bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumour markers requesting pattern with regards to different organizational settings in Italy: a survey of hospital laboratories
Authors: Franceschini Roberta , Trevisiol Chiara , Dittadi Ruggero , Gion Massimo
Published: June 2009

Background

Tumour markers are frequently used in clinical practice and the reason for ordering varies considerably and often seems to be inappropriate. We carried out a survey of Italian laboratories on their current pattern of use.

Methods

Forty-four laboratories located in health-care institutions with inpatient beds were surveyed about the organizational, clinical and methodological aspects of tumour markers ordering.

Results

Thirty-one laboratories (70%) filled in and returned the questionnaire. Overall, 977,786 tumour marker tests were scrutinized. The pattern of tumour marker use did not seem to be influenced by the institutional setting, by availability of oncology facilities or by adoption of clinical guidelines. In addition, the information flow from clinicians to the laboratory and vice versa was poor and informal.

Conclusions

Monitoring tumour marker pattern use can provide valuable information for health-care decision makers, highlighting potential inadequacies in laboratory services but also identifying problems in other areas of health-care delivery that could benefit from educational programmes.
Hypobetalipoproteinaemia secondary to chronic hepatitis C virus infection in a patient with familial hypercholesterolaemia
Authors: Bima Abdulhadi I , Hooper Amanda J , van Bockxmeer Frank M , Burnett John R
Published: June 2009

Familial hypercholesterolaemia (FH) is a common genetic disorder characterized by high plasma low-density lipoprotein (LDL)-cholesterol and premature coronary artery disease. Many factors, such as illness, high-dose statin therapy or a strict vegan diet can cause hypobetalipoproteinaemia (HBL). The more common secondary causes of HBL in the hospital setting include cachexia, intestinal malabsorption, malnutrition, severe liver disease and hyperthyroidism. We report a case of HBL in a 43-year-old man with previously demonstrated marked hypercholesterolaemia who attended a lipid disorders clinic for FH cascade screening. Surprisingly, a lipid profile taken at that time showed low plasma LDL-cholesterol and apolipoprotein B concentrations of 1.6 mmol/L and 0.61 g/L, respectively. He was not on lipid-lowering therapy. DNA sequencing showed that he was heterozygous for the LDLR gene mutation (C677R) present in other affected family members. Of interest, his serum transaminases were increased by ∼3-fold and hepatitis serology and genotyping confirmed a diagnosis of hepatitis C virus (HCV) infection. In summary, we describe a case of HBL secondary to chronic HCV infection in a patient with FH, confirmed by mutational analysis.
Variability in the measurement of lipoprotein(a) in the British Isles
Authors: Mackness Mike , Hughes Elizabeth
Published: June 2009

Background

Elevated Lipoprotein(a) concentrations are a risk factor for coronary heart disease; however, methodological problems have prevented its introduction to routine clinical practice.

Methods

Thirty-six laboratories each assayed 20 samples (the same 20 in each laboratory) using two different Lp(a) kits per laboratory, randomly assigned from the total of 12 used in the study.

Results

The duplicate error, i.e. the error between-duplicate analyses for each sample, for all kits was small, indicating all kits had a good precision for all the assays. However, there was a very large variation between the kits in the Lp(a) concentration assigned to a sample that could be over 100%. All methods showed a negative or positive bias as the concentration of Lp(a) increased. Most worryingly, as used in this study, several Lp(a) kits detected Lp(a) in a solution of 5% bovine serum albumin in phosphate-buffered saline. The between-laboratory variation in Lp(a) concentration measured using the same kit was very large, e.g. for a sample with a mean concentration of 78.8 mg/dL Lp(a) the between-laboratory variation was 29.7 mg/dL (37.7%). Even with samples with a relatively low Lp(a) concentration of 16.0 mg/dL had a between-laboratory variation of 12.3 mg/dL (76.8%).

Conclusion

There is wide variability in reported Lp(a) concentrations, assayed in the same sample, using different Lp(a) assays. At the present time these differences prevent the use of Lp(a) as a routine diagnostic tool.
Unspanned Stochastic Volatility in Affine Models: Evidence from Eurodollar Futures and Options
Authors: Bikbov Ruslan , Chernov Mikhail
Published: June 2009

Unspanned stochastic volatility (USV) refers to the inability of bonds to replicate volatility-sensitive derivative securities. Affine term structure models require special restrictions on the parameters to exhibit USV. We use a joint Eurodollar futures and options data set to estimate affine three-factor models with and without USV restrictions. The unrestricted model captures prices of futures and options well. Option pricing errors are much larger in the USV model. The USV model is rejected in favor of the unrestricted model based on the likelihood ratio and Wald tests. We use the implications of the unrestricted model as a benchmark for understanding the extant evidence that favors USV. Specifically, we replicate extant tests in samples simulated from the unrestricted model. We show that none of the existing findings contradict the model without USV restrictions.
Product Variety and Endogenous Pricing with Evaluation Costs
Authors: Villas-Boas J. Miguel
Published: June 2009

