bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential Postsynaptic Maturation Governs the Temporal Order of GABAergic and Glutamatergic Synaptogenesis in Rat Embryonic Cultures
Authors: Deng Lunbin , Yao Jun , Fang Cheng , Dong Ning , Luscher Bernhard , Chen Gong
Published: October 2007

Sequential formation of GABAergic and glutamatergic synapses is thought to be crucial for constructing the stereotypic neural networks during brain development. However, why GABAergic synapses are formed earlier than glutamatergic synapses in the developing brain is not well understood. We used electrophysiology and fluorescence imaging to study GABAergic and glutamatergic synaptogenesis in embryonic hypothalamic cultures, which contain ∼40% GABAergic and ∼60% glutamatergic neurons. The newly dissociated embryonic hypothalamic neurons contained a significant pool of functional GABAAreceptors but a very low level of glutamate receptors. Within the first week of culture, the time course of GABAergic synaptogenesis in embryonic neurons coincided with that of presynaptic vesicle cycling, but both measurements lagged behind the detection of functional GABAAreceptors. Remarkably, the GABAAreceptors of newly dissociated embryonic neurons can be rapidly clustered into postsynaptic apparatus and generate functional synaptic currents within 4–6 h when cocultured with mature neurons. Consistent with earlier expression of GABAAreceptors in immature neurons, synaptic GABAergic events were always detected before the onset of glutamatergic events in both purely embryonic and heterochronic cultures. Interestingly, overexpression of glutamate receptors in embryonic neurons not only increased whole-cell glutamate currents but also significantly increased the frequency of excitatory synaptic events. We conclude that the sequential formation of GABAergic and glutamatergic synapses in immature neurons is likely governed by a sequential expression of GABAAand glutamate receptors during neuronal development.
Navigating Neocortical Neurogenesis and Neuronal Specification: A Positional Information System Encoded by Neurogenetic Gradients
Authors: Suter Bernhard , Nowakowski Richard S. , Bhide Pradeep G. , Caviness Verne S.
Published: October 2007

The projection neurons of the neocortex are produced in the pseudostratified ventricular epithelium (PVE) lining the embryonic lateral ventricles. Over a 7 d period in mouse, these neurons arise in an overlapping layer VI-to-II sequence and in an anterolateral to posteromedial gradient [the transverse neurogenetic gradient (TNG)]. At any time in the 7 d neurogenetic interval, a given PVE cell must know what class of precursor cell or neuron to form next. How this information is encoded in the PVE is not known. With comparative experiments in wild-type and double-transgenic mice, overexpressing the cell cycle inhibitor p27Kip1, we show that a gradient of expression of Lhx2 (inferred from its mRNA levels), a LIM homeodomain transcription factor, together with a gradient in duration of the G1phase of the cell cycle (TG1), are sufficient to specify a positional mapping system that informs the PVE cell what class of neuron to produce next. Lhx2 likely is representative of an entire class of transcription factors expressed along the TNG. This mapping system consisting of a combination of signals from two different sources is a novel perspective on the source of positional information for neuronal specification in the developing CNS.
Supplementary Motor Area and Presupplementary Motor Area: Targets of Basal Ganglia and Cerebellar Output
Authors: Akkal Dalila , Dum Richard P. , Strick Peter L.
Published: October 2007

We used retrograde transneuronal transport of neurotropic viruses inCebusmonkeys to examine the organization of basal ganglia and cerebellar projections to two cortical areas on the medial wall of the hemisphere, the supplementary motor area (SMA) and the pre-SMA. We found that both of these cortical areas are the targets of disynaptic projections from the dentate nucleus of the cerebellum and from the internal segment of the globus pallidus (GPi). On average, the number of pallidal neurons that project to the SMA and pre-SMA is approximately three to four times greater than the number of dentate neurons that project to these cortical areas. GPi neurons that project to the pre-SMA are located in a rostral, “associative” territory of the nucleus, whereas GPi neurons that project to the SMA are located in a more caudal and ventral “sensorimotor” territory. Similarly, dentate neurons that project to the pre-SMA are located in a ventral, “nonmotor” domain of the nucleus, whereas dentate neurons that project to the SMA are located in a more dorsal, “motor” domain. The differential origin of subcortical projections to the SMA and pre-SMA suggests that these cortical areas are nodes in distinct neural systems. Although both systems are the target of outputs from the basal ganglia and the cerebellum, these two cortical areas seem to be dominated by basal ganglia input.
The Metalloprotease Inhibitor TIMP-3 Regulates Amyloid Precursor Protein and Apolipoprotein E Receptor Proteolysis
Authors: Hoe Hyang-Sook , Cooper Matthew J. , Burns Mark P. , Lewis Patrick A. , van der Brug Marcel , Chakraborty Geetanjali , Cartagena Casandra M. , Pak Daniel T. S. , Cookson Mark R. , Rebeck G. William
Published: October 2007

