Federico; Uberti, Ettore Degli; Zatelli, Maria Chiara

    2014-12-01

    Mitotane is currently employed as adjuvant therapy as well as in the medical treatment of adrenocortical carcinoma (ACC), alone or in combination with chemotherapeutic agents. It was previously demonstrated that mitotane potentiates chemotherapeutic drugs cytotoxicity in cancer cells displaying chemoresistance due to P-glycoprotein (P-gp), an efflux pump involved in cancer multidrug resistance. The majority of ACC expresses high levels of P-gp and is highly chemoresistent. The aim of our study was to explore in vitro whether mitotane, at concentrations lower than those currently reached in vivo, may sensitize ACC cells to the cytotoxic effects of doxorubicin and whether this effect is due to a direct action on P-gp. NCI-H295 and SW13 cell lines as well as 4 adrenocortical neoplasia primary cultures were treated with mitotane and doxorubicin, and cell viability was measured by MTT assay. P-gp activity was measured by calcein and P-gp-Glo assays. P-gp expression was evaluated by Western blot. We found that very low mitotane concentrations sensitize ACC cells to the cytotoxic effects of doxorubicin, depending on P-gp expression. In addition, mitotane directly inhibits P-gp detoxifying function, allowing doxorubicin cytotoxic activity. These data provide the basis for the greater efficacy of combination therapy (mitotane plus chemotherapeutic drugs) on ACC patients. Shedding light on mitotane mechanisms of action could result in an improved design of drug therapy for patients with ACC.

  13. Virilizing para-adrenocortical adenoma associated with idiopathic-acquired generalized anhidrosis in an adolescent girl.

    PubMed

    Gumus, Pinar; Luquette, Mark; Haymon, Marie Louise; Valerie, Evans; Morales, Jaime; Vargas, Alfonso

    2011-01-01

    Adrenocortical tumors are rare in childhood and adolescence. Virilization, alone or in combination with signs of overproduction of other adrenal hormones, is the most common clinical presentation. Here we report an unusual case of an African-American female adolescent presenting with idiopathic acquired generalized anhidrosis, dysregulation of body temperature, absence of adult body odor and dry skin in the face of a virilizing para-adrenocortical adenoma. Virilization signs regressed soon after removal of the tumor, but normalization of the 3alpha-androstenediol glucuronide (3alpha-AG) took longer compared to other measurable androgens; accompanied by anhidrosis. The association of remitting anhidrosis with normalized levels of 3alpha-AG suggests it might be a possible mechanism for anhidrosis. High 3alpha-AG levels might implicate the increased peripheral conversion of weak pro-androgens with different biochemical structure. We recommend obtaining 3alpha-AG beside other androgens in virilized patients with atypical dermatological symptoms in the face of hyperandrogenism.

  14. Environmental enrichment affects adrenocortical stress responses in the endangered black-footed ferret

    USGS Publications Warehouse

    Poessel, S.A.; Biggins, D.E.; Santymire, R.M.; Livieri, T.M.; Crooks, K.R.; Angeloni, L.

    2011-01-01

    Potential stressors of wildlife living in captivity, such as artificial living conditions and frequent human contact, may lead to a higher occurrence of disease and reduced reproductive function. One successful method used by wildlife managers to improve general well-being is the provision of environmental enrichment, which is the practice of providing animals under managed care with environmental stimuli. The black-footed ferret (Mustela nigripes) is a highly-endangered carnivore species that was rescued from extinction by removal of the last remaining individuals from the wild to begin an ex situ breeding program. Our goal was to examine the effect of environmental enrichment on adrenocortical activity in ferrets by monitoring fecal glucocorticoid metabolites (FGM). Results demonstrated that enrichment lowered FGM in juvenile male ferrets, while increasing it in adult females; enrichment had no effect on FGM in juvenile females and adult males. These results correspond with our findings that juvenile males interacted more with the enrichment items than did adult females. However, we did not detect an impact of FGM on the incidence of disease or on the ability of ferrets to become reproductive during the following breeding season. We conclude that an environmental enrichment program could benefit captive juvenile male ferrets by reducing adrenocortical activity. ?? 2011 Elsevier Inc.

  15. Species differences in 3-methylsulphonyl-DDE bioactivation by adrenocortical tissue.

    PubMed

    Lindström, Veronica; Brandt, Ingvar; Lindhe, Orjan

    2008-03-01

    The CYP11B1-activated adrenocortical toxicant 3-methylsulphonyl-DDE (3-MeSO2-DDE) is proposed as a lead compound for an improved chemotherapy for adrenocortical carcinoma. We compared the binding of 3-MeSO2-[14C]DDE in the adrenal cortex of four rodent species; hamster, guinea pig, mouse and rat, using a precision-cut adrenal slice culture system ex vivo. Localization and quantification of the bound radioactivity were carried out using light microscopy autoradiography and radioluminography. The results revealed major species differences since 3-MeSO2-[14C]DDE was extensively bound to the hamster adrenal tissue while the guinea pig adrenals were devoid of binding. A high binding in mouse adrenal cortex was confirmed while binding in rat adrenal cortex was very weak. The results support previous observations that metabolic activation of 3-MeSO2-DDE is highly species dependent. Since CYP11B1 could be expressed in tissues other than the adrenal cortex, final toxicological characterization should be carried out in a species that can bioactivate this compound.

  16. If It Goes up, Must It Come Down? Chronic Stress and the Hypothalamic-Pituitary Adrenocortical Axis in Humans

    ERIC Educational Resources Information Center

    Miller, Gregory E.; Chen, Edith; Zhou, Eric S.

    2007-01-01

    The notion that chronic stress fosters disease by activating the hypothalamic-pituitary adrenocortical (HPA) axis is featured prominently in many theories. The research linking chronic stress and HPA function is contradictory, however, with some studies reporting increased activation, and others reporting the opposite. This meta-analysis showed…

  17. High-throughput screening of chemical effects on steroidogenesis using H295R human adrenocortical carcinoma cells

    EPA Science Inventory

    Disruption of steroidogenesis by environmental chemicals can result in altered hormone levels causing adverse reproductive and developmental effects. A high-throughput assay using H295R human adrenocortical carcinoma cells was used to evaluate the effect of 2,060 chemical samples...

  18. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors.

    PubMed

    Zhao, Jianming; Roth, Jürgen; Bode-Lesniewska, Beata; Pfaltz, Madeleine; Heitz, Philipp U; Komminoth, Paul

    2002-05-01

    Identification of gene amplifications in human tumors is important for the understanding of tumorigenesis and may lead to discovery of diagnostic and prognostic markers. In this study, we used a microarray-based comparative genomic hybridization (CGH) technique, combined with conventional CGH, to identify gene amplifications in 43 tumors including eight pulmonary artery intimal sarcomas and 35 adrenocortical tumors. Conventional CGH revealed gains or amplifications of 12q13-q15 in six sarcomas and in two adrenocortical carcinomas. Using microarrays, we demonstrated that, among genes located on 12q13-q15, SAS/CDK4 were amplified in six sarcomas, and MDM2 and GLI in five and four sarcomas, respectively. The two adrenocortical tumors showed coamplifications of SAS/CDK4 and MDM2. Furthermore, PDGFRA (located on 4q12) amplification was identified in five sarcomas. Our data demonstrate: (1) amplifications of SAS/CDK4, MDM2, GLI, and PDGFRA are strongly associated with the tumorigenesis of pulmonary artery intimal sarcomas, whereas SAS/CDK4 and MDM2 coamplification may contribute to the progression of adrenocortical tumors; (2) microarray-based CGH is a useful tool for simultaneous detection of multiple gene amplifications, with a high sensitivity and resolution compared to that of conventional CGH.

  19. The Development of Self-Regulation and Executive Function in Young Children

    ERIC Educational Resources Information Center

    McClelland, Megan M.; Tominey, Shauna L.

    2014-01-01

    Self-regulation lays the foundation for positive social relationships and academic success. In this article, we provide an overview of self-regulation and the key terms related to selfregulation, such as executive function. We discuss research on how self-regulation develops and connections between self-regulation and social and academic outcomes.…

  20. The Quest for Molecular Regulation Underlying Unisexual Flower Development

    PubMed Central

    Sobral, Rómulo; Silva, Helena G.; Morais-Cecílio, Leonor; Costa, Maria M. R.

    2016-01-01

    The understanding of the molecular mechanisms responsible for the making of a unisexual flower has been a long-standing quest in plant biology. Plants with male and female flowers can be divided mainly into two categories: dioecious and monoecious, and both sexual systems co-exist in nature in ca of 10% of the angiosperms. The establishment of male and female traits has been extensively described in a hermaphroditic flower and requires the interplay of networks, directly and indirectly related to the floral organ identity genes including hormonal regulators, transcription factors, microRNAs, and chromatin-modifying proteins. Recent transcriptomic studies have been uncovering the molecular processes underlying the establishment of unisexual flowers and there are many parallelisms between monoecious, dioecious, and hermaphroditic individuals. Here, we review the paper entitled “Comparative transcriptomic analysis of male and female flowers of monoecious Quercus suber” published in 2014 in the Frontiers of Plant Science (volume 5 |Article 599) and discussed it in the context of recent studies with other dioecious and monoecious plants that utilized high-throughput platforms to obtain transcriptomic profiles of male and female unisexual flowers. In some unisexual flowers, the developmental programs that control organ initiation fail and male or female organs do not form, whereas in other species, organ initiation and development occur but they abort or arrest during different species-specific stages of differentiation. Therefore, a direct comparison of the pathways responsible for the establishment of unisexual flowers in different species are likely to reveal conserved modules of gene regulatory hubs involved in stamen or carpel development, as well as differences that reflect the different stages of development in which male and/or female organ arrest or loss-of-function occurs. PMID:26925078

  1. Unique aspects of the developing lung circulation: structural development and regulation of vasomotor tone

    PubMed Central

    Gao, Yuangsheng; Cornfield, David N.; Stenmark, Kurt R.; Thébaud, Bernard; Abman, Steven H.

    2016-01-01

    Abstract This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension. PMID:27942377

  2. Thyrostimulin Regulates Osteoblastic Bone Formation During Early Skeletal Development

    PubMed Central

    van der Spek, Anne; Logan, John G.; Gogakos, Apostolos; Bagchi-Chakraborty, Jayashree; Murphy, Elaine; van Zeijl, Clementine; Down, Jenny; Croucher, Peter I.; Boyde, Alan; Boelen, Anita

    2015-01-01

    The ancestral glycoprotein hormone thyrostimulin is a heterodimer of unique glycoprotein hormone subunit alpha (GPA)2 and glycoprotein hormone subunit beta (GPB)5 subunits with high affinity for the TSH receptor. Transgenic overexpression of GPB5 in mice results in cranial abnormalities, but the role of thyrostimulin in bone remains unknown. We hypothesized that thyrostimulin exerts paracrine actions in bone and determined: 1) GPA2 and GPB5 expression in osteoblasts and osteoclasts, 2) the skeletal consequences of thyrostimulin deficiency in GPB5 knockout (KO) mice, and 3) osteoblast and osteoclast responses to thyrostimulin treatment. Gpa2 and Gpb5 expression was identified in the newborn skeleton but declined rapidly thereafter. GPA2 and GPB5 mRNAs were also expressed in primary osteoblasts and osteoclasts at varying concentrations. Juvenile thyrostimulin-deficient mice had increased bone volume and mineralization as a result of increased osteoblastic bone formation. However, thyrostimulin failed to induce a canonical cAMP response or activate the noncanonical Akt, ERK, or mitogen-activated protein kinase (P38) signaling pathways in primary calvarial or bone marrow stromal cell-derived osteoblasts. Furthermore, thyrostimulin did not directly inhibit osteoblast proliferation, differentiation or mineralization in vitro. These studies identify thyrostimulin as a negative but indirect regulator of osteoblastic bone formation during skeletal development. PMID:26018249

  3. PCSK9: Regulation and Target for Drug Development for Dyslipidemia.

    PubMed

    Burke, Amy C; Dron, Jacqueline S; Hegele, Robert A; Huff, Murray W

    2017-01-06

    Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

  4. Regulation of protein synthesis during sea urchin early development

    SciTech Connect

    Kelso, L.C.

    1989-01-01

    Fertilization of the sea urchin egg results in a 20-40 fold increase in the rate of protein synthesis. The masked message hypothesis proposes that mRNAs are masked or unavailable for translation in the egg. We devised an in vivo assay to test this hypothesis. Our results show that masked mRNAs limit protein synthesis in the unfertilized egg. In addition, we show that protein synthesis is also regulated at the level of translational machinery. Following fertilization is a period of rapid cell divisions. This period, known as the rapid cleavage stage, is characterized by the transient synthesis of a novel set of proteins. The synthesis of these proteins is programmed by maternal mRNAs stored in the unfertilized egg. To study the behavior of these mRNAs, we prepared a cDNA library from polysomal poly (A+) RNA from 2-hour embryos. ({sup 32}P) labeled probes, prepared from the cDNA library, were used to monitor the levels of individual mRNAs in polysomes at fertilization and during early development.

  5. Genes regulating touch cell development in Caenorhabditis elegans.

    PubMed Central

    Du, H; Chalfie, M

    2001-01-01

    To identify genes regulating the development of the six touch receptor neurons, we screened the F(2) progeny of mutated animals expressing an integrated mec-2::gfp transgene that is expressed mainly in these touch cells. From 2638 mutated haploid genomes, we obtained 11 mutations representing 11 genes that affected the production, migration, or outgrowth of the touch cells. Eight of these mutations were in known genes, and 2 defined new genes (mig-21 and vab-15). The mig-21 mutation is the first known to affect the asymmetry of the migrations of Q neuroblasts, the cells that give rise to two of the six touch cells. vab-15 is a msh-like homeobox gene that appears to be needed for the proper production of touch cell precursors, since vab-15 animals lacked the four more posterior touch cells. The remaining touch cells (the ALM cells) were present but mispositioned. A similar touch cell phenotype is produced by mutations in lin-32. A more severe phenotype; i.e., animals often lacked ALM cells, was seen in lin-32 vab-15 double mutants, suggesting that these genes acted redundantly in ALM differentiation. In addition to the touch cell abnormalities, vab-15 animals variably exhibit embryonic or larval lethality, cell degenerations, malformation of the posterior body, uncoordinated movement, and defective egg laying. PMID:11333230

  6. IAN family critically regulates survival and development of T lymphocytes.

    PubMed

    Nitta, Takeshi; Nasreen, Mariam; Seike, Takafumi; Goji, Atsushi; Ohigashi, Izumi; Miyazaki, Tadaaki; Ohta, Tsutomu; Kanno, Masamoto; Takahama, Yousuke

    2006-04-01

    The IAN (immune-associated nucleotide-binding protein) family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.

  7. Symbiotic regulation of plant growth, development and reproduction

    USGS Publications Warehouse

    Rodriguez, R.J.; Freeman, D. Carl; McArthur, E.D.; Kim, Y.-O.; Redman, R.S.

    2009-01-01

    The growth and development of rice (Oryzae sativa) seedlings was shown to be regulated epigenetically by a fungal endophyte. In contrast to un-inoculated (nonsymbiotic) plants, endophyte colonized (symbiotic) plants preferentially allocated resources into root growth until root hairs were well established. During that time symbiotic roots expanded at five times the rate observed in nonsymbiotic plants. Endophytes also influenced sexual reproduction of mature big sagebrush (Artemisia tridentata) plants. Two spatially distinct big sagebrush subspecies and their hybrids were symbiotic with unique fungal endophytes, despite being separated by only 380 m distance and 60 m elevation. A double reciprocal transplant experiment of parental and hybrid plants, and soils across the hybrid zone showed that fungal endophytes interact with the soils and different plant genotypes to confer enhanced plant reproduction in soil native to the endophyte and reduced reproduction in soil alien to the endophyte. Moreover, the most prevalent endophyte of the hybrid zone reduced the fitness of both parental subspecies. Because these endophytes are passed to the next generation of plants on seed coats, this interaction provides a selective advantage, habitat specificity, and the means of restricting gene flow, thereby making the hybrid zone stable, narrow and potentially leading to speciation. ?? 2009 Landes Bioscience.

  8. Developing a strategy for a regulated electronic bioanalytical laboratory.

    PubMed

    McDowall, R D

    2014-01-01

    This perspective article considers the strategy, design and implementation of an electronic bioanalytical laboratory working to GLP and/or GCP regulations. There are a range of available automated systems and laboratory informatics that could be implemented and integrated to make an electronic laboratory. However, which are the appropriate ones to select and what is realistic and cost-effective for an individual laboratory? The answer is to develop an overall automation strategy that is updated periodically after each system or application has been implemented to assess if the strategy is still valid or needs to be changed. As many laboratory informatics applications have functional overlap or convergence, for example, Laboratory Information Management System, Electronic Laboratory Notebook, and Instrument and Chromatography Data Systems, the decision of which application performs a specific task needs to be carefully considered in the overall strategy. Ensuring data integrity and regulatory compliance, especially in light of a number of recent falsification cases, is a mandatory consideration for the overall strategy for an electronic bioanalytical laboratory submitting data to regulatory authorities.

  9. Regulating and Quality-Assuring VET: International Developments. Research Report

    ERIC Educational Resources Information Center

    Misko, Josie

    2015-01-01

    The opening-up of the market for education and training, including vocational education and training (VET), has increased the importance of regulation and quality assurance mechanisms in ensuring the integrity of qualifications. This report investigates approaches to the regulation and quality assurance of vocational education and training in a…

  10. Teaching Glucocorticoid Negative Feedback and Adrenocortical Regulation Using a Classic Paper by Dr. Dwight Ingle

    ERIC Educational Resources Information Center

    Raff, Hershel

    2005-01-01

    The American Physiological Society (APS) Legacy Project and its accompanying Essays on APS Classic Papers have allowed the scientific community on-line access to the entire collection of APS publications since their inception in 1898 (http://www.the-aps.org/publications/legacy/ and http://www.the-aps.org/publications/classics/). The availability…

  11. Space shuttle OMS helium regulator design and development

    NASA Technical Reports Server (NTRS)

    Wichmann, H.; Kelly, T. L.; Lynch, R.

    1974-01-01

    Analysis, design, fabrication and design verification testing was conducted on the technological feasiblity of the helium pressurization regulator for the space shuttle orbital maneuvering system application. A prototype regulator was fabricated which was a single-stage design featuring the most reliable and lowest cost concept. A tradeoff study on regulator concepts indicated that a single-stage regulator with a lever arm between the valve and the actuator section would offer significant weight savings. Damping concepts were tested to determine the amount of damping required to restrict actuator travel during vibration. Component design parameters such as spring rates, effective area, contamination cutting, and damping were determined by test prior to regulator final assembly. The unit was subjected to performance testing at widely ranging flow rates, temperatures, inlet pressures, and random vibration levels. A test plan for propellant compatibility and extended life tests is included.

  12. Long Non-Coding RNA Regulation of Reproduction and Development

    PubMed Central

    Taylor, David H.; Chu, Erin Tsi-Jia; Spektor, Roman; Soloway, Paul D.