One important decision firms must make is to select the product line (characteristics and number of products) to offer consumers. This paper explores the effect of the interaction between consumer evaluation costs and pricing on the optimal product line length to offer consumers. Before deciding to buy a product among all products offered, a consumer learns the product line length. Given the product line length, a consumer decides whether to evaluate the products available and their prices. This decision to evaluate depends on the expected consumer surplus after the evaluation being greater than the evaluation costs. When the firm offers few products, the firm may not attract many consumers because of lack of product fit and may be forced to offer low prices. When the firm offers many products, all consumers will find a great product fit; that is, the variance of consumer valuations per product chosen is lower. This allows the firm to charge high prices to extract ex post consumer surplus, resulting in lower ex ante expected consumer surplus, which may lead consumers not to evaluate the products in the first place. That is, by offering fewer products a firm can commit not to extract all possible consumer surplus. These two forces may then lead to the existence of an interior optimal number of products to offer. The optimal number of products offered is decreasing in the evaluation costs.
Tobacco Use Among Individuals With Intellectual or Developmental Disabilities: A Brief Review
Authors: Steinberg Marc L. , Heimlich Laura , Williams Jill M.
Published: June 2009

Tobacco use is the leading preventable cause of death in the United States. Although few tobacco control efforts target individuals with intellectual and/or developmental disabilities, this population may be especially vulnerable to the deleterious effects of tobacco use and dependence. Individuals with intellectual and developmental disabilities suffer from the health, financial, and stigmatizing effects of tobacco use. The present review examined the current literature with respect to the prevalence and patterns of tobacco use in individuals with intellectual and developmental disabilities, the importance of addressing tobacco use in these smokers, and policies surrounding tobacco use in this population. Suggestions for additional avenues of inquiry as well as modifications to current cessation treatments are proposed.
Involvement of Adult Siblings of Persons With Developmental Disabilities in Future Planning
Authors: Heller Tamar , Kramer John
Published: June 2009

This study examined factors influencing involvement of siblings of individuals with developmental disabilities in future planning and their expectation of future caregiving. The sample consisted of 139 adult siblings recruited from an online sibling list and a sibling conference. Results indicated that few families made plans or involved siblings in the planning. Siblings who were most involved in future planning were older, more involved in disability activities, and provided more support to their sibling with disabilities. About 38% of siblings expected to be primary caregivers and were more likely to expect this role if the sibling with a disability lived closer and was female, had more sibling contact, provided them with more support, and felt greater caregiving satisfaction. Major support needs of siblings were for support groups, workshops–training on how to assume caregiving responsibility, financial support, and printed material on making future plans.
Avaldsnes in Südwestnorwegen – ein Fundplatz von europäischem Rang in einer archäologischen Langzeitperspektive
Authors: Grimm Oliver
Published: June 2009

Avaldsnes liegt auf der Insel Karmøy an einem Nadelöhr der südwestnorwegischen Schifffahrtsroute. Diese Lage machte Avaldsnes schon frühzeitig zu einem Ort von großer strategischer Bedeutung. Der Artikel beschreibt zunächst einige der bedeutendsten archäologischen Befunde und Funde in Avaldsnes: zahlreiche Großgrabhügel mit einem Durchmesser bis 50 m, reich ausgestattete Gräber aus der Bronze-, Spätkaiser-, Merowinger- und Wikingerzeit, einen schriftlich bezeugten Königssitz am Übergang zum skandinavischen Mittelalter sowie einen Hafen mit Verbindungen zur Hanse. Die jüngste Forschung geht sicher nicht zu Unrecht von einem im Kern südwestnorwegischen und eventuell bereits merowingerzeitlichen Königtum mit einem Hauptsitz in Avaldsnes aus. Der Beitrag schließt mit einem mehr und mehr internationalisierten Blickwinkel, der u.a. die Erörterung von Prunkgräbern, Königssitzen und Zentralplätzen in der mittel- und nordeuropäischen Forschung einschließt. Avaldsnes erweist sich dabei als ein Ort, der in Norwegen und zum Teil auch in Nordeuropa singulär ist und sich gut auch vor dem Hintergrund mitteleuropäischer Fundplätze und Forschungen betrachten lässt.
Hinweise auf eine Pfeilspitzenwerkstatt in der ersten Hälfte des 1. Jahrtausends v. Chr.
Authors: Yalçıklı Derya
Published: June 2009