Cellular cholesterol levels alter the processing of the amyloid precursor protein (APP) to produce Aβ. Activation of liver X receptors (LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter Aβ levelsin vitroandin vivo. To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist (TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 (ADAM-10) and ADAM-17, two APP α-secretases. We found that TIMP-3 inhibited α-secretase cleavage of APP and an apolipoprotein E (apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP β-C-terminal fragment and Aβ production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and α-secretase cleavage and encourages endocytosis and β-secretase cleavage.In vivo, TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease (AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of Aβ.
On small covering codes in arbitrary mixed hamming spaces
Authors: Kéri Gerzson
Published: October 2007

Some results of Kéri and Östergård [3] regarding mixed binary/ternary covering codes are extended a) for mixed binary/ternary/quaternary codes, b) for codes in arbitrary mixed Hamming spaces. Some other results (sufficient conditions and examples of solved and unsolved cases) regarding 5-word codes in
Z2bZ3tZ4q

and
Z2bZ3tZ4qZ5f

are also provided in the paper.
Weighted approximation by Meyer-König and Zeller type operators
Authors: Vecchia Biancamaria , Duman Oktay
Published: October 2007

In this study we deal with the weighted uniform convergence of the Meyer-König and Zeller type operators with endpoint or inner singularities.
Some extensions of Pitman and Ray-Knight theorems for penalized Brownian motions and their local times, IV
Authors: Roynette Bernard , Vallois Pierre , Yor Marc
Published: October 2007

We show that Pitman’s theorem relating Brownian motion and the
BES
(3) process, as well as the Ray-Knight theorems for Brownian local times remain valid, mutatis mutandis, under the limiting laws of Brownian motion penalized by a function of its one-sided maximum.
Approximate and essential left amenability of Lau algebras with application to semigroup algebras
Authors: Lashkarizadeh Bami Mahmoud , Samea Hojatollah
Published: October 2007

In this paper we introduce the notions of essentially left amenable and approximately left amenable Lau algebras together with several characterizations of such algebras. In particular we investigate the relations between the left amenability, the essential left amenabil-ity and the approximate left amenability of certain quotient Lau algebras as well as operator projective tensor product of Lau algebras. The obtained results are applied to prove that the three notions coincide for a number of well-known semigroup algebras.
On non-uniformly parabolic functional differential equations
Authors: Simon László , Jäger Willi
Published: October 2007

We consider initial boundary value problems for second order quasilinear parabolic equations where also the main part contains functional dependence on the unknown function and the equations are not uniformly parabolic. The results are generalizations of that of [10]
God as Person
Authors: Scott Mark S M
Published: October 2007

This article explores the concept of divine personhood in modern theology, particularly in the theology of Karl Barth (1886-1968) and Karl Rahner (1904-1984). It systematically explicates what it means to call God a ‘Person’. After contextualizing the contemporary debate on divine personhood by reference to the work of John Zizioulas, it interfaces Karl Barth and Karl Rahner’s conception of divine subjectivity and its anthropological implications. It argues that the dynamics of divine personhood entails relationality, both internal (the Trinity) and external (creation). Moreover, it argues that divine subjectivity provides the model for human subjectivity.
Barbra R. Clayton. Moral Theory in Santideva’s Siksasamuccaya: Cultivating the fruits of virtue
Authors: Framarin Christopher G
Published: October 2007

Barbra R. Clayton. Moral Theory in Santideva’s Siksasamuccaya: Cultivating the fruits of virtue. New York: Routledge, 2006. Xv + 165 p. Hardcover ISBN: 0415346967. US $80.00.
John Sandys-Wunsch. What Have They Done to the Bible? A History of Modern Biblical Interpretation
Authors: Mitchell Christine
Published: October 2007

John Sandys-Wunsch. What Have They Done to the Bible? A History of Modern Biblical Interpretation. Collegeville MN: Liturgical Press, 2005. xx + 378 p. pbk ISBN 978-0-8146-5028-8. US $39.00.
Sistema de saúde universal e território: desafios de uma política regional para a Amazônia Legal
Authors: Viana Ana Luiza d'Ávila , Machado Cristiani Vieira , Baptista Tatiana Wargas de Faria , Lima Luciana Dias de , Mendonça Maria Helena Magalhães de , Heimann Luiza S. , Albuquerque Mariana Vercesi , Iozzi Fabíola Lana , David Virna Carvalho , Ibañez Pablo , Frederico Samuel
Published: October 2007

O artigo apresenta os resultados de uma pesquisa sobre a política federal de saúde para a Amazônia Legal de 2003 a 2005, visando fornecer subsídios para o desenvolvimento de políticas regionais na saúde. Tal região é marcada por uma dinâmica peculiar, extensa área de fronteira e indicadores sociais desfavoráveis. A metodologia envolveu: análise documental e financeira, observação participante, entrevistas com dirigentes federais de vários ministérios, secretários estaduais e municipais de saúde da Amazônia; caracterização de situações geográficas na Amazônia e estudos de campo em 15 municípios. Observou-se uma baixa institucionalidade da política de saúde para a Amazônia, no período, por dificuldades estruturais, institucionais e políticas. A identificação de seis situações geográficas foi útil para a sistematização de diferenças nos usos do território que repercutem na saúde e devem ser considerados na condução de políticas públicas. Há certo distanciamento entre as ações federais e a dinâmica territorial, expressa no descolamento entre a política em curso e seu reconhecimento pelos gestores locais. Além da construção de uma política regional para a Amazônia, fica evidente a necessidade de políticas diferenciadas dentro da região.
Procesos de integración en salud: una reflexión sobre los desafíos del MERCOSUR en salud
Authors: Sánchez Delia M.
Published: October 2007