    2016-01-01

    SUMMARY Noncoding RNAs (ncRNAs) have long been known to play vital roles in eukaryotic gene regulation. Studies conducted over a decade ago revealed that maturation of spliced, polyadenylated coding mRNA occurs by reactions involving small nuclear RNAs and small nucleolar RNAs; mRNA translation depends on activities mediated by transfer RNAs and ribosomal RNAs, subject to negative regulation by micro RNAs; transcriptional competence of sex chromosomes and some imprinted genes is regulated in cis by ncRNAs that vary by species; and both small-interfering RNAs and piwi-interacting RNAs bound to Argonaute-family proteins regulate post-translational modifications on chromatin and local gene expression states. More recently, gene-regulating noncoding RNAs have been identified, such as long intergenic and long noncoding RNAs (collectively referred to as lncRNAs)—a class totaling more than 100,000 transcripts in humans, which include some of the previously mentioned RNAs that regulate dosage compensation and imprinted gene expression. Here, we provide an overview of lncRNA activities, and then review the role of lncRNAs in processes vital to reproduction, such as germ cell specification, sex determination and gonadogenesis, sex hormone responses, meiosis, gametogenesis, placenta-tion, non-genetic inheritance, and pathologies affecting reproductive tissues. Results from many species are presented to illustrate the evolutionary conserved processes lncRNAs are involved in. PMID:26517592

  13. Tribal organizations and energy development: Recognized sovereignty, regulations, and planning

    NASA Astrophysics Data System (ADS)

    Wilson, Amy James

    Tribal governments' capacity to implement land use controls within their Nations is limited by the United States Constitution and federal law; however, tribal governments have inherent sovereignty to protect, guide, and govern the lands under their jurisdiction to protect and enhance the safety, health, and welfare of their members. The aim of this thesis was to investigate and identify (1) the extent to which tribal Nations have sovereignty over their lands and authority to regulate land use within their jurisdiction and (2) the present status and extent to which Native American tribal governments use their sovereignty over land use development concerning oil and natural gas development within their jurisdiction. The study was qualitative in nature and focused on a comprehensive archival review and a one-case case study. Constitutional law, federal Indian law, environmental law, and tribal law were considered. The thesis first examines the results of the archival review, which demonstrates that tribes, while limited by federal law, have sovereignty and authority to control land use within their territories. The Three Affiliated Tribes of the Fort Berthold Reservation were also examined. The Tribes were chosen based on location, level of oil and natural gas production, and accessibility of information. The most current information available was used for the study. The data for the study was obtained from the Internet. The research suggests that tribes are implementing land use controls and participating in land use and comprehensive planning; however, they are not doing so to the extent of their sovereignty. This study demonstrates that tribal governments do indeed have authority over their lands and resources and cannot fully take advantage of their sovereignty without practicing self-governance over their natural, built, and human environments. Questions remain regarding the reasons that tribal governments are not implementing land use controls and engaging in

  14. The effect of mitotane on viability, steroidogenesis and gene expression in NCI‑H295R adrenocortical cells.

    PubMed

    Lehmann, Tomasz P; Wrzesiński, Tomasz; Jagodziński, Paweł P

    2013-03-01

    Mitotane, also known as o,p'‑DDD or (RS)‑1‑chl-oro‑2‑[2,2‑dichloro‑1‑(4‑chlorophenyl)‑ethyl]‑benzene, is an adrenal cortex-specific cytotoxic drug used in the therapy of adrenocortical carcinoma (ACC). The drug also inhibits steroidogenesis, however, the mechanisms of its anticancer and antisteroidogenic effects remain unknown. At present, data on the impact of mitotane on cell viability and the regulation of genes encoding proteins associated with steroids synthesis in the adrenal cortex, including cortisol and dehydroepiandrosterone sulfate (DHEAS), are limited and contradictory. In the present study, the effect of 24‑h mitotane treatment on viability of the ACC cell line, NCI‑H295R, was analyzed, identifying a decrease in cell viability and an increase in caspase‑3 and ‑7 activities. Mitotane treatment also led to decreased cortisol and DHEAS concentration in the culture media. Concomitantly, mitotane resulted in decreased mRNA levels of two cytochromes P450 (CYP11A1 and CYP17A1), mRNAs encoding proteins involved in the synthesis of cortisol and DHEAS. Mitotane did not affect mRNA levels of cyclin dependent kinase inhibitor 1A (encoding p21) and MYC (encoding cMyc). cMyc and p21 are key transcription factors associated with cell cycle regulation. However, mitotane inhibited expression of transforming growth factor β1 gene, encoding a potent inhibitor of cell proliferation and steroidogenesis. PRKAR1A, a protein kinase A regulatory subunit, is involved in the activation of steroidogenesis. PRKAR1A mRNA levels were reduced following 24‑h treatment with mitotane. Results indicate that mitotane markedly inhibited expression of genes involved in steroidogenesis, secretion of cortisol and DHEAS. Reduced expression of TGFB1 cannot account fully for the effect of mitotane on CYP11A1 and CYP17A1. We hypothesized that reduced viability of NCI‑H295R cells in the presence of mitotane may be a result of apoptosis triggered by increased

  15. The adrenocortical response of tufted puffin chicks to nutritional deficits

    USGS Publications Warehouse

    Kitaysky, A.S.; Romano, Marc D.; Piatt, J.F.; Wingfield, J.C.; Kikuchi, M.

    2005-01-01

    In several seabirds, nutritional state of a nest-bound chick is negatively correlated with the activity of its hypothalamus-pituitary-adrenal (HPA) axis. Increased corticosterone (cort) secretion has been shown to facilitate changes in behavior that allow hungry chicks to obtain more food from parents. However, if parents are not willing/able to buffer their young from temporary food shortages, increased cort secretion could be detrimental to undernourished chicks. In a system where parents are insensitive to chick demands, low benefits and high costs of activation of the HPA-axis in hungry chicks should lead to a disassociation of the nutritional state of the young and the activity of its HPA-axis. We tested this novel hypothesis for the tufted puffin (Fratercula cirrhata), a seabird with intermittent provisioning of a nest-bound semi-precocial chick. We examined the HPA-axis activity of captive chicks exposed to the following: (1) a short-term (24 h) food deprivation; and (2) an array of prolonged (3 weeks) restrictions in feeding regimens. We found that in response to a short-term food deprivation chicks decreased baseline levels of cort and thyroid hormones. In response to prolonged restrictions, food-limited chicks exhibited signs of nutritional deficit: they had lower body mass, endogenous lipid reserves, and thyroid hormone titers compared to chicks fed ad libitum. However, baseline and maximum acute stress-induced levels of cort were also lower in food-restricted chicks compared to those of chicks fed ad libitum. These results support a major prediction of the study hypothesis that puffin chicks suppress HPA-axis activity in response to short- and long-term nutritional deficits. This physiological adaptation may allow a chick to extend its development in the nest, while eluding detrimental effects of chronic cort elevation. 

  16. Adrenocortical carcinoma: An extremely uncommon entity and the role of Immunohistochemistry in its diagnosis

    PubMed Central

    Gogoi, G.; Baruah, Manash P; Borah, P.; Borgohain, M.

    2012-01-01

    Adrenocortcal carcinoma is an extremely uncommon entity with an incidence of two in one millionth population. Here we present a 60 year gentleman with pain in abdomen, nausea, and backache, and weight loss. Contrast enhanced computed tomography (CECT) abdomen revealed a heterogenous well defined mass measuring (15 × 10.3 × 13) cm3 on the left suprarenal region with central necrosis which extended medially up to the midline. Locally, the growth infiltrated the upper pole of left kidney. Initially, the differential diagnosis included that of renal cell carcinoma arising from upper pole of left kidney involving adrenal gland. The patient underwent left radical nephrectomy and left adrenalectomy. Histological evaluation could not differentiate it from of malignant pheochromocytoma, but immunohistochemistry confirmed it as adrenocortical carcinoma. This case highlights the crucial role of immunohistochemistry in establishing the diagnosis like tumors. PMID:23565434

  17. Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome.

    PubMed

    Carney, J Aidan; Young, William F; Stratakis, Constantine A

    2011-09-01

    McCune-Albright syndrome (polyostotic fibrous dysplasia, café-au-lait skin spots, and precocious puberty) is a genetically mosaic disorder with populations of mutant and normal cells in affected organs. Cushing syndrome, a rare feature of the condition, usually affects infants and is the result of corticotropin-independent primary bilateral adrenal disease, usually interpreted as nodular adrenocortical hyperplasia. In this study of 9 patients with Cushing syndrome and McCune-Albright syndrome, light microscopy revealed a characteristic bimorphic pattern of diffuse and nodular hyperplasia and a distinctive form of cortical atrophy with apparent zona glomerulosa hyperplasia in 8 patients, all very young. The pattern could be explained by the presence of a mosaic distribution of mutant and normal cells in the adrenal glands. The findings are different from those in inherited or other forms of genetically caused Cushing syndrome. The ninth patient, aged 17 years, had an adrenal adenoma and diffuse cortical hyperplasia in each adrenal gland.

  18. Structure-activity relations between alkyl nucleophilic chemicals causing duodenal ulcer and adrenocortical necrosis

    SciTech Connect

    Szabo, S.; Reynolds, E.S.; Unger, S.H.

    1982-10-01

    Structure-activity relationships were qualitatively and quantitatively examined for 56 chemicals (e.g., derivatives of propionitrile, acrylonitrile and cysteamine) which caused duodenal ulcer and/or adrenocortical necrosis in rats. For the first time the duodenal ulcerogenic property of numerous chemicals has been studied in a rational and predictive manner. Ulcerogenic activity was most intense in the carbonitriles attached to two or three carbon backbones and diminished by shortening, lengthening, branching, unsaturating, halogenating or hydroxylating the carbon chains. Different modes of action are implied. Adrenocorticolytic potency was associated with unsaturation of the carbon chain and substitution of the nitrile by thiol or amine radicals. An action of these chemicals on the central nervous system has been suggested.

  19. Adrenocortical hemorrhagic necrosis: the role of catecholamines and retrograde medullary-cell embolism

    SciTech Connect

    Szabo, S.; McComb, D.J.; Kovacs, K.; Huettner, I.

    1981-10-01

    We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

  20. Non-invasive assessment of adrenocortical function in captive Nile crocodiles (Crocodylus niloticus).

    PubMed

    Ganswindt, Stefanie B; Myburgh, Jan G; Cameron, Elissa Z; Ganswindt, Andre

    2014-11-01

    The occurrence of stress-inducing factors in captive crocodilians is a concern, since chronic stress can negatively affect animal health and reproduction, and hence production. Monitoring stress in wild crocodiles could also be beneficial for assessing the state of health in populations which are potentially threatened by environmental pollution. In both cases, a non-invasive approach to assess adrenocortical function as a measure of stress would be preferable, as animals are not disturbed during sample collection, and therefore sampling is feedback-free. So far, however, such a non-invasive method has not been established for any crocodilian species. As an initial step, we therefore examined the suitability of two enzyme-immunoassays, detecting faecal glucocorticoid metabolites (FGMs) with a 11β,21-diol-20-one and 5β-3α-ol-11-one structure, respectively, for monitoring stress-related physiological responses in captive Nile crocodiles (Crocodylus niloticus). An adrenocorticotropic hormone (ACTH) challenge was performed on 10 sub-adult crocodiles, resulting in an overall increase in serum corticosterone levels of 272% above the pre-injection levels 5h post-injection. Saline-treated control animals (n=8) showed an overall increase of 156% in serum corticosterone levels 5h post-administration. Faecal samples pre- and post-injection could be obtained from three of the six individually housed crocodiles, resulting in FGM concentrations 136-380% above pre-injection levels, always detected in the first sample collected post-treatment (7-15 days post-injection). FGM concentrations seem comparatively stable at ambient temperatures for up to 72 h post-defaecation. In conclusion, non-invasive hormone monitoring can be used for assessing adrenocortical function in captive Nile crocodiles based on FGM analysis.

  1. Co-inhibition of EGFR and IGF1R synergistically impacts therapeutically on adrenocortical carcinoma

    PubMed Central

    Lian, Jianpo; Wang, Xiaojing; Ning, Guang; Wang, Weiqing; Zhu, Yu

    2016-01-01

    Purpose Adrenocortical carcinoma (ACC) is a rare tumor with very poor prognosis and no effective treatment. The aim of this study was to explore a novel therapy co-targeting EGFR and IGF1R in vitro and vivo. Methods The expression of EGFR and IGF1R were evaluated in a series of adrenocortical tumors by immunohistochemistry. Cell viability of ACC cell lines H295R and SW13 were determined by MTT assay after treatment with the combination of EGFR inhibitor Erlotinib and IGF1R inhibitor NVP-AEW541. Apoptosis was assessed by flow cytometry. The mechanism within intracellular signaling pathways was analyzed by Western blot. Mice bearing human ACC xenografts were treated with Erlotinib and NVP-AEW541, and the effects on tumour growth were assessed. Results Our results show a significant over-expression of EGFR (66.67%) and IGF1R (80.0%) in ACC. Besides, the co-overexpression of EGFR and IGF1R was seen in 8/15 ACCs, as compared with ACAs (P<0.05). Erlotinib and NVP-AEW541 significantly inhibited cell viability and induced apoptosis by blocking phosphorylation of MEK/ERK and AKT, respectively. Meanwhile, we found that single inhibition of IGF1R induced compensatory activation of MEK/ERK, leading to sustained activation of mTOR, which represent as aggregation of EGFR and IGF1R downstream components. More importantly, the combination of Erlotinib and NVP-AEW541 enhances anti-tumour efficacy compared to treatment with either agent alone or to untreated control in vitro and vivo. Conclusions In conclusion, coinhibition therapy targeting EGFR and IGF1R may be considerable for treatment of ACC in the future. PMID:27105537

  2. Adrenocortical response to low-dose ACTH test in female patients with rheumatoid arthritis.

    PubMed

    Radikova, Zofia; Rovensky, Jozef; Vlcek, Miroslav; Penesova, Adela; Kerlik, Jana; Vigas, Milan; Imrich, Richard

    2008-12-01

    Alterations in adrenal steroid production have been suggested in females with rheumatoid arthritis (RA). The aim of the present study was to assess adrenocortical function in RA females. We examined 11 female RA patients (RA: age 30 +/- 2 years, BMI 21.0 +/- 0.7 kg/m(2)) and 10 matched healthy controls (C: age 31 +/- 1 years, BMI 21.6 +/- 0.6 kg/m(2)). Low-dose adrenocorticotropic hormone (ACTH) test (i.v. bolus of 1 microg synthetic ACTH) was performed at 10.00 h with blood sampling every 15 min for 90 min. Cortisol, 17-OH-progesterone (17OHP), androstenedione (ASD), and dehydroepiandrosterone (DHEA) were assayed in plasma. Baseline cortisol levels were higher in RA patients (RA: 385 +/- 38 versus C: 229 +/- 28 nmol/L, P= 0.007). In both study groups, ACTH administration increased all the four steroids measured (P < 0.001). Cortisol response to ACTH administration was diminished in RA patients when compared to controls (Delta(max): 284 +/- 24 in RA versus 424 +/- 31 nmol/L in C, P= 0.002). ACTH-induced maximal rise in plasma DHEA was significantly lower in RA patients when compared to controls (Delta(max): 2.59 +/- 0.68 in RA versus 5.57 +/- 1.25 ng/mL in C, P= 0.015). No significant between-groups differences were found in responses of ASD or 17OHP. The molar ratio of ASD:cortisol was significantly lower (P < 0.05) in RA patients at base line, but did not differ during ACTH test. After ACTH bolus, the cortisol:17OHP ratio decreased significantly in the RA group (P < 0.001), whereas there was no change in the control group. The present results show decreased secretion of cortisol and DHEA in RA patients in response to ACTH, suggesting a subtle HPA hypofunction at the adrenocortical level.

  3. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells.

    PubMed

    Pan, Zhi-qiang; Xie, Ding; Choudhary, Vivek; Seremwe, Mutsa; Tsai, Ying-Ying; Olala, Lawrence; Chen, Xunsheng; Bollag, Wendy B

    2014-08-25

    Pioglitazone belongs to the class of drugs called thiazolidinediones (TZDs), which are widely used as insulin sensitizers in the treatment of diabetes. A major side effect of TZDs is fluid retention. The steroid hormone aldosterone also promotes sodium and fluid retention; however, the effect of pioglitazone on aldosterone production is controversial. We analyzed the effect of pioglitazone alone and in combination with angiotensin II (AngII) on the late rate-limiting step of adrenocortical steroidogenesis in human adrenocortical carcinoma HAC15 cells. Treatment with pioglitazone for 24 h significantly increased the expression of CYP11B2 and enhanced AngII-induced CYP11B2 expression. Despite the observed changes in mRNA levels, pioglitazone significantly inhibited AngII-induced aldosterone production and CYP11B2 protein levels. On the other hand, pioglitazone stimulated the expression of the unfolded protein response (UPR) marker DDIT3, with this effect occurring at early times and inhibitable by the PPARγ antagonist GW9962. The levels of DDIT3 (CHOP) and phospho-eIF2α (Ser51), a UPR-induced event that inhibits protein translation, were also increased. Thus, pioglitazone promotes CYP11B2 expression but nevertheless inhibits aldosterone production in AngII-treated HAC15 cells, likely by blocking global protein translation initiation through DDIT3 and phospho-eIF2α. In contrast, pioglitazone promoted AngII-induced CYP11B1 expression and cortisol production. Since cortisol enhances lipolysis, this result suggests the possibility that PPARs, activated by products of fatty acid oxidation, stimulate cortisol secretion to promote utilization of fatty acids during fasting. In turn, the ability of pioglitazone to stimulate cortisol production could potentially underlie the effects of this drug on fluid retention.

  4. Development regulation changes local elected leaders can make to promote energy conservation

    SciTech Connect

    Kron, Jr, N F

    1980-07-01

    This report lists actions that local officials can make to change their community's development regulations and thereby lessen the effects of local energy problems. The term development regulations, as used here, is a general reference to local or state controls over land use and development that affect design, orientation, placement, location, and related characteristics of buildings and infrastructure. The regulations include items such as zoning, subdivision controls, setbacks, yard and height requirements, and solar-access ordinances.

  5. ABCB1 (MDR1)-type P-glycoproteins at the blood-brain barrier modulate the activity of the hypothalamic-pituitary-adrenocortical system: implications for affective disorder.

    PubMed

    Müller, Marianne B; Keck, Martin E; Binder, Elisabeth B; Kresse, Adelheid E; Hagemeyer, Thomas P; Landgraf, Rainer; Holsboer, Florian; Uhr, Manfred

    2003-11-01

    Multidrug-resistance gene 1-type P-glycoproteins (ABCB1-type P-gps) protect the brain against the accumulation of many toxic xenobiotics and drugs. We recently could show that the access of the endogenous glucocorticoids corticosterone and cortisol to the brain are regulated by ABCB1-type P-gps in vivo. ABCB1-type P-gp function, therefore, is likely to exert a profound influence on the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Hyperactivity of the HPA system is frequently observed in human affective disorder, and a considerable amount of evidence has been accumulated suggesting that normalization of the HPA system might be the final step necessary for stable remission of the disease. To examine whether blood-brain barrier (BBB) function influences neuroendocrine regulation, we investigated HPA system activity in abcb1ab (-/-) mice under basal conditions and following stress. Abcb1ab (-/-) mice showed consistently lower plasma ACTH levels and lower evening plasma corticosterone levels. CRH mRNA expression in the hypothalamic paraventricular nucleus was decreased and pituitary POMC mRNA expressing cells were significantly reduced in number in abcb1ab (-/-) mutants; however, they showed a normal activation of the HPA system following CRH stimulation. Lower doses of dexamethasone were required to suppress plasma corticosterone levels in mutants. Our data thus provide evidence for a sustained suppression of the HPA system at the hypothalamic level in abcb1ab (-/-) mice, suggesting that BBB function significantly regulates HPA system activity. Whether naturally occurring polymorphisms in the human ABCB1 gene might result in persistent changes in the responsiveness and regulation of the HPA system will be the subject of future investigations, correlating both genetic information with individual characteristics of the neuroendocrine phenotype.

  6. Angiotensin II regulates growth of the developing papillas ex vivo

    PubMed Central

    Song, Renfang; Preston, Graeme; Khalili, Ali; El-Dahr, Samir S.

    2012-01-01

    We tested the hypothesis that lack of angiotensin (ANG) II production in angiotensinogen (AGT)-deficient mice or pharmacologic antagonism of ANG II AT1 receptor (AT1R) impairs growth of the developing papillas ex vivo, thus contributing to the hypoplastic renal medulla phenotype observed in AGT- or AT1R-null mice. Papillas were dissected from Hoxb7GFP+ or AGT+/+, +/−, −/− mouse metanephroi on postnatal day P3 and grown in three-dimentional collagen matrix gels in the presence of media (control), ANG II (10−5 M), or the specific AT1R antagonist candesartan (10−6 M) for 24 h. Percent reduction in papillary length was attenuated in AGT+/+ and in AGT+/− compared with AGT−/− (−18.4 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, −22.8 ± 1.3 vs. −32.2 ± 1.6%, P < 0.05, respectively). ANG II blunted the decrease in papilla length observed in respective media-treated controls in Hoxb7GFP+ (−1.5 ± 0.3 vs. −10.0 ± 1.4%, P < 0.05) or AGT+/+, +/−, and −/− papillas (−12.8 ± 0.7 vs. −18.4 ± 1.3%, P < 0.05, −16.8 ± 1.1 vs. −23 ± 1.2%, P < 0.05; −26.2 ± 1.6 vs. −32.2 ± 1.6%, P < 0.05, respectively). In contrast, percent decrease in the length of Hoxb7GFP+ papillas in the presence of the AT1R antagonist candesartan was higher compared with control (−24.3 ± 2.1 vs. −10.5 ± 1.8%, P < 0.05). The number of proliferating phospho-histone H3 (pH3)-positive collecting duct cells was lower, whereas the number of caspase 3-positive cells undergoing apoptosis was higher in candesartan- vs. media-treated papillas (pH3: 12 ± 1.4 vs. 21 ± 2.1, P < 0.01; caspase 3: 3.8 ± 0.5 vs. 1.7 ± 0.2, P < 0.01). Using quantitative RT-PCR, we demonstrate that AT1R signaling regulates the expression of genes implicated in morphogenesis of the renal medulla. We conclude that AT1R prevents shrinkage of the developing papillas observed ex vivo via control of Wnt7b, FGF7, β-catenin, calcineurin B1, and α3 integrin gene expression, collecting duct cell

  7. Developing Self-Regulation Skills: The Important Role of Homework

    ERIC Educational Resources Information Center

    Ramdass, Darshanand; Zimmerman, Barry J.

    2011-01-01

    The article evaluates the relationship between homework and self-regulation from the elementary grades to college. It reveals that quality measures of homework such as managing distractions, self-efficacy and perceived responsibility for learning, setting goals, self-refection, managing time, and setting a place for homework completion are more…

  8. Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy.