Im 8./7. Jahrtausend v. Chr. traten in Anatolien erste metallurgische Aktivitäten in Erscheinung, im 5. Jahrtausend v. Chr. und später wies die metallurgische Technologie dann eine rasche Entwicklung auf. Diese technologischen Entwicklungen können dank der bei archäologischen Grabungen entdeckten Werkstätten und der Metallfunde verfolgt werden. Auf einem Teil der Metallfunde aus Anatolien befinden sich verschiedenförmige einfache Zeichen. Wenn auch allgemein die Ansicht vertreten wird, dass diese Zeichen jeweils einer bestimmten Werkstatt oder einem bestimmten Metallmeister zuzuordnen seien, so sind die aus Anatolien bekannten Zeichen bisher doch noch nicht näher untersucht worden. Aber auch wir vertreten nach der genauen Untersuchung von Metallfunden aus dem Anatolien der ersten Hälfte des 1. Jahrtausends v. Chr. die Auffassung, dass es sich bei dem auf 18 Pfeilspitzen festgestellten Zeichen aus drei Kerben ebenso wie bei den Zeichen aus früheren Epochen um ein einer bestimmten Werkstatt oder einem bestimmten Metallmeister zuzuordnendes Zeichen handelt. Bei diesen in Zentral- und Nordanatolien verbreiteten und den Skythen zuzuschreibenden Pfeilspitzen handelt es sich um Gegenstände, die uns auch hinsichtlich der Verbreitung und der politischen Aktivitäten dieser Gesellschaften in der Mitte des 7./6. Jahrhunderts v. Chr. wichtige Hinweise geben können.
Zum Gräberfeld von Schirndorf: ein Beitrag zur Chronologie der Hallstattzeit Nordostbayerns
Authors: Müller-Scheeßel Nils
Published: June 2009

Das Gräberfeld von Schirndorf stellt eine der wenigen nahezu vollständig ausgegrabenen Nekropolen der Hallstattzeit Süddeutschlands dar; durch die Publikationen von A. Stroh und R. Hughes ist es zudem in vorbildlicher Weise für die Forschung erschlossen. Der vorliegende Beitrag stellt die sechs Bände vor und bewertet die erzielten Ergebnisse. Insbesondere wurde eine computergestützte Neuanalyse der Keramikseriation von Hughes vorgenommen. Als Ergebnis liegt eine zeitliche Gliederung der Gräber von Schirndorf in vier Gruppen vor. Ein Vergleich mit den beigegebenen Metalltypen erlaubt die Lokalisierung des Übergangs von der Älteren zur Jüngeren Hallstattzeit innerhalb der vierten Gruppe. Eine Gegenüberstellung mit Chronologiesystemen angrenzender Regionen schließt den Beitrag ab.
Correlation between Thermal and Mechanical Properties of the 10NiCr11
Authors: Ghrib Taher , Bouhafs Mahmoud , Yacoubi Noureddine
Published: June 2009

In this work we have studied the effect of the carburizing duration on the evolution of the thermal and mechanical properties of the 10NiCr11 steel. The thermal properties are determined by the photothermal deflection technique and it was shown that the thermal conductivity as well as the thermal diffusivity decrease with the carbon fraction in the steel unlike the Vickers hardness which increases. From this study we have established an empiric mathematical formula between Vickers hardness, the thermal properties, and the carburizing duration which permit to deduce the Vickers hardness value without needing to measure it.
Genetic Modifiers ofdFMR1Encode RNA Granule Components in Drosophila
Authors: Cziko Anne-Marie J , McCann Cathal T , Howlett Iris C , Barbee Scott A , Duncan Rebecca P , Luedemann Rene , Zarnescu Daniela , Zinsmaier Konrad E , Parker Roy R , Ramaswami Mani
Published: June 2009

Mechanisms of neuronal mRNA localization and translation are of considerable biological interest. Spatially regulated mRNA translation contributes to cell-fate decisions and axon guidance during development, as well as to long-term synaptic plasticity in adulthood. The Fragile-X Mental Retardation protein (FMRP/dFMR1) is one of the best-studied neuronal translational control molecules and here we describe the identification and early characterization of proteins likely to function in the dFMR1 pathway. Induction of the dFMR1 in sevenless-expressing cells of the Drosophila eye causes a disorganized (rough) eye through a mechanism that requires residues necessary for dFMR1/FMRP's translational repressor function. Several mutations in dco, orb2, pAbp, rm62, and smD3 genes dominantly suppress the sev-dfmr1 rough-eye phenotype, suggesting that they are required for dFMR1-mediated processes. The encoded proteins localize to dFMR1-containing neuronal mRNPs in neurites of cultured neurons, and/or have an effect on dendritic branching predicted for bona fide neuronal translational repressors. Genetic mosaic analyses indicate that dco, orb2, rm62, smD3, and dfmr1 are dispensable for translational repression of hid, a microRNA target gene, known to be repressed in wing discs by the bantam miRNA. Thus, the encoded proteins may function as miRNA- and/or mRNA-specific translational regulators in vivo.
Transcriptional Regulation of Metabolism Associated With the Increased Desiccation Resistance of the Cactophilic Drosophila mojavensis
Authors: Matzkin Luciano M , Markow Therese A
Published: June 2009