Se describen los antecedentes institucionales de integración en América Latina, tanto económica como en salud y se propone una sistematización de las posibles modalidades de integración en salud. Se identifican factores facilitadores e inhibidores del proceso de integración según cada modalidad y se discute su viabilidad en el presente contexto. Se presenta una breve descripción de la estructura y funcionamiento de las estructuras de salud del MERCOSUR (Reunión de Ministros y Subgrupo de Trabajo 11), así como el grado de avance alcanzado hasta el presente, reflexionando sobre las posibles causas del avance desigual en las diversas áreas.
O desafio da integração social no MERCOSUL: uma discussão sobre a cidadania e o direito à saúde
Authors: Dal Prá Keli Regina , Mendes Jussara Maria Rosa , Mioto Regina Célia Tamaso
Published: October 2007

O artigo aborda, mediante revisão teórica, a garantia do direito à saúde e do exercício da cidadania na linha das fronteiras do Brasil com os países do MERCOSUL (Argentina, Paraguai e Uruguai) tendo em vista o trânsito interfronteiras e a demanda gerada pela população fronteiriça ao Sistema Único de Saúde (SUS). O objetivo é discutir a garantia do direito e da cidadania, bem como a livre circulação de pessoas e a dimensão da territorialidade, temas correlacionados ao trânsito da população fronteiriça nos municípios brasileiros. Identifica-se a predominância da dimensão econômica no MERCOSUL em detrimento dos avanços regulatórios/legais referentes à dimensão social e à previsão da livre circulação de pessoas intrabloco. A análise é realizada por intermédio dos elementos da cidadania nacional e do território quando se pensa na extensão do direito à saúde à população fronteiriça. Leva-se em consideração a requisição de alternativas à extensão dos direitos e do estabelecimento e ampliação das políticas sociais públicas em saúde na linha das fronteiras do MERCOSUL para o atendimento da demanda fronteiriça que busca assistência no SUS.
A diversidade ética e política na garantia e fruição do direito à saúde nos municípios brasileiros da linha da fronteira do MERCOSUL
Authors: Nogueira Vera Maria Ribeiro , Dal Prá Keli Regina , Fermiano Sabrina
Published: October 2007

Apresenta-se parte das conclusões do estudo realizado na fronteira entre o Brasil e países do MERCOSUL, e identificam-se os perfis de atenção que evidenciam a diversidade ética e política na fruição do direito à saúde, com a caracterização das demandas e as respostas dos sistemas locais. A base empírica foi a garantia ou não do acesso às ações e aos serviços de saúde pelos usuários não brasileiros. Para a coleta de dados, aplicaram-se formulários nos municípios com mais de 10 mil habitantes, registro em diários de campo, reuniões e entrevistas. O destaque foi a diversidade de compreensão sobre o significado do direito à saúde, indicando dois fatores: inexistência de princípios éticos e políticos comuns e níveis de institucionalidade frágeis, incapazes de absorver a demanda dos usuários não brasileiros. Verificou-se que os acordos entre os governos nacionais não têm tido repercussão, ocorrendo desconhecimento pelos gestores e profissionais. Na população estrangeira, permanece a incerteza quanto ao atendimento. No Brasil, evidencia-se a inexistência de padrões uniformes de atenção, favorecendo decisões pessoais dos gestores e profissionais de saúde, dificultando as ações integradas.
O trabalho em saúde no MERCOSUL: uma abordagem brasileira sobre a questão
Authors: Machado Maria Helena , Paula Aïda El-Khoury de , Aguiar Filho Wilson
Published: October 2007

No MERCOSUL, o processo de integração regional, a gestão do trabalho e da educação em saúde têm sido uma preocupação dos governos dos Estados Partes (Brasil, Argentina, Paraguai, Uruguai e Venezuela), tendo em vista as especificidades do setor saúde. Uma questão de interesse especial diz respeito à regulação do exercício profissional e à harmonização da legislação vigente. O presente artigo apresenta as iniciativas desenvolvidas no Fórum Permanente MERCOSUL para o trabalho em saúde nessa área. O Fórum caracteriza-se como espaço de diálogo criado a partir da interlocução de diversos atores - Ministério da Saúde, trabalhadores e conselhos profissionais, com o objetivo de subsidiar os trabalhos da Subcomissão de Desenvolvimento e Exercício Profissional, do Subgrupo de Trabalho 11 Saúde/MERCOSUL, auxiliando na formulação de políticas de gestão e de educação na saúde. O desafio atual passa pela criação de mecanismos para a implementação de ações conjuntas que possam equacionar os problemas ligados ao processo regulatório do exercício profissional, principalmente nos municípios de fronteira.
SFRP2 Regulates Cardiomyogenic Differentiation by Inhibiting a Positive Transcriptional Autofeedback Loop of Wnt3a
Authors: Deb Arjun , Davis Bryce H. , Guo Jian , Ni Aiguo , Huang Jing , Zhang Zhiping , Mu Hui , Dzau Victor J.
Published: October 2007