    PubMed

    Nagasaki, Keisuke; Horikawa, Reiko; Nagaishi, Jun-Ichi; Honna, Toshiro; Sekiguchi, Akihiko; Tsunematsu, Yukiko; Tanaka, Toshiaki

    2004-01-01

    We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation. Development of facial acne and pubic hair were noted at 3 yr and 2 mo. The levels of androgens were high. Diurnal variation in ACTH and cortisol were absent. Abdominal computed tomography revealed a large right suprarenal mass, with extension into the inferior vena cava and right atrium. Based on the diagnosis of a right virilizing adrenocortical tumor with Cushing syndrome, surgery was performed by a combined thoracoabdominal approach with the patient on cardiopulmonary bypass. The tumor was 7 × 5.5 × 3.5 cm in size, and weighed 95 g. The histological diagnosis was adrenocartical carcinoma with high-grade malignancy according to the category of Weiss. A heterozygous mutation of the p53 tumor-suppressor gene (codon 248 CGC→TGG) was found. We did not perform adjuvant chemotherapy because of radical resection on macroscopic observation and no metastasis in radiological findings. Five months after the surgery, her chest X ray and computed tomography revealed multiple lung metastases and a single liver metastasis. In this type of patient with histological high-grade malignancy and p53 mutations, postoperative adjuvant chemotherapy is indicated even if macroscopic total surgical removal had been performed.

  9. Current Development in Isoprenoid Precursor Biosynthesis and Regulation

    PubMed Central

    Chang, Wei-chen; Song, Heng; Liu, Hung-wen; Liu, Pinghua

    2013-01-01

    Isoprenoids are one of the largest classes of natural products and all of them are constructed from two precursors, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). For decades, the mevalonic acid (MVA) pathway was proposed to be the only IPP and DMAPP biosynthetic pathway. This review summarizes the newly discovered IPP and DMAPP production pathways since late 1990s, their distribution among different kingdoms, and their roles in secondary metabolite production. These new IPP and DMAPP production pathways include the methylerythritol phosphate (MEP) pathway, a modified MVA pathway, and the 5-Methylthioadenosine shunt pathway. Relative to the studies on the MVA pathway, information on the MEP pathway regulation is limited and the mechanistic details of several of its novel transformations remain to be addressed. Current status on both MEP pathway regulation and mechanistic issues are also presented. PMID:23891475

  10. TGF-β in tolerance, development and regulation of immunity

    PubMed Central

    Johnston, Chris J.C.; Smyth, Danielle J.; Dresser, David W.; Maizels, Rick M.

    2016-01-01

    The TGF-β superfamily is an ancient metazoan protein class which cuts across cell and tissue differentiation, developmental biology and immunology. Its many members are regulated at multiple levels from intricate control of gene transcription, post-translational processing and activation, and signaling through overlapping receptor structures and downstream intracellular messengers. We have been interested in TGF-β homologues firstly as key players in the induction of immunological tolerance, the topic so closely associated with Ray Owen. Secondly, our interests in how parasites may manipulate the immune system of their host has also brought us to study the TGF-β pathway in infections with longlived, essentially tolerogenic, helminth parasites. Finally, within the spectrum of mammalian TGF-β proteins is an exquisitely tightly-regulated gene, anti-Müllerian hormone (AMH), whose role in sex determination underpins the phenotype of freemartin calves that formed the focus of Ray’s seminal work on immunological tolerance. PMID:26617281

  11. Differential effects of transforming growth factor type beta on the growth and function of adrenocortical cells in vitro.

    PubMed Central

    Hotta, M; Baird, A

    1986-01-01

    Transforming growth factor type beta (TGF-beta) suppresses basal as well as corticotropin (ACTH)-stimulated steroid formation by bovine adrenocortical cells in culture. The effect is dose dependent and is not accompanied by any change in adrenocortical cell growth. The minimum effective dose of TGF-beta is 4 X 10(-13) M (10 pg/ml), and maximal inhibition is observed at a concentration of 4 X 10(-11) M (1 ng/ml). A 16- to 20-hr incubation with TGF-beta is required to decrease steroidogenesis, and 12-18 hr are required before cells treated with TGF-beta recover complete responsiveness to corticotropin. Increases in cAMP mediated by corticotropin, forskolin, and isobutylmethylxanthine are not modified by the addition of TGF-beta; thus adenylate cyclase activity is unaffected by TGF-beta. Although TGF-beta inhibits the formation of all of the delta 4-steroids measured (including cortisol, corticosterone, aldosterone, and androstenedione), its effect can be completely reversed by the addition of 25-hydroxycholesterol, pregnenolone, or progesterone to the cells. In contrast, the addition of low density lipoprotein has no effect suggesting that TGF-beta targets the conversion of cholesterol precursors to cholesterol. The results demonstrate a highly potent effect of TGF-beta on the differentiated function of the adrenocortical cell. The inhibition of steroidogenesis can be dissociated from any effect on cell proliferation, and it occurs distal to the formation of cAMP but proximal to the formation of cholesterol. The results suggest that in the adrenal, TGF-beta or TGF-beta-like proteins may be playing an important role in modifying the differentiated state of the adrenocortical cell. PMID:3020557

  12. Habituation of hypothalamic-pituitary-adrenocortical axis hormones to repeated homotypic stress and subsequent heterotypic stressor exposure in male and female rats.

    PubMed

    Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge

    2014-05-01

    Understanding potential sex differences in repeated stress-induced hypothalamic-pituitary-adrenocortical (HPA) axis habituation could provide insight into the sex-biased prevalence of certain affective disorders such as anxiety and depression. Therefore in these studies, male and female rats were exposed to 30 min of either audiogenic or restraint stress daily for 10 days in order to determine whether sex regulates the extent to which HPA axis hormone release is attenuated upon repeated homotypic stressor presentation. In response to the initial exposure, both stressors robustly increased plasma concentrations of both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in both sexes. Acutely, females displayed higher ACTH and CORT concentrations following restraint stress, whereas males exhibited higher hormone concentrations following loud noise stress. HPA axis hormone responses to both stressors decreased incrementally over successive days of exposure to each respective stressor. Despite the differential effect of sex on acute hormone responses, the extent to which HPA axis hormone response was attenuated did not differ between male and female animals following either stressor. Furthermore, ACTH and CORT responses to a novel environment were not affected by prior exposure to stress of either modality in either male or female rats. These experiments demonstrate that despite the acute stress response, male and female rats exhibit similar habituation of HPA axis hormones upon repeated homotypic stressor presentations, and that exposure to repeated stress does not produce exaggerated HPA axis hormone responses to a novel environment in either female or male rats.

  13. The adrenocortical response of greater sage grouse (Centrocercus urophasianus) to capture, ACTH injection, and confinement, as measured in fecal samples

    USGS Publications Warehouse

    Jankowski, M.D.; Wittwer, D.J.; Heisey, D.M.; Franson, J. Christian; Hofmeister, Erik K.

    2009-01-01

    Investigators of wildlife populations often utilize demographic indicators to understand the relationship between habitat characteristics and population viability. Assessments of corticosterone may enable earlier detection of populations at risk of decline because physiological adjustments to habitat disturbance occur before reproductive diminutions. Noninvasive methods to accomplish these assesments are important in species of concern, such as the greater sage grouse (GRSG). Therefore, we validated a radioimmunoassay that measures immunoreactive corticosterone metabolites (ICM) in fecal samples and used it to characterize the adrenocortical response of 15 GRSG exposed to capture, intravenous injection of 50 IU/kg adrenocorticotrophic hormone (ACTH) or saline, and 22 h of confinement. Those animals injected with ACTH exhibited a more sustained (P = 0.0139) and less variable (P = 0.0012) response than those injected with saline, indicating different levels of adrenocortical activity. We also found that potential field-collection protocols of fecal samples did not alter ICM concentrations: samples held at 4??C for up to 16 h contained similar levels of ICM as those frozen (-20??C) immediately. This study demonstrates a multiphasic adrenocortical response that varied with the level of stimulation and indicates that the assay used to measure this phenomenon is applicable for studies of wild GRSG. ?? 2009 by The University of Chicago. All rights reserved.

  14. Tissue mercury concentrations and adrenocortical responses of female big brown bats (Eptesicus fuscus) near a contaminated river.

    PubMed

    Wada, Haruka; Yates, David E; Evers, David C; Taylor, Robert J; Hopkins, William A

    2010-10-01

    Much of the research on mercury (Hg) in wild vertebrates has focused on piscivores and other animals at high trophic levels. However, recent studies indicated that insectivorous terrestrial vertebrates may also be at risk. In the present study, we examined blood and fur Hg concentrations as well as the adrenocortical responses of insectivorous big brown bats (Eptesicus fuscus) near the Hg-contaminated South River, VA and a nearby reference area. Baseline glucocorticoids and adrenocortical responses to handling have been widely used to assess the influence of environmental stressors because plasma glucocorticoids rise in response to various physical, psychological, and physiological challenges. Female bats captured at the contaminated site had 2.6 times higher blood and fur Hg concentrations than those captured at the reference site (blood: 0.11 vs. 0.04 μg/g wet weight; fur: 28.0 vs. 10.9 μg/g fresh weight). Fur Hg concentrations at the contaminated site were higher than most wild omnivorous and carnivorous mammals reported in the literature. Although fur and blood Hg concentrations were tightly correlated, fur Hg concentrations averaged 260 times higher than concentrations in blood. This suggests that fur may be an important depuration route for bats, just as it is in other mammals. Despite the high Hg concentrations in bat tissue, we did not observe any site difference in adrenocortical responses. Our results suggest that the bats at the contaminated site were exposed to Hg concentrations below those causing adverse effects on their adrenal axis.

  15. Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

    SciTech Connect

    Cerquetti, Lidia; Sampaoli, Camilla; Amendola, Donatella; Bucci, Barbara; Masuelli, Laura; Marchese, Rodolfo; Misiti, Silvia; De Venanzi, Agostino; Poggi, Maurizio; Toscano, Vincenzo; Stigliano, Antonio

    2011-06-10

    Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

  16. Adrenocortical nuclear progesterone-binding protein: Identification by photoaffinity labeling and evidence for deoxyribonucleic acid binding and stimulation by adrenocorticotropin

    SciTech Connect

    Demura, T.; Driscoll, W.J.; Lee, Y.C.; Strott, C.A. )

    1991-01-01

    Nuclei of the guinea pig adrenal cortex contain a protein that specifically binds progesterone and that, biochemically, is clearly distinct from the classical progesterone receptor. The adrenocortical nuclear progesterone-binding protein has now been purified more than 2000-fold by steroid-affinity chromatography with a 75% yield. The purified protein preparation demonstrated three major bands on sodium dodecyl sulfate-polyacrylamide gel of 79K, 74K, and 50K. To determine which of the three might represent the progesterone-binding protein, steroid photoaffinity labeling was performed which resulted in the specific and exclusive labeling of a 50K band. Thus, the adrenocortical nuclear progesterone-binding protein appears to be distinct from the classical progesterone receptor not only biochemically, but also on the basis of molecular size. To test whether the adrenocortical nuclear progesterone-binding protein can be hormonally stimulated, guinea pigs were treated with ACTH. The chronic administration of ACTH caused a 4- to 6-fold increase in the specific progesterone binding capacity without a change in the binding affinity. There appeared to be no significant difference in nuclear progesterone binding between the zona fasciculata and zona reticularis. This finding suggests a mediating role for the progesterone-binding protein in ACTH action. In addition, the nuclear progesterone-binding protein bound to nonspecific DNA sequences, further suggesting a possible transcriptional regulatory role.

  17. Individual Development and Evolution: Experiential Canalization of Self-Regulation

    ERIC Educational Resources Information Center

    Blair, Clancy; Raver, C. Cybele

    2012-01-01

    In this article, we contrast evolutionary and psychobiological models of individual development to address the idea that individual development occurring in prototypically risky and unsupportive environments can be understood as adaptation. We question traditional evolutionary explanations of individual development, calling on the principle of…

  18. Moving Ahead in the Study of the Development of Emotion Regulation

    ERIC Educational Resources Information Center

    Cole, Pamela M.

    2014-01-01

    This special section on the development of emotion regulation highlights several important new directions for research. Specifically, the findings of these studies indicate that: (1) emotion regulation develops across the lifespan and not just in early childhood and does so in complex ways, (2) it is necessary to distinguish among emotions to…

  19. Observations of a Working Class Family: Implications for Self-Regulated Learning Development

    ERIC Educational Resources Information Center

    Vassallo, Stephen

    2012-01-01

    Guardians have been implicated in the development of children's academic self-regulation. In this case study, which involved naturalistic observations and interviews, the everyday practices of a working class family were considered in the context of self-regulated learning development. The family's practices, beliefs, dispositions and home…

  20. Dynamic regulation of Polycomb group activity during plant development.

    PubMed

    Bemer, Marian; Grossniklaus, Ueli

    2012-11-01

    Polycomb group (PcG) complexes play important roles in phase transitions and cell fate determination in plants and animals, by epigenetically repressing sets of genes that promote either proliferation or differentiation. The continuous differentiation of new organs in plants, such as leaves or flowers, requires a highly dynamic PcG function, which can be induced, modulated, or repressed when necessary. In this review, we discuss the recent advance in understanding PcG function in plants and focus on the diverse molecular mechanisms that have been described to regulate and counteract PcG activity in Arabidopsis.

  1. Use Your Words: The Role of Language in the Development of Toddlers' Self-Regulation.

    PubMed

    Vallotton, Claire; Ayoub, Catherine

    2011-01-01

    Self-regulation emerges throughout early childhood, and predicts later success in socially and cognitively challenging situations. Vygotsky proposed that symbols, particularly words, serve as mental tools to be used in service of self-regulation. Cross-sectional research indicates a positive but inconsistent association between language and self-regulation skills throughout toddlerhood, but research has not accounted for general cognitive development, nor gender differences in these domains. We used growth modeling of longitudinal data for 120 toddlers collected when children were 14, 24, and 36 months to test the impact of two expressive language skills - spoken vocabulary and talkativeness - on the growth of toddlers' self-regulation, and to determine whether associations between these domains exist when controlling for cognitive development. Results reveal gender differences in self-regulation trajectories, and in the impact of language on self-regulation. Vocabulary is a better predictor of self-regulation than talkativeness, and both concurrent and prior vocabulary positively predicted children's levels of self-regulation. When cognitive development was controlled, 24-month vocabulary still predicted the trajectory of self-regulation. Results reveal that, even in early development, words are tools that can be applied to the task of self-regulation, and may be a more necessary tool for boys than for girls at this age.

  2. Collaboration and Self-Regulation in Teachers' Professional Development

    ERIC Educational Resources Information Center

    Butler, Deborah L.; Lauscher, Helen Novak; Jarvis-Selinger, Sandra; Beckingham, Beverly

    2004-01-01

    This paper describes a professional development model with promise for supporting meaningful shifts in practice. We begin by introducing the theoretical principles underlying our professional development model, with a focus on explicating the interface between collaborative inquiry in a learning community (Lave, 1991, In L.B. Resnick, J.M. Levine,…

  3. Combined Use of Etomidate and Dexmedetomidine Produces an Additive Effect in Inhibiting the Secretion of Human Adrenocortical Hormones.

    PubMed

    Gu, Hongbin; Zhang, Mazhong; Cai, Meihua; Liu, Jinfen

    2015-11-16

    BACKGROUND The direct effects of etomidate were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of human of animals. Dexmedetomidine (DEX) is an anesthetic agent that may interfere with cortisol secretion via an unknown mechanism, such as involving inhibition of 11b-hydroxylase and the cholesterol side-chain cleavage enzyme system. The aim of this study was to determine whether dexmedetomidine (DEX) has a similar inhibitory effect on adrenocortical function, and whether combined use of etomidate (ETO) and DEX could produce a synergistic action in inhibiting the secretion of human adrenocortical hormones. MATERIAL AND METHODS Human adrenocortical cells were exposed to different concentrations of ETO and DEX. The dose-effect model between the ETO concentration and the mean secretion of cortisone (CORT) and aldosterone (ALDO) per hour was estimated. RESULTS Hill's equation well-described the dose-effect correlation between the ETO concentration and the amount of ALDO and CORT secretion. When the DEX concentration was introduced into the model by using E0 (basal secretion) as the covariate, the goodness of fit of the ETO-CORT dose-effect model was improved significantly and the objective function value was reduced by 4.55 points (P<0.05). The parameters of the final ETO-ALDO pharmacodynamics model were EC50=9.74, Emax=1.20, E0=1.33, and γ=18.5; the parameters of the final ETO-CORT pharmacodynamics model were EC50=9.49, Emax=8.16, E0=8.57, and γ=37.0. In the presence of DEX, E0 was 8.57-0.0247×(CDEX-4.6), and the other parameters remained unchanged. All parameters but γ were natural logarithm conversion values. CONCLUSIONS Combined use of DEX and ETO reduced ETO's inhibitory E0 (basal secretion) of CORT from human adrenocortical cells in a dose-dependent manner, suggesting that combined use of ETO and DEX produced an additive effect in inhibiting the secretion of human adrenocortical hormones.

  4. [Modulation of transcriptional regulation during bone and cartilage development and their disease].

    PubMed

    Nishimura, Riko; Hata, Kenji; Takashima, Rikako; Yoshida, Michiko; Nakamura, Eriko; Kida, Junpei; Yagi, Hiroko

    2013-11-01

    Genetic and biochemical studies have identified transcription factors critical and specific for bone and cartilage development. More recent studies revealed the molecular mechanisms how these transcription factors regulate bone and cartilage development. Especially, we appreciate recent advances in molecular function of the complex assembled by these transcription factors and epigenetic regulation of them. Aging, inflammation, biological stress, and disorder of endocrine system induce several bone and/or cartilage diseases by affecting the transcriptional and epigenetic regulation. In this review, we would like to describe the transcriptional and epigenetic regulation during developmental and pathological stages. In addition, we discuss possible application of these information in regeneration of bone and cartilage.

  5. [A contribution to the development of advertising in pharmacy II. Historical development of regulation of advertising of medicinal products].

    PubMed

    Vranová, Vilma

    2012-10-01

    The article deals with the development of regulation of advertising of medicinal products in the Czech Lands of the Habsburg Monarchy and Czechoslovakia in the years 1775-1938. Advertising medicines had and has its specifics and its regulation had been addressed by specific standards and linked to other health laws and regulations. Regulation of advertising of medicinal products has undergone a long process from the initial total ban on advertising to the establishment of clear rules, some of which, such as restrictions on advertising prescription-only medicines only to the professional healthcare press, are still valid.

  6. REGULATION OF THE THYROID AXIS IN DEVELOPING XENOPUS LAEVIS

    EPA Science Inventory

    The focus of the research presented here is the development of an in vitro pituitary gland culture system to test the effect of chemicals directly on the gland without influence of other parts of the HPT axis.

  7. Identification of Genes Regulating the Development of Breast Cancer

    DTIC Science & Technology

    2008-04-01

    Tumor Development Hua Wang, Douglas Teske , Alyssa Tess, Rebecca Kohlhepp, YounJeong Choi, Christina Kendziorski, and Amy Rapaich Moser Cancer Res...Tumor Development Hua Wang, 1,3 Douglas Teske , 1 Alyssa Tess, 1 Rebecca Kohlhepp, 1 YounJeong Choi, 2 Christina Kendziorski, 2 and Amy Rapaich Moser 1... Teske ), and palpable tumors were recorded when first noted and then confirmed at necropsy. The total tumor number was determined at necropsy by noting

  8. Youth development program participation and intentional self-regulation skills: contextual and individual bases of pathways to positive youth development.

    PubMed

    Mueller, Megan Kiely; Phelps, Erin; Bowers, Edmond P; Agans, Jennifer P; Urban, Jennifer Brown; Lerner, Richard M

    2011-12-01

    The present research used data from Grades 8, 9, and 10 of the 4-H Study of Positive Youth Development, a longitudinal study involving U.S. adolescents, in order to better elucidate the process through which the strengths of youth and the ecological resources promoting healthy development (such as out-of-school-time programs) may contribute to thriving. We examined the relationship between adolescents' self-regulation skills (selection, optimization, and compensation) and their participation in youth development (YD) programs across Grades 8 and 9 in predicting Grade 10 PYD and Contribution. Results indicated that while self-regulation skills alone predicted PYD, self regulation and YD program participation both predicted Contribution. In addition, Grade 8 YD participation positively predicted Grade 9 self regulation, which, in turn, predicted Grade 10 PYD and Contribution. We discuss how the alignment of youth strengths and resources within the environment may promote positive youth development.

  9. Development and regulation of placental androstenedione during rat pregnancy

    SciTech Connect

    Jackson, J.A.