In Drosophila, adaptation to xeric environments presents many challenges, greatest among them the maintenance of water balance. Drosophila mojavensis, a cactophilic species from the deserts of North America, is one of the most desiccation resistant in the genus, surviving low humidity primarily by reducing its metabolic rate. Genetic control of reduced metabolic rate, however, has yet to be elucidated. We utilized the recently sequenced genome of D. mojavensis to create an oligonucleotide microarray to pursue the identities of the genes involved in metabolic regulation during desiccation. We observed large differences in gene expression between male and female D. mojavensis as well as both quantitative and qualitative sex differences in their ability to survive xeric conditions. As expected, genes associated with metabolic regulation and carbohydrate metabolism were differentially regulated between stress treatments. Most importantly, we identified four points in central metabolism (Glyceraldehyde 3-phosphate dehydrogenase, transaldolase, alcohol dehydrogenase, and phosphoenolpyruvate carboxykinase) that indicate the potential mechanisms controlling metabolic rate reduction associated with desiccation resistance. Furthermore, a large number of genes associated with vision pathways also were differentially expressed between stress treatments, especially in females, that may underlie the initial detection of stressful environments and trigger subsequent metabolic changes.
Domains of Heterochromatin Protein 1 Required forDrosophila melanogasterHeterochromatin Spreading
Authors: Hines Karrie A , Cryderman Diane E , Flannery Kaitlin M , Yang Hongbo , Vitalini Michael W , Hazelrigg Tulle , Mizzen Craig A , Wallrath Lori L
Published: June 2009

Centric regions of eukaryotic genomes are packaged into heterochromatin, which possesses the ability to spread along the chromosome and silence gene expression. The process of spreading has been challenging to study at the molecular level due to repetitious sequences within centric regions. A heterochromatin protein 1 (HP1) tethering system was developed that generates “ectopic heterochromatin” at sites within euchromatic regions of the Drosophila melanogaster genome. Using this system, we show that HP1 dimerization and the PxVxL interaction platform formed by dimerization of the HP1 chromo shadow domain are necessary for spreading to a downstream reporter gene located 3.7 kb away. Surprisingly, either the HP1 chromo domain or the chromo shadow domain alone is sufficient for spreading and silencing at a downstream reporter gene located 1.9 kb away. Spreading is dependent on at least two H3K9 methyltransferases, with SU(VAR)3-9 playing a greater role at the 3.7-kb reporter and dSETDB1 predominately acting at the 1.9 kb reporter. These data support a model whereby HP1 takes part in multiple mechanisms of silencing and spreading.
Corepressor/Coactivator Paradox: Potential Constitutive Coactivation by Corepressor Splice Variants
Authors: Meng Xianwang , Arulsundaram Vishnuka D. , Yousef Ahmed F. , Webb Paul , Baxter John D. , Mymryk Joe S. , Walfish Paul G.
Published: June 2009

The functional consequences of the interaction of transcriptional coregulators with the human thyroid hormone receptor (TR) in mammalian cells are complex. We have used the yeast, Saccharomyces cerevisiae, which lack endogenous nuclear receptors (NRs) and NR coregulators, as a model to decipher mechanisms regulating transcriptional activation by TR. In effect, this system allows the reconstitution of TR mediated transcription complexes by the expression of specific combinations of mammalian proteins in yeast. In this yeast system, human adenovirus 5 early region 1A (E1A), a natural N-CoR splice variant (N-CoRI) or an artificial N-CoR truncation (N-CoRC) coactivate unliganded TRs and these effects are inhibited by thyroid hormone (TH). E1A contains a short peptide sequence that resembles known corepressor-NR interaction motifs (CoRNR box motif, CBM), and this motif is required for TR binding and coactivation. N-CoRI and N-CoRC contain three CBMs, but only the C-terminal CBM1 is critical for coactivation. These observations in a yeast model system suggest that E1A and N-CoRI are naturally occurring TR coactivators that bind in the typical corepressor mode. These findings also raise the possibility that alternative splicing events which form corepressor proteins containing only C-terminal CBM motifs could represent a novel mechanism in mammalian cells for regulating constitutive transcriptional activation by TRs.
An improved high throughput protein-protein interaction assay for nuclear hormone receptors
Authors: Goodson Michael L. , Farboud Behnom , Privalsky Martin L.
Published: June 2009