Wnts comprise a family of 20 lipid-modified glycoproteins in mammals and play critical roles during embryological development and organogenesis of several organ systems, including the heart. They are required for mesoderm formation and have been implicated in promoting cardiomyogenic differentiation of mammalian embryonic stem cells, but the underlying mechanisms regulating Wnt signaling during cardiomyogenesis remain poorly understood. In this report, we show that in a pluripotent mouse embryonal carcinoma stem cell line, SFRP2 inhibits cardiomyogenic differentiation by regulating Wnt3a transcription. SFRP2 inhibited early stages of cardiomyogenesis, preventing mesoderm specification and maintaining the cells in the undifferentiated state. Using a gain- and loss-of-function approach, we demonstrate that although addition of recombinant SFRP2 decreased Wnt3a transcription and cardiomyogenic differentiation, silencing of Sfrp2 led to enhanced Wnt3a transcription, mesoderm formation, and increased cardiomyogenesis. We show that the inhibitory effects of SFRP2 on Wnt transcription are secondary to interruption of a positive feedback effect of Wnt3a on its own transcription. Wnt3a increased its own transcription via the canonical pathway and TCF4 family of transcription factors, and the inhibitory effects of SFRP2 on Wnt3a transcription were associated with disruption of downstream canonical Wnt signaling. The inhibitory effects of Sfrp2 on Wnt3a expression identify Sfrp2 as a “checkpoint gene,” which exerts its control on cardiomyogenesis through regulation of Wnt3a transcription.

Disclosure of potential conflicts of interest is found at the end of this article.
Toll-Like Receptors on Human Mesenchymal Stem Cells Drive Their Migration and Immunomodulating Responses
Authors: Tomchuck Suzanne L. , Zwezdaryk Kevin J. , Coffelt Seth B. , Waterman Ruth S. , Danka Elizabeth S. , Scandurro Aline B.
Published: October 2007

Adult human bone marrow-derived mesenchymal stem cells (hMSCs) are under study as therapeutic delivery agents that assist in the repair of damaged tissues. To achieve the desired clinical outcomes for this strategy requires a better understanding of the mechanisms that drive the recruitment, migration, and engraftment of hMSCs to the targeted tissues. It is known that hMSCs are recruited to sites of stress or inflammation to fulfill their repair function. It is recognized that toll-like receptors (TLRs) mediate stress responses of other bone marrow-derived cells. This study explored the role of TLRs in mediating stress responses of hMSCs. Accordingly, the presence of TLRs in hMSCs was initially established by reverse transcription-polymerase chain reaction assays. Flow cytometry and fluorescence immunocytochemical analyses confirmed these findings. The stimulation of hMSCs with TLR agonists led to the activation of downstream signaling pathways, including nuclear factor κB, AKT, and MAPK. Consequently, activation of these pathways triggered the induction and secretion of cytokines, chemokines, and related TLR gene products as established from cDNA array, immunoassay, and cytokine antibody array analyses. Interestingly, the unique patterns of affected genes, cytokines, and chemokines measured identify these receptors as critical players in the clinically established immunomodulation observed for hMSCs. Lastly, hMSC migration was promoted by TLR ligand exposure as demonstrated by transwell migration assays. Conversely, disruption of TLRs by neutralizing TLR antibodies compromised hMSC migration. This study defines a novel TLR-driven stress and immune modulating response for hMSCs that is critical to consider in the design of stem cell-based therapies.

Disclosure of potential conflicts of interest is found at the end of this article.
Absence of Conclusive Evidence for the Safety and Efficacy of Gonadotropin-Releasing Hormone Analogue Treatment in Protecting Against Chemotherapy-Induced Gonadal Injury
Authors: Oktay Kutluk , Sönmezer Murat , Öktem Özgür , Fox Kevin , Emons Günter , Bang Heejung
Published: October 2007

Every year, an increasing number of women with malignant and nonmalignant diseases is successfully treated with cytotoxic chemotherapy and/or radiotherapy. Many of these patients suffer from infertility and gonadal failure as a result of these treatments. At present, these patients may resort to assisted-reproduction techniques to protect their future childbearing potential before the implementation of cytotoxic therapy. While embryo cryopreservation is an established technology, oocyte and ovarian tissue freezing techniques are still investigational. Nevertheless both of these techniques have resulted in live births. Apart from assisted-reproduction techniques, it has been extensively debated whether administration of gonadotropin-releasing hormone (GnRH) analogues in conjunction with chemotherapy can protect ovarian reserve against cytotoxic insult. In this manuscript, we debate the rationale for the effectiveness of GnRH analogue coadministration in preservation of fertility by reviewing the literature, and provide preliminary data to support our views.
Early Epirubicin-Induced Myocardial Dysfunction Revealed by Serial Tissue Doppler Echocardiography: Correlation with Inflammatory and Oxidative Stress Markers
Authors: Mercuro Giuseppe , Cadeddu Christian , Piras Alessandra , Dessì Mariele , Madeddu Clelia , Deidda Martino , Serpe Roberto , Massa Elena , Mantovani Giovanni
Published: October 2007

Learning Objectives

After completing this course, the reader will be able to: Interpret modern techniques to detect early instrumental and biochemical signs of epirubicin-induced myocardial dysfunction.Evaluate the correlation between instrumental signs and biochemical/biological variables with the aim of defining more exhaustively the clinical effects of drugs.Discuss the effectiveness and safety of an important antineoplastic drug such as epirubicin.

Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com
Increased incidence of lobular breast cancer in women treated with hormone replacement therapy: implications for diagnosis, surgical and medical treatment
Authors: Biglia Nicoletta , Mariani Luca , Sgro Luca , Mininanni Paola , Moggio Giulia , Sismondi Piero
Published: October 2007

A growing body of evidence support the association between the use of hormone replacement therapy (HRT) and a higher risk of both invasive lobular carcinoma (ILC) and invasive ductal–lobular mixed carcinoma (IDLC). Overall biological and clinical features of ILC entail a more cautious diagnostic and therapeutic approach as compared with invasive ductal carcinoma (IDC). ILCs are more frequently multifocal, multicentric and/or bilateral. Mammography and ultrasound show, therefore, significant limitations, while the higher sensitivity of magnetic resonance imaging in the detection of multifocal and/or multicentric lesions seems to improve the accuracy of preoperative staging of ILCs. Early diagnosis is even more challenging because the difficult in the localization and the sparse cellularity of lobular tumours may determine a false negative core biopsy. ILC is characterized by low proliferative activity, C-ErbB-2 negativity, bcl-2 positivity, p53 and VEGF negativity, oestrogen and progesterone positive receptors, low grade and low likelihood of lymphatic-vascular invasion. However, this more favourable biological behaviour does not reflect into a better disease-free and overall survival as compared with IDC. Since lobular histology is associated with a higher risk of positive margins, mastectomy is often preferred to breast conservative surgery. Moreover, only few patients with ILC achieve a pathologic response to preoperative chemotherapy and, therefore, in most patients mastectomy can be regarded as the safer surgical treatment. The preoperative staging and the follow-up of patients with ILC are also complicated by the particular metastatic pattern of such histotype. In fact, metastases are more frequently distributed to the gastrointestinal tract, peritoneum/retroperitoneum and gynaecological organs than in IDC.
Estrogenically regulated LRP16 interacts with estrogen receptor α and enhances the receptor’s transcriptional activity
Authors: Han W-D , Zhao Y-L , Meng Y-G , Zang L , Wu Z-Q , Li Q , Si Y-L , Huang K , Ba J-M , Morinaga H , Nomura M , Mu Y-M
Published: October 2007

Previous studies have shown that leukemia related protein 16 (LRP16) is estrogenically regulated and that it can stimulate the proliferation of MCF-7 breast cancer cells, but there are no data on the mechanism of this pathway. Here, we demonstrate that the LRP16 expression is estrogen dependent in several epithelium-derived tumor cells. In addition, the suppression of the endogenous LRP16 in estrogen receptor α (ERα)-positive MCF-7 cells not only inhibits cells growth, but also significantly attenuates the cell line’s estrogen-responsive proliferation ability. However, ectopic expression of LRP16 in ERα-negative MDA-MB-231 cells has no effect on proliferation. These data suggest the involvement of LRP16 in estrogen signaling. We also provide novel evidence by both ectopic expression and small interfering RNA knockdown approaches that LRP16 enhances ERα-mediated transcription activity. In stably LRP16-inhibitory MCF-7 cells, the estrogen-induced upregulation of several well-known ERα target genes including cyclin D1 and c-myc is obviously impaired. Results from glutathione S-transferase pull-down and coimmunoprecipitation assays revealed that LRP16 physically interacts with ERα in a manner that is estrogen independent but is enhanced by estrogen. Furthermore, a mammalian two-hybrid assay indicated that the binding region of LRP16 localizes to the A/B activation function 1 domain of ERα. Taken together, these results present new data supporting a role for estrogenically regulated LRP16 as an ERα coactivator, providing a positive feedback regulatory loop for ERα signal transduction.
High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors
Authors: Marot Didier , Bieche Ivan , Aumas Chantal , Esselin Stéphanie , Bouquet Céline , Vacher Sophie , Lazennec Gwendal , Perricaudet Michel , Kuttenn Frederique , Lidereau Rosette , de Roux Nicolas
Published: October 2007