    1986-01-01

    The present study determined the ability of the rat placenta to convert (/sup 3/H) pregnenolone (P/sub 5/) substrate to (/sup 3/H)..delta../sup 4/A and (/sup 3/H)T and to the intermediate steroid (/sup 3/H)P/sub 4/ in vitro on days 12 to 18 of gestation. Placental androgen formation increased and the amount of P/sub 4/ formed and not further metabolized to ..delta../sup 4/A decreased during gestation, with the formation of ..delta../sup 4/A 2- to 4-fold greater (p<0.01) than the formation of T. Moreover, the ovarian conversion of (/sup 3/H)..delta../sup 4/A to (/sup 3/H)E/sub 2/ was 2- to 4-fold greater (p<0.05) than the conversion from (/sup 3/H)T. To determine if the ovary, specifically estrogen, regulates placental ..delta../sup 4/A production, rats were ovariectomized (OVX) on day 9 of gestation and given a Silastic capsule containing either E/sub 2/ or vehicle. On day 14 OVX animals had an increased (p <0.01) ability to form placental ..delta../sup 4/A and decreased (p <0.05) ability to form P/sub 4/. The formation of placental ..delta../sup 4/A invitro was correlated with elevated peripheral serum ..delta../sup 4/A concentrations in OVX animals, an effect which was reversed by E/sub 2/.

  10. Development of a drinking water regulation for perchlorate in California.

    PubMed

    Tikkanen, Maria W

    2006-05-10

    Perchlorate is an environmental contaminant often associated with military installations and rocket propellant manufacture and testing facilities across the U.S. Highly water soluble, perchlorate has been found by federal and state agencies at almost 400 sites within the U.S. in groundwater, surface water, soil or public drinking water. There is no federal drinking water standard for perchlorate, but it is on the drinking water Contaminant Candidate List, and falls under the Unregulated Contaminant Monitoring Rule (UCMR) for which monitoring is required. The recent National Academy of Science (NAS) report on the potential health effects of perchlorate recommended a perchlorate reference dose of 0.0007 mg/kg of body weight which would be equivalent to a drinking water concentration of 24.5 microg/L. In California, approximately 395 wells in 96 water systems have been shown to contain perchlorate, and about 90% of these are located in Southern California. Water taken from the Colorado River, a major surface water supply to Southern California, has had reported detections of perchlorate ranging from non-detect to 9 microg/L. California has established a Public Health Goal (PHG) of 6 microg/L for perchlorate, and a proposed drinking water regulation is imminent. This review details the regulatory process involved with particular attention given to the occurrence of perchlorate in California drinking water sources and analytical methodology utilized.

  11. Building better drugs: developing and regulating engineered therapeutic proteins.

    PubMed

    Kimchi-Sarfaty, Chava; Schiller, Tal; Hamasaki-Katagiri, Nobuko; Khan, Mansoor A; Yanover, Chen; Sauna, Zuben E

    2013-10-01

    Most native proteins do not make optimal drugs and thus a second- and third-generation of therapeutic proteins, which have been engineered to improve product attributes or to enhance process characteristics, are rapidly becoming the norm. There has been unprecedented progress, during the past decade, in the development of platform technologies that further these ends. Although the advantages of engineered therapeutic proteins are considerable, the alterations can affect the safety and efficacy of the drugs. We discuss both the key technological innovations with respect to engineered therapeutic proteins and advancements in the underlying basic science. The latter would permit the design of science-based criteria for the prediction and assessment of potential risks and the development of appropriate risk management plans. This in turn holds promise for more predictable criteria for the licensure of a class of products that are extremely challenging to develop but represent an increasingly important component of modern medical practice.

  12. Microglia development follows a stepwise program to regulate brain homeostasis.

    PubMed

    Matcovitch-Natan, Orit; Winter, Deborah R; Giladi, Amir; Vargas Aguilar, Stephanie; Spinrad, Amit; Sarrazin, Sandrine; Ben-Yehuda, Hila; David, Eyal; Zelada González, Fabiola; Perrin, Pierre; Keren-Shaul, Hadas; Gury, Meital; Lara-Astaiso, David; Thaiss, Christoph A; Cohen, Merav; Bahar Halpern, Keren; Baruch, Kuti; Deczkowska, Aleksandra; Lorenzo-Vivas, Erika; Itzkovitz, Shalev; Elinav, Eran; Sieweke, Michael H; Schwartz, Michal; Amit, Ido

    2016-08-19

    Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

  13. Moral behavior and the development of verbal regulation

    PubMed Central

    Hayes, Steven C.; Gifford, Elizabeth V.; Hayes, Gregory J.

    1998-01-01

    The present paper examines the relationship between the development of moral behavior and the development of verbal regulatory processes. Relational frame theory and the distinctions among pliance, tracking, and augmenting forms of rule governance are applied to the domain of moral behavior and its development, in order to identify the specific social and verbal contingencies that are responsible for an evolving moral repertoire. It is argued that moral behavior is controlled by relational and rule-following repertoires, and that these can be arranged into a rough progression: pliance, tracking, augmenting, social concern for pliance, social concern for tracking, and social concern for augmenting. Congruence with data derived from other research traditions is examined, and applied implications are explored. PMID:22478311

  14. Regulation of podocyte structure during the development of nephrotic syndrome.

    PubMed

    Smoyer, W E; Mundel, P

    1998-03-01

    Nephrotic syndrome is a common kidney disease seen in both children and adults. The clinical syndrome includes massive proteinuria, hypoalbuminemia, edema, and usually hypercholesterolemia. Development of these clinical changes is closely correlated with profound structural changes in glomerular epithelial cells, or podocytes, which together with the glomerular basement membrane and endothelium comprise the kidney's blood filtration barrier. Although relatively little is known about the cellular or molecular changes which occur within podocytes during the development of nephrotic syndrome, cytoskeletal proteins very likely play a central role in these changes since they are primarily responsible for the maintenance of cell structure in almost all cells. This review focuses on: (a) the structure and function of podocytes in both the normal state and during nephrotic syndrome and (b) the potential roles of several cytoskeleton-associated proteins identified in podocytes in the development of and/or recovery from the pathophysiological cytoskeletal changes which occur in podocytes during nephrotic syndrome.

  15. Abundant protein phosphorylation potentially regulates Arabidopsis anther development

    PubMed Central

    Ye, Juanying; Zhang, Zaibao; You, Chenjiang; Zhang, Xumin; Lu, Jianan; Ma, Hong

    2016-01-01

    As the male reproductive organ of flowering plants, the stamen consists of the anther and filament. Previous studies on stamen development mainly focused on single gene functions by genetic methods or gene expression changes using comparative transcriptomic approaches, especially in model plants such as Arabidopsis thaliana. However, studies on Arabidopsis anther protein expression and post-translational modifications are still lacking. Here we report proteomic and phosphoproteomic studies on developing Arabidopsis anthers at stages 4–7 and 8–12. We identified 3908 high-confidence phosphorylation sites corresponding to 1637 phosphoproteins. Among the 1637 phosphoproteins, 493 were newly identified, with 952 phosphorylation sites. Phosphopeptide enrichment prior to LC-MS analysis facilitated the identification of low-abundance proteins and regulatory proteins, thereby increasing the coverage of proteomic analysis, and facilitated the analysis of more regulatory proteins. Thirty-nine serine and six threonine phosphorylation motifs were uncovered from the anther phosphoproteome and further analysis supports that phosphorylation of casein kinase II, mitogen-activated protein kinases, and 14-3-3 proteins is a key regulatory mechanism in anther development. Phosphorylated residues were preferentially located in variable protein regions among family members, but they were they were conserved across angiosperms in general. Moreover, phosphorylation might reduce activity of reactive oxygen species scavenging enzymes and hamper brassinosteroid signaling in early anther development. Most of the novel phosphoproteins showed tissue-specific expression in the anther according to previous microarray data. This study provides a community resource with information on the abundance and phosphorylation status of thousands of proteins in developing anthers, contributing to understanding post-translational regulatory mechanisms during anther development. PMID:27531888

  16. Development of Hydrogels and Biomimetic Regulators as Tissue Engineering Scaffolds

    PubMed Central

    Shi, Junbin; Xing, Malcolm M. Q.; Zhong, Wen

    2012-01-01

    This paper reviews major research and development issues relating to hydrogels as scaffolds for tissue engineering, the article starts with a brief introduction of tissue engineering and hydrogels as extracellular matrix mimics, followed by a description of the various types of hydrogels and preparation methods, before a discussion of the physical and chemical properties that are important to their application. There follows a short comment on the trends of future research and development. Throughout the discussion there is an emphasis on the genetic understanding of bone tissue engineering application. PMID:24957963

  17. BACULOVIRUS REPLICATION ALTERS HORMONE-REGULATED HOST DEVELOPMENT.

    EPA Science Inventory

    The baculovirus Lymantria dispar nuclear polyhedrosis virus interferes with insect larval development by altering the host's hormonal system. The level of haemolymph ecdysteroids, the insect moulting hormone, was found to be higher in virus-infected larvae than in uninfected cont...

  18. Tbx1 regulates oral epithelial adhesion and palatal development

    PubMed Central

    Funato, Noriko; Nakamura, Masataka; Richardson, James A.; Srivastava, Deepak; Yanagisawa, Hiromi

    2012-01-01

    Cleft palate, the most frequent congenital craniofacial birth defect, is a multifactorial condition induced by the interaction of genetic and environmental factors. In addition to complete cleft palate, a large number of human cases involve soft palate cleft and submucosal cleft palate. However, the etiology of these forms of cleft palate has not been well understood. T-box transcriptional factor (Tbx) family of transcriptional factors has distinct roles in a wide range of embryonic differentiation or response pathways. Here, we show that genetic disruption of Tbx1, a major candidate gene for the human congenital disorder 22q11.2 deletion syndrome (Velo-cardio-facial/DiGeorge syndrome), led to abnormal epithelial adhesion between the palate and mandible in mouse, resulting in various forms of cleft palate similar to human conditions. We found that hyperproliferative epithelium failed to undergo complete differentiation in Tbx1-null mice (Tbx1−/−). Inactivation of Tbx1 specifically in the keratinocyte lineage (Tbx1KCKO) resulted in an incomplete cleft palate confined to the anterior region of the palate. Interestingly, Tbx1 overexpression resulted in decreased cell growth and promoted cell-cycle arrest in MCF7 epithelial cells. These findings suggest that Tbx1 regulates the balance between proliferation and differentiation of keratinocytes and is essential for palatal fusion and oral mucosal differentiation. The impaired adhesion separation of the oral epithelium together with compromised palatal mesenchymal growth is an underlying cause for various forms of cleft palate phenotypes in Tbx1−/− mice. Our present study reveals new pathogenesis of incomplete and submucous cleft palate during mammalian palatogenesis. PMID:22371266

  19. Use of 3-Dimensional Volumetric Modeling of Adrenal Gland Size in Patients with Primary Pigmented Nodular Adrenocortical Disease.

    PubMed

    Chrysostomou, P P; Lodish, M B; Turkbey, E B; Papadakis, G Z; Stratakis, C A

    2016-04-01

    Primary pigmented nodular adrenocortical disease (PPNAD) is a rare type of bilateral adrenal hyperplasia leading to hypercortisolemia. Adrenal nodularity is often appreciable with computed tomography (CT); however, accurate radiologic characterization of adrenal size in PPNAD has not been studied well. We used 3-dimensional (3D) volumetric analysis to characterize and compare adrenal size in PPNAD patients, with and without Cushing's syndrome (CS). Patients diagnosed with PPNAD and their family members with known mutations in PRKAR1A were screened. CT scans were used to create 3D models of each adrenal. Criteria for biochemical diagnosis of CS included loss of diurnal variation and/or elevated midnight cortisol levels, and paradoxical increase in urinary free cortisol and/or urinary 17-hydroxysteroids after dexamethasone administration. Forty-five patients with PPNAD (24 females, 27.8±17.6 years) and 8 controls (19±3 years) were evaluated. 3D volumetric modeling of adrenal glands was performed in all. Thirty-eight patients out of 45 (84.4%) had CS. Their mean adrenal volume was 8.1 cc±4.1, 7.2 cc±4.5 (p=0.643) for non-CS, and 8.0cc±1.6 for controls. Mean values were corrected for body surface area; 4.7 cc/kg/m(2)±2.2 for CS, and 3.9 cc/kg/m(2)±1.3 for non-CS (p=0.189). Adrenal volume and midnight cortisol in both groups was positively correlated, r=0.35, p=0.03. We conclude that adrenal volume measured by 3D CT in patients with PPNAD and CS was similar to those without CS, confirming empirical CT imaging-based observations. However, the association between adrenal volume and midnight cortisol levels may be used as a marker of who among patients with PPNAD may develop CS, something that routine CT cannot do.

  20. Pea3 expression is regulated by FGF signaling in developing retina

    PubMed Central

    McCabe, Kathryn Leigh; McGuire, Chris; Reh, Thomas A.

    2008-01-01

    FGF signaling has been implicated as an important regulator of retinal development. As a first step in characterizing potential downstream targets of FGF signaling in the retina, we have analyzed expression of Pea3, a member of the Pea3 class of Ets-domain transcription factors, in the developing eye. We find that Pea3 is expressed in the developing retina, and its transcription is regulated by FGF receptor activation. In addition, FGF signaling activates Cath5, a gene necessary for retinal ganglion cell differentiation. These results suggest that FGF signaling via MAPK up-regulates transcription factors that in turn control retinal ganglion cell differentiation. PMID:16273524

  1. The Development of Adolescent Self-Regulation: Reviewing the Role of Parent, Peer, Friend, and Romantic Relationships

    PubMed Central

    Farley, Julee P.; Kim-Spoon, Jungmeen

    2014-01-01

    Self-regulation plays an important role in adolescent development, predicting success in multiple domains including school and social relationships. While researchers have paid increasing attention to the influence of parents on the development of adolescent self-regulation, we know little about the influence of peers and friends and even less about the influence of romantic partners on adolescent development of self-regulation. Extant studies examined a unidirectional model of self-regulation development rather than a bidirectional model of self-regulation development. Given that relationships and self-regulation develop in tandem, a model of bidirectional development between relationship context and adolescent self-regulation may be relevant. This review summarizes extant literature and proposes that in order to understand how adolescent behavioral and emotional self-regulation develops in the context of social relationships one must consider that each relationship builds upon previous relationships and that self-regulation and relationship context develop bidirectionally. PMID:24793391

  2. The development of adolescent self-regulation: reviewing the role of parent, peer, friend, and romantic relationships.

    PubMed

    Farley, Julee P; Kim-Spoon, Jungmeen

    2014-06-01

    Self-regulation plays an important role in adolescent development, predicting success in multiple domains including school and social relationships. While researchers have paid increasing attention to the influence of parents on the development of adolescent self-regulation, we know little about the influence of peers and friends and even less about the influence of romantic partners on adolescent development of self-regulation. Extant studies examined a unidirectional model of self-regulation development rather than a bidirectional model of self-regulation development. Given that relationships and self-regulation develop in tandem, a model of bidirectional development between relationship context and adolescent self-regulation may be relevant. This review summarizes extant literature and proposes that in order to understand how adolescent behavioral and emotional self-regulation develops in the context of social relationships one must consider that each relationship builds upon previous relationships and that self-regulation and relationship context develop bidirectionally.

  3. The transcriptomic and evolutionary signature of social interactions regulating honey bee caste development.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The caste fate of developing female honey bee larvae is strictly socially regulated by adult nurse workers. As a result of this social regulation, nurse-expressed genes as well as larval-expressed genes may affect caste expression and evolution. We used a novel transcriptomic approach to identify ge...

  4. Developing Young Adolescents' Self-Regulation by Means of Formative Assessment: A Theoretical Perspective

    ERIC Educational Resources Information Center

    Meusen-Beekman, Kelly D.; Joosten-ten Brinke, Desirée; Boshuizen, Henny P. A.

    2015-01-01

    Fostering self-regulated learning (SRL) has become increasingly important at various educational levels. Most studies on SRL have been conducted in higher education. The present literature study aims toward understanding self-regulation processes of students in primary and secondary education. We explored the development of young students'…

  5. 76 FR 8221 - Small Business Size Regulations; 8(a) Business Development/Small Disadvantaged Business Status...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-11

    ... February 11, 2011 Part VII Small Business Administration 13 CFR Parts 121 and 124 Small Business Size Regulations; 8(a) Business Development/Small Disadvantaged Business Status Determinations; Final Rule #0;#0... BUSINESS ADMINISTRATION 13 CFR Parts 121 and 124 RIN 3245-AF53 Small Business Size Regulations;...

  6. 77 FR 28237 - Small Business Size Regulations; 8(a) Business Development/Small Disadvantaged Business Status...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-14

    ... / Monday, May 14, 2012 / Rules and Regulations#0;#0; ] SMALL BUSINESS ADMINISTRATION 13 CFR Part 124 RIN 3245-AF53 Small Business Size Regulations; 8(a) Business Development/Small Disadvantaged Business Status Determinations; Correction AGENCY: U.S. Small Business Administration. ACTION:...

  7. Arsenic drinking water regulations in developing countries with extensive exposure.

    PubMed

    Smith, Allan H; Smith, Meera M Hira

    2004-05-20

    The United States Public Health Service set an interim standard of 50 microg/l in 1942, but as early as 1962 the US Public Health Service had identified 10 microg/l as a goal which later became the World Health Organization Guideline for drinking water in 1992. Epidemiological studies have shown that about one in 10 people drinking water containing 500 microg/l of arsenic over many years may die from internal cancers attributable to arsenic, with lung cancer being the surprising main contributor. A prudent public health response is to reduce the permissible drinking water arsenic concentrations. However, the appropriate regulatory response in those developing countries with large populations with much higher concentrations of arsenic in drinking water, often exceeding 100 microg/l, is more complex. Malnutrition may increase risks from arsenic. There is mounting evidence that smoking and arsenic act synergistically in causing lung cancer, and smoking raises issues of public health priorities in developing countries that face massive mortality from this product. Also, setting stringent drinking water standards will impede short term solutions such as shallow dugwells. Developing countries with large populations exposed to arsenic in water might reasonably be advised to keep their arsenic drinking water standards at 50 microg/l.

  8. Euchromatin histone methyltransferase 1 regulates cortical neuronal network development

    PubMed Central

    Bart Martens, Marijn; Frega, Monica; Classen, Jessica; Epping, Lisa; Bijvank, Elske; Benevento, Marco; van Bokhoven, Hans; Tiesinga, Paul; Schubert, Dirk; Nadif Kasri, Nael

    2016-01-01

    Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome. PMID:27767173

  9. RNA binding proteins in the regulation of heart development.

    PubMed

    Blech-Hermoni, Yotam; Ladd, Andrea N

    2013-11-01

    In vivo, RNA molecules are constantly accompanied by RNA binding proteins (RBPs), which are intimately involved in every step of RNA biology, including transcription, editing, splicing, transport and localization, stability, and translation. RBPs therefore have opportunities to shape gene expression at multiple levels. This capacity is particularly important during development, when dynamic chemical and physical changes give rise to complex organs and tissues. This review discusses RBPs in the context of heart development. Since the targets and functions of most RBPs--in the heart and at large--are not fully understood, this review focuses on the expression and roles of RBPs that have been implicated in specific stages of heart development or developmental pathology. RBPs are involved in nearly every stage of cardiogenesis, including the formation, morphogenesis, and maturation of the heart. A fuller understanding of the roles and substrates of these proteins could ultimately provide attractive targets for the design of therapies for congenital heart defects, cardiovascular disease, or cardiac tissue repair.

  10. Upregulation of TLR2 and TLR4 in the human adrenocortical cells differentially modulates adrenal steroidogenesis.

    PubMed

    Kanczkowski, Waldemar; Tymoszuk, Piotr; Chavakis, Triantafyllos; Janitzky, Volker; Weirich, Torsten; Zacharowski, Kai; Ehrhart-Bornstein, Monika; Bornstein, Stefan R

    2011-04-10

    Rapid activation of adrenal steroid release plays a pivotal role in an organism's first line of defense during sepsis. Adrenal gland function is often suppressed in critically ill patients and negatively impacts the overall survival rate. Increasingly, experimental and clinical evidence suggests that Toll-like receptors (TLRs), components of the innate immune system, play a key role in the mediation of systemic responses to invading pathogens during sepsis. In the present study, we aimed to elucidate the effect of TLR2, TLR4 and CD14 upregulation on adrenocortical cell steroidogenesis. We found that TLR4 and CD14 but not TLR2 overexpression in NCI-H295R cells inhibited basal and acute cortisol and aldosterone production. This effect could be partially explained by reduced expression of enzymes involved in the synthesis of latter steroids--CYP11B1 and CYP11B2. Together, these data suggest that TLR upregulation in the steroid producing cells may be involved in the adrenal gland dysfunction during sepsis.

  11. [Primary pigmented nodular adrenocortical disease as cause of Cushing's syndrome associated with Carney complex].