The Glutathione-S-Transferase (GST) “pulldown” assay has been used extensively to assay protein interactions in vitro. This methodology has been especially useful for investigating the interactions of nuclear hormone receptors with a wide variety of their interacting partners and coregulatory proteins. Unfortunately, the original GST-pulldown technique relies on multiple binding, washing and elution steps performed in individual microfuge tubes, and requires repeated centrifugation, aspiration, and suspension steps. This type of batch processing creates a significant liquid handling bottleneck, limiting the number of sample points that can be incorporated into one experiment and producing inherently less efficient washing and elution than would a flow-through methodology. In this manuscript, we describe the adaptation of this GST-pulldown assay to a 96-well filter plate format. The use of a multi-well filter plate makes it possible to assay more samples in significantly less time using less reagents and more efficient sample processing than does the traditional single tube assay.
Visualizing the action of steroid hormone receptors in living cells
Authors: Griekspoor Alexander , Zwart Wilbert , Neefjes Jacques , Michalides Rob
Published: June 2009

Transcription controlled by Steroid Hormone Receptors (SHRs) plays a key role in many important physiological processes like organ development, metabolite homeostasis, and response to external stimuli. Understandably, the members of this family have drawn a lot of attention from the scientific community since their discovery, four decades ago. Still, after many years of research we are only beginning to unravel the complex nature of these receptors. The pace at which we do has improved significantly in recent years with the discovery of genetically encoded fluorescent probes, and the accompanying revival of biophysical approaches that allow more detailed study of SHRs. Here, we will look into the different aspects of SHR signalling, and discuss how biophysical techniques have contributed to visualizing their function in their native context, the living cell.
Kinases and protein phosphorylation as regulators of steroid hormone action
Authors: Weigel Nancy L. , Moore Nicole L.
Published: June 2009

Although the primary signal for the activation of steroid hormone receptors is binding of hormone, there is increasing evidence that the activities of cell signaling pathways and the phosphorylation status of these transcription factors and their coregulators determine the overall response to the hormone. In some cases, enhanced cell signaling is sufficient to cause activation of receptors in medium depleted of steroids. Steroid receptors are targets for multiple kinases. Many of the phosphorylation sites contain Ser/Thr-Pro motifs implicating proline-directed kinases such as the cyclin-dependent kinases and the mitogen-activated kinases (MAPK) in receptor phosphorylation. Although some sites are constitutively phosphorylated, others are phosphorylated in response to hormone. Still others are only phosphorylated in response to specific cell signaling pathways. Phosphorylation of specific sites has been implicated not only in overall transcriptional activity, but also in nuclear localization, protein stability, and DNA binding. The studies of the roles of phosphorylation in coregulator function are more limited, but it is now well established that many of them are highly phosphorylated and that phosphorylation regulates their function. There is good evidence that some of the phosphorylation sites in the receptors and coregulators are targets of multiple signaling pathways. Individual sites have been associated both with functions that enhance the activity of the receptor, as well as with functions that inhibit activity. Thus, the specific combinations of phosphorylations of the steroid receptor combined with the expression levels and phosphorylation status of coregulators will determine the genes regulated and the biological response.
Steroid Receptor RNA Activator (SRA1): Unusual Bifaceted Gene Products with Suspected Relevance to Breast Cancer
Authors: Leygue Etienne
Published: June 2009

The steroid receptor RNA activator (SRA) is a unique modulator of steroid receptor transcriptional activity, as it is able to mediate its coregulatory effects as a RNA molecule. Recent findings, however, have painted a more complex picture of the SRA gene (SRA1) products. Indeed, even though SRA was initially thought to be noncoding, several RNA isoforms have now been found to encode an endogenous protein (SRAP), which is well conserved among Chordata. Although the function of SRAP remains largely unknown, it has been proposed that, much like its corresponding RNA, the protein itself might regulate estrogen and androgen receptor signaling pathways. As such, data suggest that both SRA and SRAP might participate in the mechanisms underlying breast, as well as prostate tumorigenesis. This review summarizes the published literature dealing with these two faces of the SRA gene products and underscores the relevance of this bifaceted system to breast cancer development.
The coregulator Alien
Authors: Papaioannou Maria , Melle Christian , Baniahmad Aria
Published: June 2009

Alien has characteristics of a corepressor for selected members of the nuclear hormone receptor (NHR) superfamily and also for transcription factors involved in cell cycle regulation and DNA repair. Alien mediates gene silencing and represses the transactivation of specific NHRs and other transcription factors to modulate hormone response and cell proliferation. Alien is a highly conserved protein and is expressed in a wide variety of tissues. Knockout of the gene encoding Alien in mice is embryonic lethal at a very early stage, indicating an important evolutionary role in multicellular organisms. From a mechanistic perspective, the corepressor function of Alien is in part mediated by histone deacetylase (HDAC) activity. In addition, Alien seems to modulate nucleosome assembly activity. This suggests that Alien is acting on chromatin not only through recruitment of histone-modifying activities, but also through enhancing nucleosome assembly.
Steroid Receptor Coactivator 2 is Required for Female Fertility and Mammary Morphogenesis: Insights from the Mouse, Relevance to the Human
Authors: Mukherjee Atish , Amato Paula , Allred D. Craig , DeMayo Francesco J. , Lydon John P.
Published: June 2009