KiSS1 is a putative metastasis suppressor gene in melanoma and breast cancer-encoding kisspeptins, which are also described as neuroendocrine regulators of the gonadotropic axis. Negative as well as positive regulation of KiSS1 gene expression by estradiol (E2) has been reported in the hypothalamus. Estrogen receptor α (ERα level is recognized as a marker of breast cancer, raising the question of whether expression of KiSS1 and its G-protein-coupled receptor (GPR54) is down- or upregulated by estrogens in breast cancer cells. KiSS1 was found to be expressed in MDA-MB-231, MCF7, and T47D cell lines, but not in ZR75-1, L56Br, and MDA-MB-435 cells. KiSS1 mRNA levels decreased significantly in ERα-negative MDA-MB-231 cells expressing recombinant ERα. In contrast, tamoxifen (TAM) treatment of ERα-positive MCF7 and T47D cells increased KiSS1 and GPR54 levels. The clinical relevance of this negative regulation of KiSS1 and GPR54 by E2 was then studied in postmenopausal breast cancers. KiSS1 mRNA increased with the grade of the breast tumors. ERα-positive invasive primary tumors expressed sevenfold lower KiSS1 levels than ERα-negative tumors. Among ERα-positive breast tumors from postmenopausal women treated with TAM, high KiSS1 combined with high GPR54 mRNA tumoral levels was unexpectedly associated with shorter relapse-free survival (RFS) relative to tumors expressing low tumoral mRNA levels of both genes. The contradictory observation of putative metastasis inhibitor role of kisspeptins and RFS to TAM treatment suggests that evaluation of KiSS1 and its receptor tumoral mRNA levels could be new interesting markers of the tumoral resistance to anti-estrogen treatment.
The Mia/Cd-rap gene expression is downregulated by the high-mobility group A proteins in mouse pituitary adenomas
Authors: De Martino Ivana , Visone Rosa , Palmieri Dario , Cappabianca Paolo , Chieffi Paolo , Forzati Floriana , Barbieri Antonio , Kruhoffer Mogens , Lombardi Gaetano , Fusco Alfredo , Fedele Monica
Published: October 2007

The high-mobility group A (HMGA) family of proteins orchestrates the assembly of nucleoprotein structures playing important roles in gene transcription, recombination, and chromatin structure through a complex network of protein–DNA and protein–protein interactions. Recently, we have generated transgenic mice carrying wild type or truncated HMGA2 genes under the transcriptional control of the cytomegalovirus promoter. These mice developed pituitary adenomas secreting prolactin and GH mainly due to an increased E2F1 activity, directly consequent to the HMGA2 overexpression. To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 gene, in this study we have analyzed the gene expression profile of three HMGA2-pituitary adenomas in comparison with a pool of ten normal pituitary glands from control mice, using the Affymetrix MG MU11K oligonucleotide array representing ~13 000 unique genes. We have identified 82 transcripts that increased and 72 transcripts that decreased at least four-fold in all the mice pituitary adenomas analyzed compared with normal pituitary glands. Among these genes, we focused our attention on the Mia/Cd-rap gene, whose expression was essentially suppressed in all of the pituitary adenomas tested by the microarray. We demonstrated that the HMGA proteins directly bind to the promoter of the Mia/Cd-rap gene and are able to downregulate its expression. In order to understand a possible role of Mia/Cd-rap in pituitary cell growth, we performed a colony assay in GH3 and GH4 cells. Interestingly, Mia/Cd-rap expression inhibits their proliferation, suggesting a potential tumor suppressor role of Mia/Cd-rap in pituitary cells.
Expression of GnRH type II is regulated by the androgen receptor in prostate cancer
Authors: Darby S , Stockley J , Khan M M , Robson C N , Leung H Y , Gnanapragasam V J
Published: October 2007

GnRH II has important functional effects in steroid hormone-dependent tumours. Here we investigated the expression and regulation of GnRH II in prostate cancer. GnRH II protein was equally expressed in benign (73%) and malignant (78%) biopsies studied in a prostate tissue microarray (P = 0.779). There was no relationship between expression and clinical parameters in the cancer cohort. GnRH II was, however, significantly reduced in tumour biopsies following hormone ablation. This was further investigated in a prostate xenograft model where androgens increased GnRH II levels, while their withdrawal reduced it. In cell lines, we confirmed high levels of GnRH II in androgen receptor (AR)-positive LNCaP cells but low levels in AR-negative PC3 cells. In LNCaP cells, GnRH II induction by androgens was blocked by the AR inhibitor casodex, but not by cycloheximide treatment. Sequence analysis subsequently revealed a putative androgen response element in the upstream region of the GnRH II gene and direct interaction with the AR was confirmed in chromatin immunoprecipitation experiments. Finally, to test whether the effects of GnRH II were dependent on AR expression, LNCaP and PC3 cells were exposed to exogenous peptide. In both cell lines, GnRH II inhibited cell proliferation and migration, suggesting that its function is independent of AR status. These results provide evidence that GnRH II is widely expressed in prostate cancer and is an AR-regulated gene. Further studies are warranted to characterise the effects of GnRH II on prostate cancer cells and investigate its potential value as a novel therapy.
Activin and estrogen crosstalk regulates transcription in human breast cancer cells
Authors: Burdette Joanna E , Woodruff Teresa K
Published: October 2007