    PubMed

    Dumić, Miroslav; Janjanin, Nevena; Uroić, Anita Spehar; Ille, Jasenka; Skegro, Mate; Kusec, Vesna; Marjanac, Igor; Matić, Toni; Jelasić, Drazen

    2006-01-01

    We report a 11-year-old girl and two 14-year-old boys with Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). In these patients, hypercortisolism is a consequence of autonomous cortisol secretion from adrenal glands and is ACTH-independent. Besides PPNAD, the girl had lentigines, spotty pigmentation on her bucal mucosa and lips and she also had schwannoma. One of the reported boys had prolactinoma. Considering this, those two patients fulfill the criteria for Carney complex which is a type of multiple endocrine neoplasia syndromes inherited in an autosomal dominant trait. The other boy had PPNAD but no other obvious signs of Carney complex were noticed. Family study didn't reveal any clinical or laboratory signs of Carney complex in our patients' first relatives. All of our patients underwent bilateral adrenalectomy (in one of the boys laparoscopic surgery was performed). Glucocorticoid and mineralocorticoid substitution has been started. Adrenal glands were macroscopically normal but pathohistological analysis confirmed the diagnosis of PPNAD.

  12. Minimally Invasive Resection of Adrenocortical Carcinoma: A Multi-Institutional Study of 201 Patients

    PubMed Central

    Lee, Christina W.; Salem, Ahmed I.; Schneider, David F.; Leverson, Glen E.; Tran, Thuy B.; Poultsides, George A.; Postlewait, Lauren M.; Maithel, Shishir K.; Wang, Tracy S.; Hatzaras, Ioannis; Shenoy, Rivfka; Phay, John E.; Shirley, Lawrence; Fields, Ryan C.; Jin, Linda X.; Pawlik, Timothy M.; Prescott, Jason D.; Sicklick, Jason K.; Gad, Shady; Yopp, Adam C.; Mansour, John C.; Duh, Quan-Yang; Seiser, Natalie; Solorzano, Carmen C.; Kiernan, Colleen M.; Votanopoulos, Konstantinos I.; Levine, Edward A.; Weber, Sharon M.

    2016-01-01

    Background and Objectives Minimally invasive surgery for adrenocortical carcinoma (ACC) is controversial. We sought to evaluate the perioperative and long-term outcomes following minimally invasive (MIS) and open resection (OA) of ACC in patients treated with curative intent surgery. Methods Retrospective data from patients who underwent adrenalectomy for primary ACC at 13 tertiary care cancer centers were analyzed, including demographics, clinicopathological, and operative outcomes. Outcomes following MIS were compared to OA. Results A total of 201 patients were evaluated including 47 MIS and 154 OA. There was no difference in utilization of MIS approach among institutions (p=0.24) or 30-day morbidity (29.3%, MIS versus 30.9%, OA, p=0.839). The only preoperatively determined predictor for MIS was smaller tumor size (p<0.001). There was no difference in rates of intraoperative tumor rupture (p=0.612) or R0 resection (p=0.953). Only EBL (p=0.038) and T stage (p=0.045) were independent prognostic indicators of overall survival after adjusting for significant factors. The surgical approach was not associated with overall or disease-free survival. Conclusion MIS adrenalectomy may be utilized for preoperatively determined ACC ≤ 10.0 cm, however OA should be utilized for adrenal masses with either preoperative or intraoperative evidence of local invasion or enlarged lymph nodes, regardless of size. PMID:27770290

  13. Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells

    PubMed Central

    Chen, T-Y; Syu, J-S; Lin, T-C; Cheng, H-l; Lu, F-l; Wang, C-Y

    2015-01-01

    The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT. PMID:26690546

  14. Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

    PubMed Central

    Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

    2016-01-01

    Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

  15. First case report of an adrenocortical carcinoma caused by a BRCA2 mutation

    PubMed Central

    El Ghorayeb, Nada; Grunenwald, Solange; Nolet, Serge; Primeau, Vanessa; Côté, Stéphanie; Maugard, Christine M.; Lacroix, André; Gaboury, Louis; Bourdeau, Isabelle

    2016-01-01

    Abstract Background: Adrenocortical carcinoma (ACC) may rarely be a component of inherited cancer syndromes such as Li-Fraumeni syndrome and Beckwith-Wiedemann syndrome. ACC caused by a BRCA2 mutation has never been reported. Methods: Nucleotide sequencing of BRCA2 in lymphocyte and tumoral DNA of a 50-year-old male who presented with an androgen-secreting ACC and a strong family history of breast, ovarian, and pancreatic cancers. Results: A germline BRCA2 2 bp heterozygous deletion at nucleotide 8765 (8765delAG) leading to a frameshift mutation (p.Glu2846GlyfsX23) was detected. Only the BRCA2 deleted allele was retained in the ACC tumoral DNA compared with the control DNA supporting a loss of heterozygosity in the tumor. Conclusion: This is the first reported case of a patient with ACC associated with a BRCA2 germline mutation. Loss of heterozygosity in ACC DNA suggests a causal link with the BRCA2 8765delAG mutation. PMID:27603373

  16. Metformin as a new anti-cancer drug in adrenocortical carcinoma

    PubMed Central

    Fucci, Rossella; Santi, Raffaella; Canu, Letizia; Nesi, Gabriella; Mannelli, Massimo; Luconi, Michaela

    2016-01-01

    Adrenocortical carcinoma (ACC) is a rare heterogeneous malignancy with poor prognosis. Since radical surgery is the only available treatment, more specific and effective drugs are urgently required. The anti-diabetic drug metformin has been associated with a decreased cancer prevalence and mortality in several solid tumors, prompting its possible use for ACC treatment. This paper evaluates the in vitro and in vivo anti-cancer effects of metformin using the ACC cell model H295R. Metformin treatment significantly reduces cell viability and proliferation in a dose- and time-dependent manner and associates with a significant inhibition of ERK1/2 and mTOR phosphorylation/activation, as well as with stimulation of AMPK activity. Metformin also triggers the apoptotic pathway, shown by the decreased expression of Bcl-2 and HSP27, HSP60 and HSP70, and enhanced membrane exposure of annexin V, resulting in activation of caspase-3 apoptotic effector. Metformin interferes with the proliferative autocrine loop of IGF2/IGF-1R, which supports adrenal cancer growth. Finally, in the ACC xenograft mouse model, obtained by subcutaneous injection of H295R cells, metformin intraperitoneal administration inhibits tumor growth, confirmed by the significant reduction of Ki67%. Our data suggest that metformin inhibits H295R cell growth both in vitro and in vivo. Further preclinical studies are necessary to validate the potential anti-cancer effect of metformin in patients affected by ACC. PMID:27391065

  17. Adrenocortical responses to offspring-directed threats in two open-nesting birds.

    PubMed

    Butler, Luke K; Bisson, Isabelle-Anne; Hayden, Timothy J; Wikelski, Martin; Romero, L Michael

    2009-07-01

    Dependent young are often easy targets for predators, so for many parent vertebrates, responding to offspring-directed threats is a fundamental part of reproduction. We tested the parental adrenocortical response of the endangered black-capped vireo (Vireo atricapilla) and the common white-eyed vireo (V. griseus) to acute and chronic threats to their offspring. Like many open-nesting birds, our study species experience high offspring mortality. Parents responded behaviorally to a predator decoy or human 1-2m from their nests, but, in contrast to similar studies of cavity-nesting birds, neither these acute threats nor chronic offspring-directed threats altered plasma corticosterone concentrations of parents. Although parents in this study showed no corticosterone response to offspring-directed threats, they always increased corticosterone concentrations in response to capture. To explain these results, we propose that parents perceive their risk of nest-associated death differently depending on nest type, with cavity-nesting adults perceiving greater risk to themselves than open-nesters that can readily detect and escape from offspring-directed threats. Our results agree with previous studies suggesting that the hypothalamic-pituitary-adrenal axis, a major physiological mechanism for coping with threats to survival, probably plays no role in coping with threats to offspring when risks to parents and offspring are not correlated. We extend that paradigm by demonstrating that nest style may influence how adults perceive the correlation between offspring-directed and self-directed threats.

  18. Two different P2Y receptors linked to steroidogenesis in bovine adrenocortical cells.

    PubMed

    Nishi, H

    1999-10-01

    Both extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) induced corticoid production (steroidogenesis) concentration-dependently in bovine adrenocortical cells (BA cells). Pertussis toxin (PTX, approx. 2 microg/ml) partially inhibited (approx. 55% inhibition) extracellular ATP (100 microM)-induced steroidogenesis in BA cells. However, PTX did not inhibit extracellular UTP (100 microM)-induced steroidogenesis. Both ATP- and UTP-induced steroidogeneses were significantly inhibited by suramin (50-200 microM). These effects were inhibited significantly by reactive blue-2 (more than 100 microM) and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (more than 100 microM). Both nucleotides (1-100 microM) induced inositol phosphates accumulation and intracellular Ca2+ mobilization, but PTX did not inhibit them. The RT-PCR procedure identified only P2Y2-receptor mRNA in BA cells. These results suggest that extracellular ATP induces steroidogenesis via a unique P2 receptor linked to PTX-sensitive guanine nucleotide-binding protein (G-protein), while extracellular UTP induces steroidogenesis via P2 receptor linked to PTX-insensitive G-protein. Thus, it was concluded that at least two different P2Y-like receptors linking to steroidogenesis exist in BA cells.

  19. Excitatory influence of the locus coeruleus in hypothalamic-pituitary-adrenocortical axis responses to stress.

    PubMed

    Ziegler, D R; Cass, W A; Herman, J P

    1999-05-01

    The locus coeruleus (LC) is a key brainstem region involved in arousal and is highly responsive to alerting/stressful stimuli, including those that activate the hypothalamic-pituitary-adrenocortical (HPA) axis. It is currently unclear whether the LC exerts any regulatory influence on the HPA axis and, consequently, on neuroendocrine responses to stress. The present studies were designed to test the hypothesis that the LC promotes HPA axis responses to acute and chronic stress. Adult male rats received bilateral (6-hydroxydopamine) lesions of the LC that produced severe cell loss in the LC and 80% depletion of noradrenaline in medial prefrontal cortex. Notably, lesions did not affect dopamine-beta-hydroxylase protein content in the parvocellular paraventricular nucleus (PVN), indicating a lack of collateral damage to other ascending noradrenergic pathways. LC lesions significantly reduced peak adrenocorticotropic hormone (ACTH) and corticosterone responses to 30 min acute restraint stress. However, LC lesions did not significantly attenuate neuroendocrine or other physiological responses to a 4-week chronic variable stress regimen. LC lesions did not substantially affect basal concentrations of plasma corticosterone or corticotropin-releasing hormone mRNA expression in the hypothalamic paraventricular nucleus following chronic stress. We conclude that the LC is a HPA-excitatory brain region, promoting neuroendocrine and physiological responses primarily to acute stress. However, a potential role for the LC in the induction of HPA axis hyperactivity following chronic stress can not be ruled out.

  20. Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies

    PubMed Central

    Ross, J S; Wang, K; Rand, J V; Gay, L; Presta, M J; Sheehan, C E; Ali, S M; Elvin, J A; Labrecque, E; Hiemstra, C; Buell, J; Otto, G A; Yelensky, R; Lipson, D; Morosini, D; Chmielecki, J; Miller, V A; Stephens, P J

    2014-01-01

    Aims Adrenocortical carcinoma (ACC) carries a poor prognosis and current systemic cytotoxic therapies result in only modest improvement in overall survival. In this retrospective study, we performed a comprehensive genomic profiling of 29 consecutive ACC samples to identify potential targets of therapy not currently searched for in routine clinical practice. Methods DNA from 29 ACC was sequenced to high, uniform coverage (Illumina HiSeq) and analysed for genomic alterations (GAs). Results At least one GA was found in 22 (76%) ACC (mean 2.6 alterations per ACC). The most frequent GAs were in TP53 (34%), NF1 (14%), CDKN2A (14%), MEN1 (14%), CTNNB1 (10%) and ATM (10%). APC, CCND2, CDK4, DAXX, DNMT3A, KDM5C, LRP1B, MSH2 and RB1 were each altered in two cases (7%) and EGFR, ERBB4, KRAS, MDM2, NRAS, PDGFRB, PIK3CA, PTEN and PTCH1 were each altered in a single case (3%). In 17 (59%) of ACC, at least one GA was associated with an available therapeutic or a mechanism-based clinical trial. Conclusions Next-generation sequencing can discover targets of therapy for relapsed and metastatic ACC and shows promise to improve outcomes for this aggressive form of cancer. PMID:25078331

  1. Social crowding stress diminishes the pituitary-adrenocortical and hypothalamic histamine response to adrenergic stimulation.

    PubMed

    Bugajski, J; Gadek-Michalska, A; Borycz, J

    1993-12-01

    Social stress of crowding almost totally reduced the rise in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic receptor agonist, after 3 and 7 day of crowding and substantially diminished that response after 14 and 21 days. Crowding stress totally abolished the increase in hypothalamic histamine induced by isoprenaline in control rats. Crowding also significantly diminished the increase in serum corticosterone evoked by clonidine, an alpha 2-adrenergic agonist, and abolished the clonidine-induced elevation in hypothalamic histamine levels. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, on corticosterone secretion was only moderately diminished in crowded rats. Neither phenylephrine nor crowding stress changed significantly the hypothalamic histamine levels. These results indicate that social stress of crowding considerably impairs the hypothalamic-pituitary-adrenocortical responsiveness to central beta- and alpha 2-adrenergic receptor stimulation. Crowding also abolishes the rise in hypothalamic histamine induced by beta- and alpha 2-adrenergic agonist, suggesting a role of hypothalamic histamine in the HPA adaptation to the social stress of crowding.

  2. Adrenocortical and behavioral attunement in parents with 1-year-old infants.

    PubMed

    van Bakel, Hedwig J A; Riksen-Walraven, J Marianne

    2008-03-01

    Sethre-Hofstad et al. [2002, Psychoneuroendocrinology 27:731-747] found that behaviorally well-attuned or sensitive parents showed better physiological attunement with their 2- to 4-year-old toddlers' adrenocortical responses to a potentially challenging task than less sensitive parents. In the present study we aimed to replicate this finding in a sample of 83 parents with 15-month-old infants. Parental and infant cortisol responses were assessed using saliva samples collected before and 21 min after the child's confrontation with a stranger and a moving robot. Infant behaviors reflecting distress/uncertainty during the stranger-robot session were rated from videotape. Parental sensitivity was observed during a parent-infant teaching episode. Our findings replicate those of Sethre-Hofstad et al. [2002, Psychoneuroendocrinology 27:731-747] by showing correlated parent-infant cortisol responses for sensitive parents but not for less sensitive parents. Furthermore, sensitive parents cortisol responses were associated with their children's distress/uncertainty during the stranger-robot episode, whereas this was not true for less sensitive parents. Results indicate an important connection between behavior and physiology in parent-infant interactions that deserve more research.

  3. Regulation of plant growth and development by the GROWTH-REGULATING FACTOR and GRF-INTERACTING FACTOR duo.

    PubMed

    Hoe Kim, Jeong; Tsukaya, Hirokazu

    2015-10-01

    Transcription factors are key regulators of gene expression and play pivotal roles in all aspects of living organisms. Therefore, identification and functional characterization of transcription factors is a prerequisite step toward understanding life. This article reviews molecular and biological functions of the two transcription regulator families, GROWTH-REGULATING FACTOR (GRF) and GRF-INTERACTING FACTOR (GIF), which have only recently been recognized. A myriad of experimental evidence clearly illustrates that GRF and GIF are bona fide partner proteins and form a plant-specific transcriptional complex. One of the most conspicuous outcomes from this research field is that the GRF-GIF duo endows the primordial cells of vegetative and reproductive organs with a meristematic specification state, guaranteeing the supply of cells for organogenesis and successful reproduction. It has recently been shown that GIF1 proteins, also known as ANGUSTIFOLIA3, recruit chromatin remodelling complexes to target genes, and that AtGRF expression is directly activated by the floral identity factors, APETALA1 and SEPALLATA3, providing an important insight into understanding of the action of GRF-GIF. Moreover, GRF genes are extensively subjected to post-transcriptional control by microRNA396, revealing the presence of a complex regulatory circuit in regulation of plant growth and development by the GRF-GIF duo.

  4. Tbx18 Regulates Development of the Epicardium and Coronary Vessels

    PubMed Central

    Wu, San-Pin; Dong, Xiu-Rong; Regan, Jenna N.; Su, Chang; Majesky, Mark W.

    2013-01-01

    The epicardium and coronary vessels originate from progenitor cells in the proepicardium. Here we show that Tbx18, a T-box family member highly expressed in the proepicardium, controls critical early steps in coronary development. In Tbx18-/- mouse embryos, both the epicardium and coronary vessels exhibit structural and functional defects. At E12.5, the Tbx18-deficient epicardium contains protrusions and cyst-like structures overlying a disorganized coronary vascular plexus that contains ectopic structures resembling blood islands. At E13.5, the left and right coronary stems form correctly in mutant hearts. However, analysis of PECAM-1 whole mount immunostaining, distribution of SM22αlacZ/+ activity, and analysis of coronary vascular casts suggest that defective vascular plexus remodeling produces a compromised arterial network at birth consisting of fewer distributing conduit arteries with smaller lumens and a reduced capacity to conduct blood flow. Gene expression profiles of Tbx18-/- hearts at E12.5 reveal altered expression in 79 genes that are associated with development of vascular system including sonic hedgehog signaling components patched and smoothened, VEGF-A, angiopoietin-1, endoglin, and Wnt factors compared to wild type hearts. Thus, formation of coronary vasculature is responsive to Tbx18-dependent gene targets in the epicardium, and a poorly structured network of coronary conduit vessels is formed in Tbx18 null hearts due to defects in epicardial cell signaling and fate during heart development. Lastly, we demonstrate that Tbx18 possesses a SRF/CArG box dependent repressor activity capable of repressing progenitor cell differentiation into smooth muscle cells, suggesting a potential function of Tbx18 in maintaining the progenitor status of epicardial-derived cells. PMID:24016759

  5. Strigolactones' ability to regulate root development may be executed by induction of the ethylene pathway.

    PubMed

    Koltai, Hinanit

    2011-07-01

    The newly defined phytohormones strigolactones (SLs) were recently shown to act as regulators of root development. Their positive effect on root-hair (RH) elongation enabled examination of their cross talk with auxin and ethylene. Analysis of wild-type plants and hormone-signaling mutants combined with hormonal treatments suggested that SLs and ethylene regulate RH elongation via a common regulatory pathway, in which ethylene is epistatic to SLs. The SL and auxin hormonal pathways were suggested to converge for regulation of RH elongation; this convergence was suggested to be mediated via the ethylene pathway, and to include regulation of auxin transport.

  6. Survey of environmental regulations applying to geothermal exploration, development, and use.

    SciTech Connect

    Beeland, G.V.

    1984-03-01

    Federal, State, and local environmental laws and regulations that apply to geothermal energy development are summarized. Most attention is given to those regulations which deal with air pollution, water pollution, solid wastes and impact assessments. Analyses are made of the regulations with respect to resource definition, pollutants currently not controlled, duplicity and overlap in permit and impact assessment requirements, the lack of uniformity of regulations between states, and the probable future approaches to the regulatory problems. This project updates a similar document (EPA/600/7-78-014) dated February 1978.

  7. [Mentalisation and affect regulation--how the infantile self develops].

    PubMed

    Kalisch, Konrad

    2012-01-01

    The text comprises the different elements of the psychoanalytic mentalization theory of Peter Fonagy et al. and tries to explain them. Part of this theory are above all the affect mirroring as well as the affect reciprocity theory and the two modes of the "as if" character and the psychic equivalence (playing with reality). You can find clear examples for each of these theoretical components. Moreover there are many correlations to other authors and their respective development theories: that is to Wilfred Bion, Donald Winnicott and John Bowlby. The text is based above all on Martin Dornes' approaches on this topic (2004, 2006).

  8. Getting in the Loop: Regulation of Development in Caulobacter crescentus

    PubMed Central

    Curtis, Patrick D.; Brun, Yves V.

    2010-01-01

    Summary: Caulobacter crescentus is an aquatic Gram-negative alphaproteobacterium that undergoes multiple changes in cell shape, organelle production, subcellular distribution of proteins, and intracellular signaling throughout its life cycle. Over 40 years of research has been dedicated to this organism and its developmental life cycles. Here we review a portion of many developmental processes, with particular emphasis on how multiple processes are integrated and coordinated both spatially and temporally. While much has been discovered about Caulobacter crescentus development, areas of potential future research are also highlighted. PMID:20197497

  9. Genomic Perspectives of Transcriptional Regulation in Forebrain Development

    PubMed Central

    Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; Rubenstein, John L. R.

    2015-01-01

    The forebrain is the seat of higher order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain. PMID:25569346

  10. SIRT1 regulates dendritic development in hippocampal neurons.

    PubMed

    Codocedo, Juan F; Allard, Claudio; Godoy, Juan A; Varela-Nallar, Lorena; Inestrosa, Nibaldo C

    2012-01-01

    Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.

  11. SIRT1 Regulates Dendritic Development in Hippocampal Neurons

    PubMed Central

    Godoy, Juan A.; Varela-Nallar, Lorena; Inestrosa, Nibaldo C.