Although the importance of the progesterone receptor (PR) to female reproductive and mammary gland biology is firmly established, the coregulators selectively co-opted by PR in these systems have not been clearly delineated. A selective gene-knockout approach applied to the mouse, which abrogates gene function only in cell types that express PR, recently disclosed steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) to be an indispensable coregulator for uterine and mammary gland responses that require progesterone. Uterine cells positive for PR (but devoid of SRC-2) were found to be incapable of facilitating embryo implantation, a necessary first step toward the establishment of the materno-fetal interface. Importantly, such an implantation defect is not exhibited by knockouts for SRC-1 or SRC-3, underscoring the unique coregulator importance of SRC-2 in peri-implantation biology. Moreover, despite normal levels of PR, SRC-1 and SRC-3, progesterone-dependent branching morphogenesis and alveologenesis fails to occur in the murine mammary gland in the absence of SRC-2, thereby establishing a critical coregulator role for SRC-2 in signaling cascades that mediate progesterone-induced mammary epithelial proliferation. Finally, the recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer.
AR, the cell cycle, and prostate cancer
Authors: Balk Steven P. , Knudsen Karen E.
Published: June 2009

The androgen receptor (AR) is a critical effector of prostate cancer development and progression. The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention. These strategies are initially effective, and induce a mixed response of cell cycle arrest or apoptosis in prostate cancer cells. However, recurrent, incurable tumors ultimately arise as a result of inappropriately restored AR function. Based on these observations, it is imperative to define the mechanisms by which AR controls cancer cell proliferation. Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation. These functions appear to be independent of the recently identified TMPRSS2-ETS fusions. Once engaged, several components of the cell cycle machinery actively modulate AR activity throughout the cell cycle, thus indicating that crosstalk between the AR and cell cycle pathways likely modulate the mitogenic response to androgen. As will be discussed, discrete aberrations in this process can alter the proliferative response to androgen, and potentially subvert hormonal control of tumor progression.
Estrogen Receptor β: An Overview and Update
Authors: Zhao Chunyan , Dahlman-Wright Karin , Gustafsson Jan-Åke
Published: June 2009

The discovery of a second estrogen receptor (ER), designated ERβ (NR3A2), has redefined our knowledge about the mechanisms underlying cellular signaling by estrogens and has broad implications for our understanding of regulation of estrogen-responsive tissues. Highly variable and even contrasting effects of estrogens in different tissues seem to be at least partially explained by different estrogen signaling pathways, involving ERα (NR3A1) and/or ERβ. To date, two key conclusions can be drawn from the significant body of work carried out on the specific roles of the two receptor subtypes in diverse estrogen target tissues. First, ERα and ERβ have different biological functions, as indicated by their specific expression patterns and the distinct phenotypes observed in ERα and ERβ knockout (αERKO and βERKO) mice. Second, ERα and ERβ appear to have overlapping but also unique sets of downstream target genes, as judged from a set of microarray experiments. Thus, ERα and ERβ have different transcriptional activities in certain ligand, cell-type, and promoter contexts, which may help to explain some of the major differences in their tissue-specific biological actions. The phenotypes observed for βERKO mice have suggested certain therapeutic areas to be further explored. The development of ERβ-selective ligands active in animal disease models indicates new avenues for clinical exploration. ERβ agonists are being explored and validated as drugs for a growing number of indications. Hopefully, some ERβ targeted drugs will prove to be efficient in enhancing human health.
E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors
Authors: Ramamoorthy Sivapriya , Nawaz Zafar
Published: June 2009

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.
Regulatory function of the P295-T311 motif of the estrogen receptor α - does proteasomal degradation of the receptor induce emergence of peptides implicated in estrogenic responses?
Authors: Gallo Dominique , Haddad Iman , Laurent Guy , Vinh Joëlle , Jacquemotte Françoise , Jacquot Yves , Leclercq Guy
Published: June 2009