Activin is a member of the transforming growth factor β superfamily that regulates mammary cell function during development, lactation, and in cancer. Activin slows the growth of breast cancer cells by inducing G0/G1 cell cycle arrest. Estrogen is a steroid hormone that stimulates the proliferation of mammary epithelial cells in development and oncogenesis. The crosstalk between estrogen and activin that regulates activin ligand expression, activin and estrogen signal transduction, and cell cycle arrest was investigated in this study. Estrogen antagonized activin-dependent production of plasminogen activator inhibitor 1 (PAI-1) mRNA, while activin repressed estrogen-dependent transcription of trefoil factor 1. The repression of estrogen signaling by activin was recapitulated using a simple estrogen response element-luciferase construct and was enhanced in the presence of overexpressed estrogen receptor α (ERα). In contrast, estrogen-mediated repression of activin signaling could not be recapitulated on a simple CAGA Smad-binding element but did inhibit the short PAI-1 promoter, p3TP-luciferase, especially when ERα was overexpressed. Repression of both estrogen- and activin-regulated transcription was found to be ligand induced and Smad3 dependent. In addition to transcriptional repression, estrogen also reduced the amount of activin B mRNA and protein produced by MCF7 breast cancer cells. These studies demonstrate the importance of activin and estrogen crosstalk during mammary cell growth and cancer initiation.
Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells
Authors: Yuan Ta-Chun , Veeramani Suresh , Lin Ming-Fong
Published: October 2007

Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as ‘NE-like PCa cells’. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.
A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors
Authors: Wierinckx Anne , Auger Carole , Devauchelle Pauline , Reynaud Arlette , Chevallier Pascale , Jan Michel , Perrin Gilles , Fèvre-Montange Michelle , Rey Catherine , Figarella-Branger Dominique , Raverot Gérald , Belin Marie-Françoise , Lachuer Joël , Trouillas Jacqueline
Published: October 2007

Although most pituitary tumors are benign, some are invasive or aggressive. In the absence of specific markers of malignancy, only tumors with metastases are considered malignant. To identify markers of invasion and aggressiveness, we focused on prolactin (PRL) tumors in the human and rat. Using radiology and histological methods, we classified 25 human PRL tumors into three groups (non-invasive, invasive, and aggressive–invasive) and compared them with a model of transplantable rat PRL tumors with benign and malignant lineages. Combining histological(mitoses and labeling for Ki-67, P53, pituitary transforming tumor gene (PTTG), and polysialic acid neural cell adhesion molecule) and transcriptomic (microarrays and q-RTPCR) methods with clinical data (post-surgical outcome with case–control statistical analysis), we found nine genes implicated in invasion (ADAMTS6, CRMP1, and DCAMKL3) proliferation (PTTG, ASK, CCNB1, AURKB, and CENPE), or pituitary differentiation (PITX1) showing differential expression in the three groups of tumors (P = 0.015 to 0.0001). A case–control analysis, comparing patients in remission (9 controls) and patients with persistent or recurrent tumors (14 cases) revealed that eight out of the nine genes were differentially up- or downregulated (P = 0.05 to 0.002), with only PTTG showing no correlation with clinical course (P = 0.258). These combined histological and transcriptomic analyses improve the pathological diagnosis of PRL tumors, indicating a reliable procedure for predicting tumor aggressiveness and recurrence potential. The similar gene profiles found between non-invasive human and benign rat tumors, as well as between aggressive–invasive human and malignant rat tumors provide new insights into malignancy in human pituitary tumors.
Chromogranin A and biochemical progression-free survival in prostate adenocarcinomas submitted to radical prostatectomy
Authors: Alessandro Sciarra , Vincenzo Gentile , Maria Autran Gomez Ana , Stefano Salciccia , Alessandro Gentilucci , Salvatore Monti , Vincenzo Toscano , Franco Di Silverio
Published: October 2007

The primary aim of the present study was to determine the prognostic role of elevated levels of chromogranin A (CgA) in terms of biochemical prostate-specific antigen (PSA) progression after radical prostatectomy (RRP) for prostate adenocarcinoma. Two hundred and sixty-four consecutive men with non-metastatic prostate adenocarcinoma submitted to RRP represented our population. In all cases, a blood sample for the determination of serum total PSA and CgA levels was obtained (RIA). Two different upper reference values for serum CgA levels were used: > 60 and > 90 ng/ml. The main end point of this study was biochemical (PSA) progression-free survival. In our population, 35.0% (91/264 cases) of cases presented a serum CgA level > 60 ng/ml and only 6.4% (17/264) presented CgA > 90 ng/ml. After RRP, during a mean follow-up of 64.59 ± 26.34 months (median 60 months; range 12–120 months), 59 patients (22.3%) showed a biochemical (PSA) progression. Using 60 ng/ml as upper reference value for CgA, 10.4 and 45.0% of cases showed PSA progression after RRP in the group with preoperative CgA levels ≤ 60 and > 60 ng/ml respectively. The proportion of PSA progression-free survival was significantly lower in cases with preoperative CgA > 60 ng/ml than in cases with CgA ≤ 60 ng/ml (P < 0.0001). In addition, at the multivariate analysis, preoperative serum CgA levels were confirmed as an independent prognostic factor for PSA progression after RRP. In non-metastatic prostate carcinomas, we described a significant prognostic role of CgA in terms of biochemical progression-free survival.
Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect
Authors: Pechlivanis Sonali , Pardini Barbara , Bermejo Justo Lorenzo , Wagner Kerstin , Naccarati Alessio , Vodickova Ludmila , Novotny Jan , Hemminki Kari , Vodicka Pavel , Försti Asta
Published: October 2007

Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case–control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54–0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11–0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.
RAD-BY-RAD (BIT-BY-BIT): Triumph of Evidence over Activities Fostering Fear of Radiogenic Cancers at Low Doses
Authors: Strzelczyk J. , Potter W. , Zdrojewicz Z.
Published: October 2007

Large segments of Western populations hold sciences in low esteem. This trend became particularly pervasive in the field of radiation sciences in recent decades. The resulting lack of knowledge, easily filled with fear that feeds on itself, makes people susceptible to prevailing dogmas. Decades-long moratorium on nuclear power in the US, resentment of “anything nuclear”, and delay/refusal to obtain medical radiation procedures are some of the societal consequences. The problem has been exacerbated by promulgation of the linear-no-threshold (LNT) dose response model by advisory bodies such as the ICRP, NCRP and others. This model assumes no safe level of radiation and implies that response is the same per unit dose regardless of the total dose. The most recent (June 2005) report from the National Research Council, BEIR VII (Biological Effects of Ionizing Radiation) continues this approach and quantifies potential cancer risks at low doses by linear extrapolation of risk values obtained from epidemiological observations of populations exposed to high doses, 0.2 Sv to 3 Sv. It minimizes the significance of a lack of evidence for adverse effects in populations exposed to low doses, and discounts documented beneficial effects of low dose exposures on the human immune system. The LNT doctrine is in direct conflict with current findings of radiobiology and important features of modern radiation oncology. Fortunately, these aspects are addressed in-depth in another major report—issued jointly in March 2005 by two French Academies, of Sciences and of Medicine. The latter report is much less publicized, and thus it is a responsibility of radiation professionals, physicists, nuclear engineers, and physicians to become familiar with its content and relevant studies, and to widely disseminate this information. To counteract biased media, we need to be creative in developing means of sharing good news about radiation with co-workers, patients, and the general public.
Auditors' Assessment and Incorporation of Expectation Precision in Evidential Analytical Procedures
Authors: McDaniel Linda S. , Simmons Laura E.
Published: October 2007

This paper reports on an experiment that investigates auditors' abilities to assess expectation precision and incorporate their assessments into judgments related to substantive analytical procedures, as required by professional standards. Auditors appear sensitive to both account predictability and level of information detail in assessing expectation precision overall; however, their assessments do not reflect differences in level of detail when the account is less predictable. This finding supports regulators' and prior researchers' calls for additional guidance to assist auditors in forming expectations that consider the nature of the account. We also find that auditors judge the level of assurance from analytical procedures consistent with their precision assessments. However, in contrast to guidance specified in professional standards, we find that auditors do not always incorporate their precision assessments into judgments about the range of possible differences between expected and recorded amounts, nor the likelihood of misstatement causes. Failing to do so may lead auditors to make important decision errors.
Auditor Change and Auditor Choice in Nonprofit Organizations
Authors: Tate Stefanie L.
Published: October 2007

As a result of the recent frauds and the U.S. Congress's passing of the Sarbanes-Oxley Act of 2002, more focus has been placed on the role of independent auditors in monitoring corporations. While the new rules are not directed toward nonprofit organizations, these organizations face many of the same monitoring concerns as their for-profit counterparts. Given their large reliance on public support through donations, it is imperative they maintain adequate levels of monitoring. This study looks at nonprofit organizations' auditor choice decisions—the factors associated with their decision to change auditors and the factors associated with the auditor selected if a change is made. Using multivariate regressions on data on almost 16,000 nonprofit organizations, I find changes in operational structure, management's reputation, and audit fee are all significant in determining whether an organization will change auditors. In addition, changes in operational structure, financing, and management contracting may have some effect on the type of auditor selected when a change is made.
Balancing Tax and Financial Reporting Objectives: Effective Tax Planning within the Property and Casualty Insurance Industry
Authors: Randolph David W. , Seida Jim A.
Published: October 2007

Tax-planning strategies will not enhance firm value if the tax benefit is less than the (nontax) costs incurred to achieve such benefit. Effective tax planning therefore requires the joint consideration of tax benefits and the costs of obtaining those benefits, rather than a myopic focus on only tax minimization. This case presents the opportunity for you to evaluate alternative sources of tax law and balance tax and nontax concerns (including ethical considerations) as you make the same loss reserve reporting decisions that property-casualty (P&C) insurers faced following the Tax Reform Act of 1986 (TRA86).
Lessons for the Classroom from Luca Pacioli
Authors: Sangster Alan , Stoner Gregory N. , McCarthy Patricia A.
Published: October 2007

In 2006, the Teaching and Curriculum Section of the American Accounting Association published a monograph, Reflections on Accounting Education Research. It includes a chapter that demonstrates how research into accounting history can be used in the classroom to inform “students about the changing environment and behavior that influences accounting action.” This paper seeks to broaden the applicability of accounting history to accounting education by demonstrating that there are lessons to be learned in both textbook writing and in classroom instruction from the earliest known accounting textbook, the bookkeeping treatise contained within Luca Pacioli's Summa de Arithmetica, Geometria, Proportioni et Proportionalita.