    2012-01-01

    Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway. PMID:23056585

  12. Molecular aspects of development and regulation of endometriosis

    PubMed Central

    2014-01-01

    Endometriosis is a common and painful condition affecting women of reproductive age. While the underlying pathophysiology is still largely unknown, much advancement has been made in understanding the progression of the disease. In recent years, a great deal of research has focused on non-invasive diagnostic tools, such as biomarkers, as well as identification of potential therapeutic targets. In this article, we will review the etiology and cellular mechanisms associated with endometriosis as well as the current diagnostic tools and therapies. We will then discuss the more recent genomic and proteomic studies and how these data may guide development of novel diagnostics and therapeutics. The current diagnostic tools are invasive and current therapies primarily treat the symptoms of endometriosis. Optimally, the advancement of “-omic” data will facilitate the development of non-invasive diagnostic biomarkers as well as therapeutics that target the pathophysiology of the disease and halt, or even reverse, progression. However, the amount of data generated by these types of studies is vast and bioinformatics analysis, such as we present here, will be critical to identification of appropriate targets for further study. PMID:24927773

  13. Preproorexin and orexin receptors are expressed in cortisol-secreting adrenocortical adenomas, and orexins stimulate in vitro cortisol secretion and growth of tumor cells.

    PubMed

    Spinazzi, R; Rucinski, M; Neri, G; Malendowicz, L K; Nussdorfer, G G

    2005-06-01

    Orexins A and B are hypothalamic peptides that originate from the proteolytic cleavage of preproorexin and act through two subtypes of receptors, named OX1-R and OX2-R. OX1-R almost exclusively binds orexin-A, whereas OX2-R is nonselective for both orexins. We previously found that orexin-A, via the OX1-R, stimulates cortisol secretion from dispersed human adrenocortical cells. In this study, we demonstrate that six of eight cortisol-secreting adenomas expressed preproorexin mRNA, and seven of 10 adenomas contained measurable amounts of orexin-A but not orexin-B. Normal adrenal cortexes neither expressed preproorexin nor contained orexins. All adenomas expressed OX1-R and OX2-R mRNAs, and real-time PCR showed that the expression of both receptors was up-regulated in adenomas, compared with normal adrenal cortex. Orexin-A concentration-dependently raised basal cortisol secretion from freshly dispersed normal and adenomatous cells, minimal and maximal effective concentrations being 10(-10) and 10(-8) m, and the peptide efficacy (percent increase elicited by 10(-8) m orexin-A) was significantly higher in adenomas than in the normal adrenal cortex. Orexin-B was ineffective, thereby indicating that orexin secretagogue action is mediated by the OX1-R. In contrast, both orexins (10(-8) m) raised the proliferative activity of cultured normal and adenomatous cells, suggesting that this effect is mediated by OX2-R or both receptor subtypes. Collectively, our findings allow us to conclude that the orexin system is overexpressed in cortisol-secreting adenomas and suggest that orexin-A may act as an autocrine-paracrine regulator of the secretory activity and growth of some of these adrenal tumors.

  14. SP8 regulates signaling centers during craniofacial development.

    PubMed

    Kasberg, Abigail D; Brunskill, Eric W; Steven Potter, S

    2013-09-15

    Much of the bone, cartilage and smooth muscle of the vertebrate face is derived from neural crest (NC) cells. During craniofacial development, the anterior neural ridge (ANR) and olfactory pit (OP) signaling centers are responsible for driving the outgrowth, survival, and differentiation of NC populated facial prominences, primarily via FGF. While much is known about the functional importance of signaling centers, relatively little is understood of how these signaling centers are made and maintained. In this report we describe a dramatic craniofacial malformation in mice mutant for the zinc finger transcription factor gene Sp8. At E14.5 they show facial prominences that are reduced in size and underdeveloped, giving an almost faceless phenotype. At later times they show severe midline defects, excencephaly, hyperterlorism, cleft palate, and a striking loss of many NC and paraxial mesoderm derived cranial bones. Sp8 expression was primarily restricted to the ANR and OP regions during craniofacial development. Analysis of an extensive series of conditional Sp8 mutants confirmed the critical role of Sp8 in signaling centers, and not directly in the NC and paraxial mesoderm cells. The NC cells of the Sp8 mutants showed increased levels of apoptosis and decreased cell proliferation, thereby explaining the reduced sizes of the facial prominences. Perturbed gene expression in the Sp8 mutants was examined by laser capture microdissection coupled with microarrays, as well as in situ hybridization and immunostaining. The most dramatic differences included striking reductions in Fgf8 and Fgf17 expression in the ANR and OP signaling centers. We were also able to achieve genetic and pharmaceutical partial rescue of the Sp8 mutant phenotype by reducing Sonic Hedgehog (SHH) signaling. These results show that Sp8 primarily functions to promote Fgf expression in the ANR and OP signaling centers that drive the survival, proliferation, and differentiation of the NC and paraxial

  15. Cytotoxic and endocrine-disrupting potential of atrazine, diazinon, endosulfan, and mancozeb in adrenocortical steroidogenic cells of rainbow trout exposed in vitro.

    PubMed

    Bisson, Marjolaine; Hontela, Alice

    2002-04-15

    An in vitro bioassay for detection and quantitative assessment of chemicals with the capacity to disrupt adrenal steroidogenesis has been developed and used to compare the cytotoxic and endocrine-disrupting potential of four pesticides. Enzymatically dispersed adrenocortical cells of rainbow trout (Oncorhynchus mykiss) were exposed in vitro to atrazine, diazinon, endosulfan, and mancozeb, and cortisol secretion in response to ACTH or dibutyryl-cAMP (dbcAMP) and cell viability were determined. The effective concentration, EC50 (concentration that inhibits cortisol secretion by 50%), the median lethal concentration, LC50 (concentration that kills 50% of the cells), and the LC50/EC50 ratio were established for the test pesticides. The pesticides were ranked as follows: EC50, endosulfan < diazinon < mancozeb < atrazine; LC50, diazinon < endosulfan < mancozeb < atrazine, with diazinon as the most cytotoxic. Endosulfan and mancozeb disrupted sites downstream of the cAMP-generating step of the cortisol synthetic pathway while atrazine seemed to act upstream from the cAMP step. The in vitro adrenal bioassay can be used for screening of adrenotoxicants and for mechanistic studies of adrenotoxicity.

  16. Innate immunity in the lung regulates the development of asthma.

    PubMed

    DeKruyff, Rosemarie H; Yu, Sanhong; Kim, Hye Young; Umetsu, Dale T

    2014-07-01

    The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin-4 (IL-4), IL-5, IL-13, interferon-γ, IL-17, and IL-22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non-allergic asthma phenotypes develop.

  17. Soybean Homologs of MPK4 Negatively Regulate Defense Responses and Positively Regulate Growth and Development1[W][OA

    PubMed Central

    Liu, Jian-Zhong; Horstman, Heidi D.; Braun, Edward; Graham, Michelle A.; Zhang, Chunquan; Navarre, Duroy; Qiu, Wen-Li; Lee, Yeunsook; Nettleton, Dan; Hill, John H.; Whitham, Steven A.

    2011-01-01

    Mitogen-activated protein kinase (MAPK) cascades play important roles in disease resistance in model plant species such as Arabidopsis (Arabidopsis thaliana) and tobacco (Nicotiana tabacum). However, the importance of MAPK signaling pathways in the disease resistance of crops is still largely uninvestigated. To better understand the role of MAPK signaling pathways in disease resistance in soybean (Glycine max), 13, nine, and 10 genes encoding distinct MAPKs, MAPKKs, and MAPKKKs, respectively, were silenced using virus-induced gene silencing mediated by Bean pod mottle virus. Among the plants silenced for various MAPKs, MAPKKs, and MAPKKKs, those in which GmMAPK4 homologs (GmMPK4s) were silenced displayed strong phenotypes including stunted stature and spontaneous cell death on the leaves and stems, the characteristic hallmarks of activated defense responses. Microarray analysis showed that genes involved in defense responses, such as those in salicylic acid (SA) signaling pathways, were significantly up-regulated in GmMPK4-silenced plants, whereas genes involved in growth and development, such as those in auxin signaling pathways and in cell cycle and proliferation, were significantly down-regulated. As expected, SA and hydrogen peroxide accumulation was significantly increased in GmMPK4-silenced plants. Accordingly, GmMPK4-silenced plants were more resistant to downy mildew and Soybean mosaic virus compared with vector control plants. Using bimolecular fluorescence complementation analysis and in vitro kinase assays, we determined that GmMKK1 and GmMKK2 might function upstream of GmMPK4. Taken together, our results indicate that GmMPK4s negatively regulate SA accumulation and defense response but positively regulate plant growth and development, and their functions are conserved across plant species. PMID:21878550

  18. Assessment of adrenocortical activity and behavior of the collared anteater (Tamandua tetradactyla) in response to food-based environmental enrichment.

    PubMed

    Eguizábal, Gabina V; Palme, Rupert; Villarreal, Daniel; Dal Borgo, Carla; Di Rienzo, Julio A; Busso, Juan M

    2013-01-01

    One of the current standard approaches to the study of animal welfare is measuring hypothalamic-pituitary-adrenal activity, frequently in association with behavioral assessment. We studied the effects of food-based environmental enrichment on adrenocortical activity and behavior in zoo-housed collared anteaters (Tamandua tetradactyla; n = 5). We successfully validated measurements of fecal cortisol metabolites (FCMs) using an 11-oxoetiocholanolone enzyme immunoassay by stimulating (ACTH injection) and suppressing (dexamethasone administration) adrenocortical activity. Three months later, we subjected animals to an ABA-type experiment (three 6-week periods): pre-enrichment (routine diet: A), enrichment (modified diet: B), and post-enrichment (routine diet: A) periods. We assessed adrenocortical activity by collecting individual feces three times a week (total number of samples: 228), and evaluated behavior by performing 3 days of behavioral observations per period (with a total of 3,600 behavioral data points for the individuals studied). Statistical analysis revealed changes in FCM concentrations (µg/g) over the periods (3.04 ± 0.68, 2.98 ± 0.66, and 4.04 ± 0.90, respectively). Additionally, it showed that the number of FCM peaks was highly reduced during enrichment; meanwhile active natural behaviors were significantly increased. We consider that these changes in response to food-based environmental enrichment improved the welfare of individual zoo-housed collared anteaters. This research might contribute to in situ and ex situ studies on the physiology and behavior of this endemic South American species.

  19. Inhibition of Human Adrenocortical Cancer Cell Growth by Temozolomide in Vitro and the Role of the MGMT Gene

    PubMed Central

    Creemers, S. G.; van Koetsveld, P. M.; van den Dungen, E. S. R.; Korpershoek, E.; van Kemenade, F. J.; Franssen, G. J. H.; de Herder, W. W.; Feelders, R. A.

    2016-01-01

    Context: Treatment of patients with adrenocortical carcinomas (ACC) with mitotane and/or chemotherapy is often associated with toxicity and poor tumor response. New therapeutic options are urgently needed. Objective: The objectives of the study were to evaluate the therapeutic possibilities of temozolomide (TMZ) in ACC cells and to assess the potential predictive role of the DNA repair gene O6-Methylguanine-DNA methyltransferase (MGMT) in adrenocortical tumors. Methods: Three human ACC cell lines and eight primary ACC cultures were used to assess effects of TMZ in vitro. In the cell lines, 11 normal adrenals, 16 adrenocortical adenomas, and 29 ACC, MGMT promoter methylation and expression were determined. Results: IC50 values of TMZ on cell growth were 39 μM, 38 μM, and 44 μM for H295R, HAC15, and SW13, respectively. TMZ induced apoptosis and provoked cytotoxic and cytostatic effects by reducing the surviving fraction of ACC colonies and the colony size. TMZ thereby induced cell cycle arrests in ACC cell lines. TMZ and mitotane both inhibited growth of ACC cells cultured as three-dimensional spheroids. TMZ inhibited cell amount in five of eight primary ACC cultures and induced apoptosis in seven of eight primary ACC cultures. In ACC cell lines and adrenal tissues, MGMT promoter methylation was low. In ACCs, methylation was inversely correlated with MGMT mRNA expression. MGMT protein expression was not correlated with MGMT methylation. Conclusions: For the first time, we show the therapeutic potential of temozolomide for ACC, offering an urgently needed potential alternative for patients not responding to mitotane alone or with etoposide, doxorubicin, and cisplatin. (Pre-)clinical studies are warranted to assess efficacy in vivo. PMID:27603910

  20. Splenorenal Arterial Bypass: Description of Technique and Case Example in an Instance of Renal Revascularization during Adrenalectomy for Adrenocortical Carcinoma.

    PubMed

    Yozawitz, J; Kissin, M; Szuchmacher, M; Sullivan, J; Nicastro, J; Coppa, G; Molmenti, E

    2016-12-01

    We present a patient with a 16 cm adrenocortical carcinoma that underwent a left adrenalectomy en bloc with resection of the involved segment of the left renal artery. A splenectomy and splenorenal bypass was performed to revascularize the left kidney. To our knowledge, this is the first instance in the literature of a splenorenal arterial bypass being reported for renal revascularization during an extirpative oncologic procedure. A 64-year-old male patient, with history significant for adrenocortical carcinoma, status post prior right adrenalectomy with partial right nephrectomy, presented for an elective left adrenalectomy. Preoperative work-up revealed an 11.4 × 13.2 × 16 cm left adrenal mass, most consistent with an adrenocortical carcinoma. At the time of surgery, the mass was found to be intimately adherent to the aorta at the takeoff of the left renal artery. Moreover, the left renal artery appeared to be coursing directly through the mass. The involved segment of the left renal artery was resected en bloc with the tumor. Because of concerns for a small and likely poorly functioning right renal remnant, a decision was made to attempt to salvage the left kidney. This was accomplished by performing a splenectomy and constructing a splenorenal bypass. Serial Duplex Doppler renal ultrasound studies were obtained over the first three postoperative days and demonstrated improved arterial waveforms. Serum creatinine reached a peak level of 3.76 mg/dL on postoperative day 3, and then began to slowly trend down to 3.37 mg/dL on the day of discharge (postoperative day7).

  1. Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia.

    PubMed

    Kang, Eunchai; Burdick, Katherine E; Kim, Ju Young; Duan, Xin; Guo, Junjie U; Sailor, Kurt A; Jung, Dhong-Eun; Ganesan, Sundar; Choi, Sungkyung; Pradhan, Dennis; Lu, Bai; Avramopoulos, Dimitrios; Christian, Kimberly; Malhotra, Anil K; Song, Hongjun; Ming, Guo-li

    2011-11-17

    Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.

  2. Polycomb repression in the regulation of growth and development in Arabidopsis.

    PubMed

    Xiao, Jun; Wagner, Doris

    2015-02-01

    Chromatin state is critical for cell identity and development in multicellular eukaryotes. Among the regulators of chromatin state, Polycomb group (PcG) proteins stand out because of their role in both establishment and maintenance of cell identity. PcG proteins act in two major complexes in metazoans and plants. These complexes function to epigenetically-in a mitotically heritable manner-prevent expression of important developmental regulators at the wrong stage of development or in the wrong tissue. In Arabidopsis, PcG function is required throughout the life cycle from seed germination to embryo formation. Recent studies have expanded our knowledge regarding the biological roles and the regulation of the activity of PcG complexes. In this review, we discuss novel functions of Polycomb repression in plant development as well as advances in understanding PcG complex recruitment, activity regulation and removal in Arabidopsis and other plant species.

  3. The Contingency of Cocaine Administration Accounts for Structural and Functional Medial Prefrontal Deficits and Increased Adrenocortical Activation

    PubMed Central

    Anderson, Rachel M.; Cosme, Caitlin V.; Glanz, Ryan M.; Miller, Mary C.; Romig-Martin, Sara A.; LaLumiere, Ryan T.

    2015-01-01

    The prelimbic region (PL) of the medial prefrontal cortex (mPFC) is implicated in the relapse of drug-seeking behavior. Optimal mPFC functioning relies on synaptic connections involving dendritic spines in pyramidal neurons, whereas prefrontal dysfunction resulting from elevated glucocorticoids, stress, aging, and mental illness are each linked to decreased apical dendritic branching and spine density in pyramidal neurons in these cortical fields. The fact that cocaine use induces activation of the stress-responsive hypothalamo-pituitary-adrenal axis raises the possibility that cocaine-related impairments in mPFC functioning may be manifested by similar changes in neuronal architecture in mPFC. Nevertheless, previous studies have generally identified increases, rather than decreases, in structural plasticity in mPFC after cocaine self-administration. Here, we use 3D imaging and analysis of dendritic spine morphometry to show that chronic cocaine self-administration leads to mild decreases of apical dendritic branching, prominent dendritic spine attrition in PL pyramidal neurons, and working memory deficits. Importantly, these impairments were largely accounted for in groups of rats that self-administered cocaine compared with yoked-cocaine- and saline-matched counterparts. Follow-up experiments failed to demonstrate any effects of either experimenter-administered cocaine or food self-administration on structural alterations in PL neurons. Finally, we verified that the cocaine self-administration group was distinguished by more protracted increases in adrenocortical activity compared with yoked-cocaine- and saline-matched controls. These studies suggest a mechanism whereby increased adrenocortical activity resulting from chronic cocaine self-administration may contribute to regressive prefrontal structural and functional plasticity. SIGNIFICANCE STATEMENT Stress, aging, and mental illness are each linked to decreased prefrontal plasticity. Here, we show that chronic

  4. Adrenocortical response in rats subjected to a stress of restraint by immobilization whether accompanied by hypothermia or not

    NASA Technical Reports Server (NTRS)

    Buchel, L.; Prioux-Guyonneau, M.; Libian, L.

    1980-01-01

    The restraint associated with hypothermia which increases the adrenal activity in rats was investigated. In rats with nomothermia or light hypothermia, the plasma and adrenal corticosterone levels increase at least threefold whatever the duration of restraint. Their return to normal values depends on the duration of the restraint. Exposure to cold produces in free rats a light hypothermia with an increase of the plasma and adrenal corticosterone levels, and in restraint animals an important hypothermia which does not potentiate the stimulation of adrenocortical activity induced by the restraint alone.

  5. Role of ACTH in the Interactive/Paracrine Regulation of Adrenal Steroid Secretion in Physiological and Pathophysiological Conditions

    PubMed Central

    Lefebvre, Hervé; Thomas, Michaël; Duparc, Céline; Bertherat, Jérôme; Louiset, Estelle

    2016-01-01

    In the normal human adrenal gland, steroid secretion is regulated by a complex network of autocrine/paracrine interactions involving bioactive signals released by endothelial cells, nerve terminals, chromaffin cells, immunocompetent cells, and adrenocortical cells themselves. ACTH can be locally produced by medullary chromaffin cells and is, therefore, a major mediator of the corticomedullary functional interplay. Plasma ACTH also triggers the release of angiogenic and vasoactive agents from adrenocortical cells and adrenal mast cells and, thus, indirectly regulates steroid production through modulation of the adrenal blood flow. Adrenocortical neoplasms associated with steroid hypersecretion exhibit molecular and cellular defects that tend to reinforce the influence of paracrine regulatory loops on corticosteroidogenesis. Especially, ACTH has been found to be abnormally synthesized in bilateral macronodular adrenal hyperplasia responsible for hypercortisolism. In these tissues, ACTH is detected in a subpopulation of adrenocortical cells that express gonadal markers. This observation suggests that ectopic production of ACTH may result from impaired embryogenesis leading to abnormal maturation of the adrenogonadal primordium. Globally, the current literature indicates that ACTH is a major player in the autocrine/paracrine processes occurring in the adrenal gland in both physiological and pathological conditions. PMID:27489549

  6. MicroRNA858 Is a Potential Regulator of Phenylpropanoid Pathway and Plant Development.

    PubMed

    Sharma, Deepika; Tiwari, Manish; Pandey, Ashutosh; Bhatia, Chitra; Sharma, Ashish; Trivedi, Prabodh Kumar

    2016-06-01

    MicroRNAs (miRNAs) are endogenous, noncoding small RNAs that function as critical regulators of gene expression. In plants, miRNAs have shown their potential as regulators of growth, development, signal transduction, and stress tolerance. Although the miRNA-mediated regulation of several processes is known, the involvement of miRNAs in regulating secondary plant product biosynthesis is poorly understood. In this study, we functionally characterized Arabidopsis (Arabidopsis thaliana) miR858a, which putatively targets R2R3-MYB transcription factors involved in flavonoid biosynthesis. Overexpression of miR858a in Arabidopsis led to the down-regulation of several MYB transcription factors regulating flavonoid biosynthesis. In contrast to the robust growth and early flowering of miR858OX plants, reduction of plant growth and delayed flowering were observed in Arabidopsis transgenic lines expressing an artificial miRNA target mimic (MIM858). Genome-wide expression analysis using transgenic lines suggested that miR858a targets a number of regulatory factors that modulate the expression of downstream genes involved in plant development and hormonal and stress responses. Furthermore, higher expression of MYBs in MIM858 lines leads to redirection of the metabolic flux towards the synthesis of flavonoids at the cost of lignin synthesis. Altogether, our study has established the potential role of light-regulated miR858a in flavonoid biosynthesis and plant growth and development.