The way in which estrogen receptor α (ERα) mediates gene transcription and hormone-dependent cancer cell proliferation is now being largely reconsidered in view of several recent discoveries. ERα-mediated transcription appears to be a cyclic and transient process where the proteasome - and thus receptor degradation - plays a pivotal role. In view of our recent investigations, which demonstrate the estrogenic activity of a synthetic peptide corresponding to a regulatory motif of the receptor (ERα17p), we propose that ERα proteasomal degradation could induce the emergence of regulatory peptide(s). The latter would function as a signal and contribute to the ERα activation process, amplifying the initial hormonal stimulation and giving rise to sustained estrogenic response.
Selective androgen receptor modulators in preclinical and clinical development
Authors: Narayanan Ramesh , Mohler Michael L. , Bohl Casey E. , Miller Duane D. , Dalton James T.
Published: June 2009

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.
Function of retinoic acid receptors during embryonic development
Authors: Mark Manuel , Ghyselinck Norbert B. , Chambon Pierre
Published: June 2009

Retinoids, the active metabolites of vitamin A, regulate complex gene networks involved in vertebrate morphogenesis, growth, cellular differentiation and homeostasis. Studies performed in vitro, using either acellular systems or transfected cells, have shown that retinoid actions are mediated through heterodimers between the RAR and RXR nuclear receptors. However, in vitro studies indicate what is possible, but not necessarily what is actually occurring in vivo, because they are performed under non-physiological conditions. Therefore, genetic approaches in the animal have been be used to determine the physiological functions of retinoid receptors. Homologous recombination in embryonic stem cells has been used to generate germline null mutations of the RAR- and RXR-coding genes in the mouse. As reviewed here, the generation of such germline mutations, combined with pharmacological approaches to block the RA signalling pathway, has provided genetic evidence that RAR/RXR heterodimers are indeed the functional units transducing the RA signal during prenatal development. However, due to (i) the complexity in “hormonal” signalling through transduction by the multiple RARs and RXRs, (ii) the functional redundancies (possibly artefactually generated by the mutations) within receptor isotypes belonging to a given family, and (iii) in utero or early postnatal lethality of certain germline null mutations, these genetic studies have failed to reveal all the physiological functions of RARs and RXRs, notably in adults. Spatio-temporally-controlled somatic mutations generated in given cell types/tissues and at chosen times during postnatal life, will be required to reveal all the functions of RAR and RXR throughout the lifetime of the mouse.
Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism
Authors: Jetten Anton M.
Published: June 2009

The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORa plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4+T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.
Developmental expression of retinoic acid receptors (RARs)
Authors: Dollé Pascal
Published: June 2009

Here, I review the developmental expression features of genes encoding the retinoic acid receptors (RARs) and the ‘retinoid X’ or rexinoid receptors (RXRs). The first detailed expression studies were performed in the mouse over two decades ago, following the cloning of the murine Rar genes. These studies revealed complex expression features at all stages of post-implantation development, one receptor gene (Rara) showing widespread expression, the two others (Rarb and Rarg) with highly regionalized and/or cell type-specific expression in both neural and non-neural tissues. Rxr genes also have either widespread (Rxra, Rxrb), or highly-restricted (Rxrg) expression patterns. Studies performed in zebrafish and Xenopus demonstrated expression of Rar and Rxr genes (both maternal and zygotic), at early pre-gastrulation stages. The eventual characterization of specific enzymes involved in the synthesis of retinoic acid (retinol/retinaldehyde dehydrogenases), or the triggering of its catabolism (CYP26 cytochrome P450s), all of them showing differential expression patterns, led to a clearer understanding of the phenomenons regulated by retinoic acid signaling during development. Functional studies involving targeted gene disruptions in the mouse, and additional approaches such as dominant negative receptor expression in other models, have pinpointed the specific, versus partly redundant, roles of the RARs and RXRs in many developing organ systems. These pleiotropic roles are summarized hereafter in relationship to the receptors’ expression patterns.
Angiogenesis as a Therapeutic Target in Malignant Gliomas
Authors: Chi Andrew S. , Sorensen A. Gregory , Jain Rakesh K. , Batchelor Tracy T.
Published: June 2009

Currently, adult glioblastoma (GBM) patients have poor outcomes with conventional cytotoxic treatments. Because GBMs are highly angiogenic tumors, inhibitors that target tumor vasculature are considered promising therapeutic agents in these patients. Encouraging efficacy and tolerability in preliminary clinical trials suggest that targeting angiogenesis may be an effective therapeutic strategy in GBM patients. However, the survival benefits observed to date in uncontrolled trials of antiangiogenic agents have been modest, and several obstacles have limited their effectiveness. This article reviews the rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in GBM patients. Although challenges remain with this approach, ongoing studies may improve upon the promising initial benefits already observed in GBM patients.
Gingival Crevicular Fluid Levels of Cathelicidin LL‐37 and Interleukin‐18 in Patients With Chronic Periodontitis
Authors: Türkoğlu Oya , Emingil Gülnur , Kütükçüler Necil , Atilla Gül
Published: June 2009

Background: Cathelicidin LL‐37, an antimicrobial peptide, is part of the host innate immune response in the oral cavity. Interleukin (IL)‐18, a proinflammatory cytokine, could play a role in the progression of the inflammatory response. The aim of the present study was to determine the levels of cathelicidin LL‐37 and IL‐18 in the gingival crevicular fluid (GCF) of patients with gingivitis and chronic periodontitis.

Methods: Fifty‐nine subjects were included in the present study. Probing depth (PD), clinical attachment level (CAL), plaque index (PI), bleeding on probing, and papilla bleeding index (PBI) were assessed in patients with chronic periodontitis or gingivitis and in healthy controls. GCF levels of cathelicidin LL‐37 and IL‐18 were analyzed by enzyme‐linked immunosorbent assay.

Results: GCF levels of cathelicidin LL‐37 were significantly elevated in patients with chronic periodontitis compared to the other groups (P <0.05). No significant difference was found in the total amount of GCF IL‐18 among the study groups (P >0.05). Spearman correlation analysis revealed a positive relationship between levels of GCF cathelicidin LL‐37 and PD, CAL, PI, and PBI at the sampled sites (P <0.01), whereas no correlation was found between the total amount of GCF IL‐18 and clinical periodontal parameters at the sampled sites (P >0.05).

Conclusion: Elevated levels of GCF cathelicidin LL‐37 in chronic periodontitis suggest that it may play a role in the host innate immune response during periodontal inflammation.
The Potential Use of Gingival Crevicular Blood for Measuring Glucose to Screen for Diabetes: An Examination Based on Characteristics of the Blood Collection Site
Authors: Strauss Shiela M. , Wheeler Alla J. , Russell Stefanie L. , Brodsky Anya , Davidson Robert M. , Gluzman Rima , Li Lin , Malo Roberto Galao , Salis Bram , Schoor Robert , Tzvetkova Krassimira
Published: June 2009

Background: This study examined conditions under which gingival crevicular blood (GCB) could be used to obtain a useful glucose reading to screen for undiagnosed diabetes during routine dental visits.

Methods: GCB and capillary finger‐stick blood (CFB) glucose readings obtained with a glucometer were compared for 46 patients recruited from an urban university dental clinic. Study participants were divided into two groups based on probing depth or bleeding on probing (BOP) at the site of collection of the GCB sample. Group 1 participants had blood collected from sites with adequate BOP to obtain a sample without touching the tooth or gingival margin, whereas group 2 participants had blood collected from sites with little or no bleeding. For each group, Pearson correlations were calculated for glucose readings obtained using GCB and CFB samples, and the limits of agreement between the two samples were examined.

Results: For group 1 participants, correlations between CFB and GCB glucose readings were high (0.89), and the limits of agreement were acceptable (−27.1 to 29.7). By contrast, for participants in group 2, correlations between the glucose readings were lower (0.78), and limits of agreement were much broader (−25.1 to 80.5).

Conclusion: GCB samples were suitable to screen for diabetes in persons with sufficient BOP to obtain a sample without touching the tooth or gingival margin (i.e., in patients having the basic clinical signs of gingivitis or periodontal disease).
Oral Inflammatory Burden and Preterm Birth
Authors: Heimonen Aura , Janket Sok‐Ja , Kaaja Risto , Ackerson Leland K. , Muthukrishnan Preetika , Meurman Jukka H.
Published: June 2009

Background: Earlier studies on the association between oral inflammation and preterm birth limited the inflammation source to periodontal disease. This might have caused an underestimation of the total inflammatory burden from the oral cavity.

Methods: We conducted a postpartum cross‐sectional study of 328 Finnish women with singleton births, of whom 77 had preterm births and 251 had full‐term births. Gingival bleeding on probing, probing depth, and the presence of dental calculus and mouth ulcers were recorded; the oral inflammatory burden index (OIBI) was constructed based on these clinical findings. A data‐driven oral inflammation score (OIS) was also created by stochastically combining the same parameters assessed independently. We used the t, Mann‐Whitney, and χ2 tests for univariate analyses and multivariate logistic regression methods to examine the association between OIBI/OIS and preterm birth. The confounders adjusted for were age, smoking (past, present, and never), diabetes (type 1, type 2, and gestational), primiparity, antimicrobial treatment as a proxy for systemic infection, infertility treatment, and weight gain during pregnancy.

Results: OIBI was significantly associated with preterm birth after adjusting for confounding factors (odds ratio [OR], 1.85; 95% confidence interval [CI]: 1.10 to 3.10; P = 0.02). Without adjusting for weight gain, OIS was significantly associated with preterm birth (OR, 1.97; 95% CI: 1.09 to 3.57; P = 0.03); however, this association became non‐significant after adding weight gain to the model.

Conclusion: The combined effects of multiple oral infections were significantly associated with preterm birth.