  7. Co-ordination of Flower Development Through Epigenetic Regulation in Two Model Species: Rice and Arabidopsis.

    PubMed

    Guo, Siyi; Sun, Bo; Looi, Liang-Sheng; Xu, Yifeng; Gan, Eng-Seng; Huang, Jiangbo; Ito, Toshiro

    2015-05-01

    Angiosperms produce flowers for reproduction. Flower development is a multistep developmental process, beginning with the initiation of the floral meristems, followed by floral meristem identity specification and maintenance, organ primordia initiation, floral organ identity specification, floral stem cell termination and finally floral organ maturation. During flower development, each of a large number of genes is expressed in a spatiotemporally regulated manner. Underlying these molecular and phenotypic events are various genetic and epigenetic pathways, consisting of diverse transcription factors, chromatin-remodeling factors and signaling molecules. Over the past 30 years, genetic, biochemical and genomic assays have revealed the underlying genetic frameworks that control flower development. Here, we will review the transcriptional regulation of flower development in two model species: Arabidopsis thaliana and rice (Oryza sativa). We focus on epigenetic regulation that functions to co-ordinate transcription pathways in flower development.

  8. New Insights Into the Role of RNA-Binding Proteins in the Regulation of Heart Development.

    PubMed

    Ladd, A N

    2016-01-01

    The regulation of gene expression during development takes place both at the transcriptional and posttranscriptional levels. RNA-binding proteins (RBPs) regulate pre-mRNA processing, mRNA localization, stability, and translation. Many RBPs are expressed in the heart and have been implicated in heart development, function, or disease. This chapter will review the current knowledge about RBPs in the developing heart, focusing on those that regulate posttranscriptional gene expression. The involvement of RBPs at each stage of heart development will be considered in turn, including the establishment of specific cardiac cell types and formation of the primitive heart tube, cardiac morphogenesis, and postnatal maturation and aging. The contributions of RBPs to cardiac birth defects and heart disease will also be considered in these contexts. Finally, the interplay between RBPs and other regulatory factors in the developing heart, such as transcription factors and miRNAs, will be discussed.

  9. Expression and regulation of glucocorticoid-induced leucine zipper in the developing anterior pituitary gland.

    PubMed

    Ellestad, Laura E; Malkiewicz, Stefanie A; Guthrie, H David; Welch, Glenn R; Porter, Tom E

    2009-02-01

    The expression profile of glucocorticoid-induced leucine zipper (GILZ) in the anterior pituitary during the second half of embryonic development in the chick is consistent with in vivo regulation by circulating corticosteroids. However, nothing else has been reported about the presence of GILZ in the neuroendocrine system. We sought to characterize expression and regulation of GILZ in the chicken embryonic pituitary gland and determine the effect of GILZ overexpression on anterior pituitary hormone levels. Pituitary GILZ mRNA levels increased during embryogenesis to a maximum on the day of hatch, and decreased through the first week after hatch. GILZ expression was rapidly upregulated by corticosterone in embryonic pituitary cells. To determine whether GILZ regulates hormone gene expression in the developing anterior pituitary, we overexpressed GILZ in embryonic pituitary cells and measured mRNA for the major pituitary hormones. Exogenous GILZ increased prolactin mRNA above basal levels, but not as high as that in corticosterone-treated cells, indicating that GILZ may play a small role in lactotroph differentiation. The largest effect we observed was a twofold increase in FSH beta subunit in cells transfected with GILZ but not treated with corticosterone, suggesting that GILZ may positively regulate gonadotroph development in a manner not involving glucocorticoids. In conclusion, this is the first report to characterize avian GILZ and examine its regulation in the developing neuroendocrine system. We have shown that GILZ is upregulated by glucocorticoids in the embryonic pituitary gland and may regulate expression of several pituitary hormones.

  10. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer.

    PubMed

    Khan, Tanweera S; Sundin, Anders; Juhlin, Claes; Wilander, Erik; Oberg, Kjell; Eriksson, Barbro

    2004-01-01

    The efficacy and tolerability of a combination of vincristine, cisplatin, teniposide, and cyclophosphamide (OPEC) in 11 patients (median age, 45 yr) with recurrent and/or metastatic adrenocortical cancer (ACC) (seven functional and four nonfunctional) were evaluated. All patients received this regimen after the failure of streptozocin and o,p'-DDD (SO) combination therapy. The regimen comprised cyclophosphamide, 600 mg/m2, and vincristine, 1.5 mg/m2, maximum dose 2.0 mg (d 1); cisplatin, 100 mg/m2 (d 2) and teniposide, 150 mg/m2 (d 4). Cycles were repeated every 4 wk. One to eight cycles (median, six cycles) of OPEC were administered to each patient. The median duration of treatment was 6 mo. The overall 2-yr survival rate was 82% and the median survival since diagnosis was 44 mo while it was 21 mo since start of OPEC therapy. Responses were obtained in nine patients: partial response in two patients, and stable disease in seven patients. The median duration of response was 6.75 mo. A total of 60 cycles of chemotherapy were given to all patients; grade 1-2 toxicity occurred in 57 cycles, while grade 3 toxicity was observed only in two cycles, according to NCI's Common Toxicity Criteria. We conclude that the OPEC regimen may be considered in recurrent or metastatic ACC as a second-line medical treatment. However, the combination is accompanied by considerable side effects and dose modifications are necessary in order to be able to recommend the treatment. This regimen needs further evaluation compared with SO therapy preferably in a randomized multicenter trial.

  11. Loner or socializer? Ravens’ adrenocortical response to individual separation depends on social integration

    PubMed Central

    Stocker, Martina; Munteanu, Alexandru; Stöwe, Mareike; Schwab, Christine; Palme, Rupert; Bugnyar, Thomas

    2016-01-01

    Non-breeding common ravens (Corvus corax) live in complex social groups with a high degree of fission–fusion dynamics. They form valuable relationships and alliances with some conspecifics, while taking coordinated action against others. In ravens, affiliates reconcile their conflicts, console each other after conflicts with a third party, and provide each other with social support — all behaviors that presumably reduce corticosterone levels and alleviate stress. However, how well an individual is socially integrated in a (sub)group might vary substantially. This raises the question whether the social integration of a raven affects its stress responses to fission–fusion dynamics. The present study aims to investigate this effect experimentally by separating single ravens (n = 16) individually from their group for four days and subsequently reintroducing them. To determine stress response patterns in the separated individuals we measured the amounts of immunoreactive corticosterone metabolites (CM) in droppings. We compared two enzyme immunoassays, which we validated by conducting an ACTH challenge, and finally decided to apply an 11-oxoetiocholanolone enzyme immunoassay. Additionally, we determined levels of social integration using focal observations. Our findings suggest that a strong social integration is related to low CM levels when the individuals are within the group and high levels during separations, implying that separation leads to stress in these birds. In contrast, poorly socially integrated ravens seem to exhibit the opposite pattern, indicating that to them group living is more stressful than being temporarily separated. We, therefore, conclude that the birds’ adrenocortical activity is modulated by their social integration. PMID:26631484

  12. Molecular Profiling of Refractory Adrenocortical Cancers and Predictive Biomarkers to Therapy

    PubMed Central

    Millis, Sherri Z.; Ejadi, Samuel; Demeure, Michael J.

    2015-01-01

    PURPOSE Current first-line chemotherapy for patients with metastatic adrenocortical cancer (ACC) includes doxorubicin, etoposide, cisplatin, and mitotane with a reported response rate of only 23.2%. New therapeutic leads for patients with refractory tumors are needed; there is no standard second-line treatment. METHODS Samples from 135 ACC tumors were analyzed by immunohistochemistry, in situ hybridization (FISH or CISH), and/or gene sequencing at a single commercial reference laboratory (Caris Life Sciences) to identify markers associated with drug sensitivity and resistance. RESULTS Overexpression of proteins related to demonstrated chemotherapy sensitivity or resistance included topoisomerase 1, progesterone receptor, and topoisomerase 2-alpha in 46%, 63%, and 42% of cases, respectively. Loss of excision repair cross-complementary group 1 (ERCC1), phosophatase and tensin homolog, O(6)-methylguanine-methyltransferase, and ribonucleotide reductase M1 (RRM1) was identified in 56%, 59%, 71%, and 58% of cases, respectively. Other aberrations included overexpression of programmed death-ligand 1 or programmed cell death protein 1 tumor-infiltrating lymphocytes in >40% of cases. In all, 35% of cases had a mutation in the canonical Wnt signaling pathway (either CTNNB1 or APC) and 48% had a mutation in TP53. No other genomic alterations were identified. CONCLUSION Biomarker alterations in ACC may be used to direct therapies, including recommendations for and potential resistance of some patients to traditional chemotherapies, which may explain the low response rate in the unselected population. Limited outcomes data support the use of mitotane and platinum therapies for patients with low levels of the proteins RRM1 and ERCC1. PMID:26715866

  13. Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma.

    PubMed

    Malandrino, Pasqualino; Al Ghuzlan, Abir; Castaing, Marine; Young, Jacques; Caillou, Bernard; Travagli, Jean-Paul; Elias, Dominique; de Baere, Thierry; Dromain, Clarisse; Paci, Angelo; Chanson, Philippe; Schlumberger, Martin; Leboulleux, Sophie; Baudin, Eric

    2010-09-01

    To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level > or =14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.

  14. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly.

    PubMed

    Daffara, Fulvia; De Francia, Silvia; Reimondo, Giuseppe; Zaggia, Barbara; Aroasio, Emiliano; Porpiglia, Francesco; Volante, Marco; Termine, Angela; Di Carlo, Francesco; Dogliotti, Luigi; Angeli, Alberto; Berruti, Alfredo; Terzolo, Massimo

    2008-12-01

    Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations >14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

  15. sHDL Nanoparticles: A Novel Therapeutic Strategy for Adrenocortical Carcinomas

    PubMed Central

    Subramanian, Chitra; Kuai, Rui; Zhu, Qing; White, Peter; Moon, James; Schwendeman, Anna; Cohen, Mark S.

    2015-01-01

    Background Chemotherapeutic strategies for adrenocortical carcinoma (ACC) carry significant toxicities. Cholesterol is critical for ACC cell growth and steroidogenesis and ACC cells over-express scavenger receptor BI (SR-BI) that uptakes cholesterol from circulating high-density lipoprotein (HDL). We hypothesize that cholesterol-free synthetic-HDL nanoparticles (sHDL) will deplete cholesterol and synergize with chemotherapeutics to achieve enhanced anticancer effects at lower (less toxic) drug levels. Methods Anti proliferative efficacy of ACC cells for the combinations of sHDL with chemotherapeutics was tested by cell-Titer Glo. Cortisol levels were measured from the culture media. Effect on steroidogenesis was measured by RT-PCR. Induction of apoptosis was evaluated by flow cytometry. Results Combination-Index (CI) for sHDL and either etoposide(E), cisplatin(P) or mitotane(M) demonstrated synergy (CI<1) for anti-proliferation. sHDL alone or in combination with chemo drugs was able to reduce cortisol production by 70-90% compared to cisplatin alone or controls (p<0.01). RT-PCR indicated significant inhibition of steroidogenic enzymes for sHDL (p<0.01 vs. no sHDL). Combination therapy with sHDL increased apoptosis by 30-50% compared to drug or sHDL alone (p<0.03) confirmed by mitochondrial potential decrease. Conclusion sHDL can act synergistically and lower the amount of M/E/P needed for anticancer efficacy in ACC in part due to cholesterol starvation. This novel treatment strategy warrants further investigation translationally. PMID:26582501

  16. Clinical Score Predicting Long-Term Survival after Repeat Resection for Recurrent Adrenocortical Carcinoma

    PubMed Central

    Tran, Thuy B; Maithel, Shishir K; Pawlik, Timothy M; Wang, Tracy S; Hatzaras, Ioannis; Phay, John E; Fields, Ryan C; Weber, Sharon M; Sicklick, Jason K; Yopp, Adam C; Duh, Quan-Yang; Solorzano, Carmen C; Votanopoulos, Konstantinos I; Poultsides, George A

    2017-01-01

    BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive malignancy typically resistant to chemotherapy and radiation. Surgery, even in the setting of locally recurrent or metastatic disease, remains the only potentially curative option. However, the subset of patients who will benefit from repeat resection in this setting remains ill defined. The objective of this study was to propose a prognostic clinical score that facilitates selection of patients for repeat resection of recurrent ACC. STUDY DESIGN Patients who underwent curative-intent repeat resection for recurrent ACC at 1 of 13 academic medical centers participating in the US ACC Study Group were identified. End points included morbidity, mortality, and overall survival. RESULTS Fifty-six patients underwent repeat curative-intent resection for recurrent ACC (representing 21% of 265 patients who underwent resection for primary ACC) from 1997 to 2014. Median age was 52 years. Sites of resected recurrence included locoregional only (54%), lung only (14%), liver only (12%), combined locoregional and lung (4%), combined liver and lung (4%), and other distant sites (12%). Thirty-day morbidity and mortality rates were 40% and 5.4%, respectively. Cox regression analysis revealed that the presence of multifocal recurrence, disease-free interval <12 months, and extrapulmonary distant metastases were independent predictors of poor survival. A clinical score consisting of 1-point each for the 3 variables demonstrated good discrimination in predicting survival after repeat resection (5-year: 72% for 0 points, 32% for 1 point, 0% for 2 or 3 points; p = 0.0006, area under the curve = 0.78). CONCLUSIONS Long-term survival after repeat resection for recurrent ACC is feasible when 2 of the following factors are present: solitary tumor, disease-free interval >12 months, and locoregional or pulmonary recurrence. PMID:27618748

  17. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    PubMed Central

    Qin, Liang; Xu, Tianyuan; Xia, Leilei; Wang, Xianjin; Zhang, Xiang; Zhang, Xiaohua; Zhu, Zhaowei; Zhong, Shan; Wang, Chuandong; Shen, Zhoujun

    2016-01-01

    Background It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo. Methods The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy. Results The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice. Conclusion The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an

  18. Contralateral adrenal suppression on adrenocortical scintigraphy provides good evidence showing subclinical cortisol overproduction from unilateral adenomas.

    PubMed

    Katabami, Takuyuki; Ishii, Satoshi; Obi, Ryusei; Asai, Shiko; Tanaka, Yasushi

    2016-12-30

    Unilateral and/or predominant uptake on adrenocortical scintigraphy (ACS) may be related to autonomous cortisol overproduction in patients with subclinical Cushing's syndrome (SCS). However, there is no information regarding whether increased tracer uptake on the tumor side or decreased uptake on the contralateral side on ACS is more greatly associated with inappropriate cortisol production. Therefore, we evaluated the relationship between quantitative (131)I-6β-iodomethyl-norcholesterol ((131)I-NP-59) uptake in both adrenal glands and parameters of autonomic cortisol secretion and attempted to set a cut off for SCS detection. The study included 90 patients with unilateral adrenal adenoma who fulfilled strict criteria. The diagnosis of SCS was based on serum cortisol ≥3.0 μg/dL after 1-mg dexamethasone suppression test (DST) with at least 1 other hypothalamus-pituitary-adrenal axis function abnormality. Twenty-two (27.7%) subjects were diagnosed with SCS. The uptake rate on the affected side in the SCS group was comparable to that in the non-functioning adenoma group. In contrast, the uptake rate on the contralateral side was lower and the laterality ratio significantly higher in the SCS group. The two ACS indices were correlated with serum cortisol levels after a 1-mg DST, but uptake on the tumor side was not. Tumor size was also important for the functional statuses of adrenal tumors and NP-59 imaging patterns. The best cut-off point for the laterality ratio to detect SCS was 3.07. These results clearly indicate that contralateral adrenal suppression in ACS is good evidence showing subclinical cortisol overproduction.

  19. Steroidogenic enzyme profile in an androgen-secreting adrenocortical oncocytoma associated with hirsustism

    PubMed Central

    Tetsi Nomigni, Milène; Ouzounian, Sophie; Benoit, Alice; Vadrot, Jacqueline; Tissier, Frédérique; Renouf, Sylvie; Lefebvre, Hervé; Christin-Maitre, Sophie; Louiset, Estelle

    2015-01-01

    Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH. PMID:26034121

  20. Steroidogenic enzyme profile in an androgen-secreting adrenocortical oncocytoma associated with hirsustism.

    PubMed

    Tetsi Nomigni, Milène; Ouzounian, Sophie; Benoit, Alice; Vadrot, Jacqueline; Tissier, Frédérique; Renouf, Sylvie; Lefebvre, Hervé; Christin-Maitre, Sophie; Louiset, Estelle

    2015-06-01

    Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH.

  1. Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.

    PubMed

    Fujisawa, Yasuko; Sakaguchi, Kimiyoshi; Ono, Hiroyuki; Yamaguchi, Rie; Kato, Fumiko; Kagami, Masayo; Fukami, Maki; Ogata, Tsutomu

    2016-05-01

    Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

  2. Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development

    PubMed Central

    Loponte, Sara; Segré, Chiara V.; Senese, Silvia; Miccolo, Claudia; Santaguida, Stefano; Deflorian, Gianluca; Citro, Simona; Mattoscio, Domenico; Pisati, Federica; Moser, Mirjam A.; Visintin, Rosella; Seiser, Christian; Chiocca, Susanna

    2016-01-01

    Histone deacetylases (HDACs) catalyze the removal of acetyl molecules from histone and non-histone substrates playing important roles in chromatin remodeling and control of gene expression. Class I HDAC1 is a critical regulator of cell cycle progression, cellular proliferation and differentiation during development; it is also regulated by many post-translational modifications (PTMs). Herein we characterize a new mitosis-specific phosphorylation of HDAC1 driven by Aurora kinases A and B. We show that this phosphorylation affects HDAC1 enzymatic activity and it is critical for the maintenance of a proper proliferative and developmental plan in a complex organism. Notably, we find that Aurora-dependent phosphorylation of HDAC1 regulates histone acetylation by modulating the expression of genes directly involved in the developing zebrafish central nervous system. Our data represent a step towards the comprehension of HDAC1 regulation by its PTM code, with important implications in unravelling its roles both in physiology and pathology. PMID:27458029

  3. NFAT regulates pre-synaptic development and activity-dependent plasticity in Drosophila

    PubMed Central

    Freeman, Amanda; Franciscovich, Amy; Bowers, Mallory; Sandstrom, David J.; Sanyal, Subhabrata

    2010-01-01

    The calcium-regulated transcription factor NFAT is emerging as a key regulator of neuronal development and plasticity but precise cellular consequences of NFAT function remain poorly understood. Here, we report that the single Drosophila NFAT homolog is widely expressed in the nervous system including motor neurons and unexpectedly controls neural excitability. Likely due to this effect on excitability, NFAT regulates overall larval locomotion and both chronic and acute forms of activity-dependent plasticity at the larval glutamatergic neuro-muscular synapse. Specifically, NFAT-dependent synaptic phenotypes include changes in the number of pre-synaptic boutons, stable modifications in synaptic microtubule architecture and pre-synaptic transmitter release, while no evidence is found for synaptic retraction or alterations in the level of the synaptic cell adhesion molecule FasII. We propose that NFAT regulates pre-synaptic development and constraints long-term plasticity by dampening neuronal excitability. PMID:21185939

  4. Advanced Spacesuit Portable Life Support System Oxygen Regulator Development and Testing

    NASA Technical Reports Server (NTRS)

    Campbell, Colin; Vogel, Matt R.; Watts, Carly

    2011-01-01

    The advanced spacesuit portable life support system (PLSS) oxygen regulators represent an evolutionary approach to regulator development. Several technology development prototypes have been produced that borrow much of the mechanical regulator design from the well proven Shuttle/ISS Extravehicular Mobility Unit (EMU) Secondary Oxygen Regulator, but incorporate a motor-settable pressure set-point feature that facilitates significantly greater operational flexibility. For example, this technology would enable EVA to begin at a higher suit pressure, which would reduce pre-breathe time, and then slowly step down to a lower pressure to increase suit mobility for the duration of the EVA. Comprehensive testing of the prototypes was performed on the component level as well as part of the PLSS 1.0 system level testing. Results from these tests characterize individual prototype performance and demonstrate successful operation during multiple nominal and contingency EVA modes

  5. Evidence of a bigenomic regulation of mitochondrial gene expression by thyroid hormone during rat brain development

    SciTech Connect

    Sinha, Rohit Anthony; Pathak, Amrita; Mohan, Vishwa; Babu, Satish; Pal, Amit; Khare, Drirh; Godbole, Madan M.

    2010-07-02

    Hypothyroidism during early mammalian brain development is associated with decreased expression of various mitochondrial encoded genes along with evidence for mitochondrial dysfunction. However, in-spite of the similarities between neurological disorders caused by perinatal hypothyroidism and those caused by various genetic mitochondrial defects we still do not know as to how thyroid hormone (TH) regulates mitochondrial transcription during development and whether this regulation by TH is nuclear mediated or through mitochondrial TH receptors? We here in rat cerebellum show that hypothyroidism causes reduction in expression of nuclear encoded genes controlling mitochondrial biogenesis like PGC-1{alpha}, NRF-1{alpha} and Tfam. Also, we for the first time demonstrate a mitochondrial localization of thyroid hormone receptor (mTR) isoform in developing brain capable of binding a TH response element (DR2) present in D-loop region of mitochondrial DNA. These results thus indicate an integrated nuclear-mitochondrial cross talk in regulation of mitochondrial transcription by TH during brain development.

  6. Recent advances on the development and regulation of flower color in ornamental plants

    PubMed Central

    Zhao, Daqiu; Tao, Jun

    2015-01-01

    Flower color is one of the most important features of ornamental plants. Its development and regulation are influenced by many internal and external factors. Therefore, understanding the mechanism of color development and its regulation provides an important theoretical basis and premise for the cultivation and improvement of new color varieties of ornamental plants. This paper outlines the functions of petal tissue structure, as well as the distribution and type of pigments, especially anthocyanins, in color development. The progress of research on flower color regulation with a focus on physical factors, chemical factors, and genetic engineering is introduced. The shortcomings of flower color research and the potential directions for future development are explored to provide a broad background for flower color improvements in ornamental plants. PMID:25964787

  7. Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development.

    PubMed

    Togher, Katie L; Togher, Katie L; O'Keeffe, Majella M; O'Keeffe, Majella M; Khashan, Ali S; Khashan, Ali S; Gutierrez, Humberto; Gutierrez, Humberto; Kenny, Louise C; Kenny, Louise C; O'Keeffe, Gerard W; O'Keeffe, Gerard W

    2014-06-01

    "Fetal programming" is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal development. Excessive fetal glucocorticoid exposure during pregnancy results in low birth weight and abnormalities in a number of tissues. The amount of fetal exposure to maternal glucocorticoids depends on the expression of HSD11B2, an enzyme predominantly produced by the syncytiotrophoblast in the placenta. This protects the fetus by converting active glucocorticoids into inactive forms. In this review we examine recent findings regarding placental HSD11B2 that suggest that its epigenetic regulation may mechanistically link maternal stress and long-term health consequences in affected offspring.

  8. Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

    PubMed Central

    Togher, Katie L; Togher, Katie L; O'Keeffe, Majella M; O'Keeffe, Majella M; Khashan, Ali S; Khashan, Ali S; Gutierrez, Humberto; Gutierrez, Humberto; Kenny, Louise C; Kenny, Louise C; O'Keeffe, Gerard W; O'Keeffe, Gerard W

    2014-01-01

    “Fetal programming” is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal development. Excessive fetal glucocorticoid exposure during pregnancy results in low birth weight and abnormalities in a number of tissues. The amount of fetal exposure to maternal glucocorticoids depends on the expression of HSD11B2, an enzyme predominantly produced by the syncytiotrophoblast in the placenta. This protects the fetus by converting active glucocorticoids into inactive forms. In this review we examine recent findings regarding placental HSD11B2 that suggest that its epigenetic regulation may mechanistically link maternal stress and long-term health consequences in affected offspring. PMID:24717516

  9. Regulator of G protein signaling 2 (Rgs2) regulates neural crest development through Pparδ-Sox10 cascade.

    PubMed

    Lin, Sheng-Jia; Chiang, Ming-Chang; Shih, Hung-Yu; Hsu, Li-Sung; Yeh, Tu-Hsueh; Huang, Yin-Cheng; Lin, Ching-Yu; Cheng, Yi-Chuan

    2017-03-01

    Neural crest cells are multipotent progenitors that migrate extensively and differentiate into numerous derivatives. The developmental plasticity and migratory ability of neural crest cells render them an attractive model for studying numerous aspects of cell progression. We observed that zebrafish rgs2 was expressed in neural crest cells. Disrupting Rgs2 expression by using a dominant negative rgs2 construct or rgs2 morpholinos reduced GTPase-activating protein activity, induced the formation of neural crest progenitors, increased the proliferation of nonectomesenchymal neural crest cells, and inhibited the formation of ectomesenchymal neural crest derivatives. The transcription of pparda (which encodes Pparδ, a Wnt-activated transcription factor) was upregulated in Rgs2-deficient embryos, and Pparδ inhibition using a selective antagonist in the Rgs2-deficient embryos repaired neural crest defects. Our results clarify the mechanism through which the Rgs2-Pparδ cascade regulates neural crest development; specifically, Pparδ directly binds to the promoter and upregulates the transcription of the neural crest specifier sox10. This study reveals a unique regulatory mechanism, the Rgs2-Pparδ-Sox10 signaling cascade, and defines a key molecular regulator, Rgs2, in neural crest development.

  10. Genetic variation in the hypothalamic-pituitary-adrenocortical axis regulatory factor, T-box 19, and the angry/hostility personality trait.

    PubMed

    Wasserman, D; Geijer, T; Sokolowski, M; Rozanov, V; Wasserman, J

    2007-06-01

    Neurotic personality traits are important factors in several psychiatric disorders and suicidal behavior. Here, we have investigated the existence of potential relationships between neurotic personality traits and genetic variation. Non-suicidal parents derived from trios (suicide attempter and both parents) and non-suicidal volunteers, examined by the Neuroticism, Extraversion and Openness (NEO) Personality Inventory - Revised (NEO PI-R), were divided into screening and replication samples. The screening sample (n= 127) was used to select potential relationships between neurotic personality traits and genetic variation among 130 single nucleotide polymorphisms (SNPs). Screening (analysis of variance) with regard to the personality dimension neuroticism indicated potential relationships at three different loci. More detailed analysis of these three SNPs at NEO PI-R facet level indicated four potential relationships. T-test analysis in the replication sample (n= 617) was used to retest the relationships indicated during screening. One of those relationships was confirmed in the replication sample (P= 0.0052; Bonferroni correction), indicating that genetic variation at the human T-box 19 (TBX19) locus is related to the personality trait angry/hostility. Furthermore, using analysis of haplotypes among trios by transmission disequilibrium test and its extension, the family-based association test, overtransmission of a haplotype GAC at the TBX19 locus was associated with increased angry/hostility scores among suicide attempters (P= 0.009; Bonferroni correction). This is to our knowledge the first report on the association of the angry hostility personality trait with genetic variation at the TBX19 locus, an important regulator of the hypothalamic-pituitary-adrenocortical axis.

  11. Long-term voluntary exercise and the mouse hypothalamic-pituitary-adrenocortical axis: impact of concurrent treatment with the antidepressant drug tianeptine.

    PubMed

    Droste, S K; Schweizer, M C; Ulbricht, S; Reul, J M H M

    2006-12-01

    We investigated whether voluntary exercise and concurrent antidepressant treatment (tianeptine; 20 mg/kg/day; 4 weeks) exert synergistic effects on the mouse hypothalamic-pituitary-adrenocortical (HPA) axis. Animals had access to a running wheel, were treated with the antidepressant, or received both conditions combined. Control mice received no running wheel and no drug treatment. Exercise resulted in asymmetric changes in the adrenal glands. Whereas sedentary mice had larger left adrenals than right ones, this situation was abolished in exercising animals, mainly due to enlargement of the right adrenal cortex. However, antidepressant treatment alone was ineffective whereas the combination of antidepressant treatment and exercise resulted in an enlargement of both adrenal cortices. In these respective conditions, the levels of tyrosine hydroxylase (TH) mRNA expression in the left and right adrenal medullas varied greatly in parallel to the changes observed in the adrenal cortex sizes. TH mRNA expression in the locus coeruleus of exercising mice was significantly increased irrespective of concomitant tianeptine treatment. Corticotrophin-releasing factor mRNA levels in the hypothalamic paraventricular nucleus were decreased after voluntary exercise but were unaffected by tianeptine. Exercise, particularly in combination with tianeptine treatment, resulted in decreased early morning baseline plasma levels of corticosterone. If animals were exposed to novelty (i.e. a mild psychological stressor), a decreased response in plasma corticosterone levels was observed in the exercising mice. By contrast, after restraint, a mixed physical and psychological stressor, exercising mice showed an enhanced response in plasma corticosterone compared to the controls; a response which was even further boosted in exercising mice concomitantly treated with tianeptine. Under either condition, plasma adrenocorticotrophic hormone levels were not different between groups. Thus, voluntary

  12. Developing Connections for Affective Regulation: Age-Related Changes in Emotional Brain Connectivity

    ERIC Educational Resources Information Center

    Perlman, Susan B.; Pelphrey, Kevin A.

    2011-01-01

    The regulation of affective arousal is a critical aspect of children's social and cognitive development. However, few studies have examined the brain mechanisms involved in the development of this aspect of "hot" executive functioning. This process has been conceptualized as involving prefrontal control of the amygdala. Here, using functional…

  13. Self-Regulated Strategy Development Instruction: Effects of Lesson Structure on a Teacher's Behaviors

    ERIC Educational Resources Information Center

    Kubina, Richard M., Jr.; Mason, Linda H.; Vostal, Brooks R.; Taft, Raol J.

    2011-01-01

    Self-regulated strategy development instruction or SRSD is a method developed for teaching students how and what to think while writing. SRSD instruction for the persuasive writing strategy POW (Pick my idea, Organize notes, Write and Say more) + TREE (Topic sentence, Reasons, Explain reasons, Ending) helps students by teaching them to develop…

  14. The Design and Development of the "Self-Regulated Learning Inventory": A Status Report.

    ERIC Educational Resources Information Center

    Lindner, Reinhard W.; And Others

    The development of an inventory to measure self-regulated learning is reported. The first step involved the generation of an item pool based on a literature review. A pool of items was developed based on the five identified factors of metacognition, learning strategies, motivation, contextual sensitivity, and environmental utilization and control.…

  15. Identification of Novel Regulators of atonal Expression in the Developing Drosophila Retina

    PubMed Central

    Melicharek, David; Shah, Arpit; DiStefano, Ginnene; Gangemi, Andrew J.; Orapallo, Andrew; Vrailas-Mortimer, Alysia D.; Marenda, Daniel R.

    2008-01-01

    Atonal is a Drosophila proneural protein required for the proper formation of the R8 photoreceptor cell, the founding photoreceptor cell in the developing retina. Proper expression and refinement of the Atonal protein is essential for the proper formation of the Drosophila adult eye. In vertebrates, expression of transcription factors orthologous to Drosophila Atonal (MATH5/Atoh7, XATH5, and ATH5) and their progressive restriction are also involved in specifying the retinal ganglion cell, the founding neural cell type in the mammalian retina. Thus, identifying factors that are involved in regulating the expression of Atonal during development are important to fully understand how retinal neurogenesis is accomplished. We have performed a chemical mutagenesis screen for autosomal dominant enhancers of a loss-of-function atonal eye phenotype. We report here the identification of five genes required for proper Atonal expression, three of which are novel regulators of Atonal expression in the Drosophila retina. We characterize the role of the daughterless, kismet, and roughened eye genes on atonal transcriptional regulation in the developing retina and show that each gene regulates atonal transcription differently within the context of retinal development. Our results provide additional insights into the regulation of Atonal expression in the developing Drosophila retina. PMID:18832354

  16. Osteoblast extracellular Ca2+ -sensing receptor regulates bone development, mineralization, and turnover.

    PubMed

    Dvorak-Ewell, Melita M; Chen, Tsui-Hua; Liang, Nathan; Garvey, Caitlin; Liu, Betty; Tu, Chialing; Chang, Wenhan; Bikle, Daniel D; Shoback, Dolores M

    2011-12-01

    The extracellular Ca(2+) -sensing receptor (CaR), a G protein-coupled receptor responsible for maintenance of calcium homeostasis, is implicated in regulation of skeletal metabolism. To discern the role of the osteoblast CaR in regulation of bone development and remodeling, we generated mice in which the CaR is excised in a broad population of osteoblasts expressing the 3.6-kb a(1) (I) collagen promoter. Conditional knockouts had abnormal skeletal histology at birth and developed progressively reduced mineralization secondary to retarded osteoblast differentiation, evident by significantly reduced numbers of osteoblasts and decreased expression of collagen I, osteocalcin, and sclerostin mRNAs. Elevated expression of ankylosis protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and osteopontin mRNAs in the conditional knockout indicate altered regulation of genes important in mineralization. Knockout of the osteoblast CaR also resulted in increased expression of the receptor activator of NF-κB ligand (RANKL), the major stimulator of osteoclast differentiation and function, consistent with elevated osteoclast numbers in vivo. Osteoblasts from the conditional knockouts exhibited delayed differentiation, reduced mineralizing capacity, altered expression of regulators of mineralization, and increased ability to promote osteoclastogenesis in coculture experiments. We conclude that CaR signaling in a broad population of osteoblasts is essential for bone development and remodeling and plays an important role in the regulation of differentiation and expression of regulators of bone resorption and mineralization.

  17. Adolescent Neurocognitive Development, Self-Regulation, and School-Based Drug Use Prevention

    PubMed Central

    Herzog, Thaddeus A.; Black, David S.; Zaman, Adnin; Riggs, Nathaniel R.; Sussman, Steve

    2014-01-01

    Adolescence is marked by several key development-related changes, including neurocognitive changes. Cognitive abilities associated with self-regulation are not fully developed until late adolescence or early adulthood whereas tendencies to take risks and seek thrilling and novel experience seem to increase significantly throughout this phase, resulting in a discrepancy between increased susceptibility to poor regulation and lower ability to exercise self-control. Increased vulnerability to drug use initiation, maintenance, and dependence during adolescence may be explained based on this imbalance in the self-regulation system. In this paper, we highlight the relevance of schools as a setting for delivering adolescent drug use prevention programs that are based on recent findings from neuroscience concerning adolescent brain development. We discuss evidence from school-based as well as laboratory research that suggests that suitable training may improve adolescents’ executive brain functions that underlie self-regulation abilities and, as a result, help prevent drug use and abuse. We note that considerable further research is needed in order (1) to determine that self-regulation training has effects at the neurocognitive level and (2) to effectively incorporate self-regulation training based on neuropsychological models into school-based programming. PMID:23408284

  18. A polymorphic form of steroidogenic factor-1 is associated with adrenocorticotropin resistance in y1 mouse adrenocortical tumor cell mutants.

    PubMed

    Frigeri, Claudia; Tsao, Jennivine; Cordova, Martha; Schimmer, Bernard P

    2002-10-01

    ACTH resistance in mutant derivatives of the Y1 mouse adrenocortical tumor cell line results from a defect that affects the activity of steroidogenic factor-1 (SF1), thereby preventing the expression of the melanocortin-2 receptor. In this report, we show that the SF1 genes in ACTH-resistant mutants differ from the gene in ACTH-responsive Y1 cells by two base changes-one that changes an Ala to Ser at codon 172, and one in the third position of codon 3 that does not affect the protein sequence. Furthermore, several of the mutants contain multiple copies of this alternate SF1 gene (SF1(S172)) on acentric chromosome fragments. The SF1(S172) allele represents a polymorphism rather than a spontaneous mutation because the two SF1 alleles can be traced to the hybrid mouse strain (C57L/J x A/HeJ) from which the original adrenal tumor was derived. The SF1(A172) allele also is found in C57Bl/6J and C57Bl/10J mice, whereas the SF1(S172) allele also is found in C3H/HeJ and DBA/2J mice. The two forms of SF1 had only modest differences in activity suggesting that the SF1 polymorphism per se is not directly responsible for ACTH resistance. Our results indicate that the SF1(S172) allele is a marker of ACTH resistance in this family of adrenocortical tumor cells.

  19. First Case Report of a Sporadic Adrenocortical Carcinoma With Gastric Metastasis and a Synchronous Gastrointestinal Stromal Tumor of the Stomach.

    PubMed

    Kovecsi, Attila; Jung, Ioan; Bara, Tivadar; Bara, Tivadar; Azamfirei, Leonard; Kovacs, Zsolt; Gurzu, Simona

    2015-09-01

    Adrenocortical carcinoma is a rare tumor with high aggresivity that can associate systemic metastases. A 71-year-old man was hospitalized for gastric cancer. The abdominal computed tomography also revealed a tumor above the right kidney. Total gastrectomy and right adrenalectomy were performed. The encapsulated tumor of the adrenal gland weighed 560 grams and presented diffuse tumor architecture under microscope, with capsular, sinusoidal, and vascular invasion. The large tumor cells had a polygonal shape, with slight basophilic, eosinophilic, or vacuolated cytoplasm, pleomorphic nuclei, and a high mitotic rate. In the stomach, the protruded tumor was covered by normal mucosa; under microscope, the tumor cells were observed only in the submucosal layer. In primary adrenal tumor and gastric metastasis the tumor cells were marked by vimentin, inhibin, synaptophysin, neuron-specific enolase, and calretinin. Based on these criteria, the diagnosis of adrenocortical carcinoma (ACC) with gastric metastasis and no lymph node metastases was established. A synchronous 10 × 10-mm-sized gastrointestinal stromal tumor (GIST) of the stomach, without mitoses, was also identified. So far, as we know, this is the 15th case of ever reported synchronous/metachronous sporadic ACCs; the ACC-related gastric metastases either synchronous ACC and GIST, has not been reported in the literature previously.

  20. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma.

    PubMed

    Kroiss, Matthias; Quinkler, Marcus; Lutz, Werner K; Allolio, Bruno; Fassnacht, Martin

    2011-11-01

    Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, (o,p'-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for various forms of glucocorticoid excess. Through still largely unknown mechanisms, mitotane inhibits adrenal steroid synthesis and adrenocortical cell proliferation. Mitotane increases hepatic metabolism of cortisol, and an increased replacement dose of glucocorticoids is standard of care during mitotane treatment. Recently, sunitinib, a multityrosine kinase inhibitor (TKI), has been found to be rapidly metabolized by CYP3A4 during mitotane treatment, indicating clinically relevant drug interactions with mitotane. We here summarize the current evidence concerning mitotane-induced changes in hepatic monooxygenase expression, list drugs potentially affected by mitotane-related CYP3A4 induction and suggest alternatives. For example, using standard doses of macrolide antibiotics is unlikely to reach sufficient plasma levels, making fluoroquinolones in many cases a superior choice. Similarly, statins such as simvastatin are metabolized by CYP3A4, whereas others like pravastatin are not. Importantly, in the past, several clinical trials using cytotoxic drugs but also targeted therapies in ACC yielded disappointing results. This lack of antineoplastic activity may be explained in part by insufficient drug exposure owing to enhanced drug metabolism induced by mitotane. Thus, induction of CYP3A4 by mitotane needs to be considered in the design of future clinical trials in ACC.

  1. A case of primary aldosteronism caused by unilateral multiple adrenocortical micronodules presenting as muscle cramps at rest: The importance of functional histopathology for identifying a culprit lesion.

    PubMed

    Ito, Atsushi; Yamazaki, Yuto; Sasano, Hironobu; Matsubara, Daisuke; Fukushima, Noriyoshi; Tamba, Mio; Tabata, Kenichi; Ashizawa, Kentaro; Takei, Akihito; Koizumi, Masaru; Sakuma, Yasunaru; Sata, Naohiro; Oshiro, Hisashi

    2017-04-01

    Unilateral multiple adrenocortical micronodules (UMNs) constitute a rare subset of primary aldosteronism (PA) characterized by the hypersecretion of aldosterone derived from multiple small nodules in the zona glomerulosa of the unilateral adrenal grand. This case study describes a 49-year-old man with PA and UMNs who presented with muscle cramps at rest due to hypokalemia. The patient had a 6-year history of hypertension treated with antihypertensive drugs. Imaging studies revealed bilateral adrenal nodules as large as 5 mm. Adrenal venous sampling confirmed unilateral PA; therefore, the patient underwent the removal of the affected adrenal gland. Macroscopically, the removed adrenal gland exhibited irregular adrenocortical thickening accompanied by ill-defined, adrenocortical macronodules as large as 6 mm. The zona glomerulosa was histologically hyperplastic. However, an immunohistochemistry test of the steroidogenic enzymes revealed that these macronodules and the hyperplastic glomerular layer tested negative for CYB11B2. Moreover, we observed adrenocortical micronodules as large as 0.5 mm that tested immunohistochemically positive for CYP11B2 and HSD3B2 but negative for CYP17A1 and CYP11B1. Thus, UMNs were diagnosed. This case instructively indicates that a grossly or histologically detectable nodular lesion is not necessarily a culprit lesion for PA. Therefore, functional histopathology is indispensable for the correct subclassification of PA.

  2. PROFILING GENE EXPRESSION IN HUMAN H295R ADRENOCORTICAL CARCINOMA CELLS AND RAT TESTES TO IDENTIFY PATHWAYS OF TOXICITY FOR CONAZOLE FUNGICIDES

    EPA Science Inventory

    Profiling Gene Expression in Human H295R Adrenocortical Carcinoma Cells and Rat Testes to Identify Pathways of Toxicity for Conazole Fungicides
    Ren1, H., Schmid1, J., Retief2, J., Turpaz2, Y.,Zhang3, X.,Jones3,