Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-γ ligand troglitazone in patients with liposarcoma

Agonist ligands for the nuclear receptor peroxisome proliferator-activated receptor-γ have been shown to induce terminal differentiation of normal preadipocytes and human liposarcoma cells in vitro. Because the differentiation status of liposarcoma is predictive of clinical outcomes, modulation of the differentiation status of a tumor may favorably impact clinical behavior. We have conducted a clinical trial for treatment of patients with advanced liposarcoma by using the peroxisome proliferator-activated receptor-γ ligand troglitazone, in which extensive correlative laboratory studies of tumor differentiation were performed. We report here the results of three patients with intermediate to high-grade liposarcomas in whom troglitazone administration induced histologic and biochemical differentiation in vivo. Biopsies of tumors from each of these patients while on troglitazone demonstrated histologic evidence of extensive lipid accumulation by tumor cells and substantial increases in NMR-detectable tumor triglycerides compared with pretreatment biopsies. In addition, expression of several mRNA transcripts characteristic of differentiation in the adipocyte lineage was induced. There was also a marked reduction in immunohistochemical expression of Ki-67, a marker of cell proliferation. Together, these data indicate that terminal adipocytic differentiation was induced in these malignant tumors by troglitazone. These results indicate that lineage-appropriate differentiation can be induced pharmacologically in a human solid tumor.

Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity

Hypertonicity (most often present as high salinity) is stressful to the cells of virtually all organisms. Cells survive in a hypertonic environment by increasing the transcription of genes whose products catalyze cellular accumulation of compatible osmolytes. In mammals, the kidney medulla is normally hypertonic because of the urinary concentrating mechanism. Cellular accumulation of compatible osmolytes in the renal medulla is catalyzed by the sodium/myo-inositol cotransporter (SMIT), the sodium/chloride/betaine cotransporter, and aldose reductase (synthesis of sorbitol). The importance of compatible osmolytes is underscored by the necrotic injury of the renal medulla and subsequent renal failure that results from the inhibition of SMIT in vivo by administration of a specific inhibitor. Tonicity-responsive enhancers (TonE) play a key role in hypertonicity-induced transcriptional stimulation of SMIT, sodium/chloride/betaine cotransporter, and aldose reductase. We report the cDNA cloning of human TonE binding protein (TonEBP), a transcription factor that stimulates transcription through its binding to TonE sequences via a Rel-like DNA binding domain. Western blot and immunohistochemical analyses of cells cultured in hypertonic medium reveal that exposure to hypertonicity elicits slow activation of TonEBP, which is the result of an increase in TonEBP amount and translocation to the nucleus.

Role of the proteasome and NF-κB in streptococcal cell wall-induced polyarthritis

The transcription factor NF-κB activates a number of genes whose protein products are proinflammatory. In quiescent cells, NF-κB exists in a latent form and is activated via a signal-dependent proteolytic mechanism in which the inhibitory protein IκB is degraded by the ubiquitin–proteasome pathway. Consequently, inhibition of the proteasome suppresses activation of NF-κB. This suppression should therefore decrease transcription of many genes encoding proinflammatory proteins and should ultimately have an anti-inflammatory effect. To this end, a series of peptide boronic acid inhibitors of the proteasome, exemplified herein by PS-341, were developed. The proteasome is the large multimeric protease that catalyzes the final proteolytic step of the ubiquitin–proteasome pathway. PS-341, a potent, competitive inhibitor of the proteasome, readily entered cells and inhibited the activation of NF-κB and the subsequent transcription of genes that are regulated by NF-κB. Significantly, PS-341 displayed similar effects in vivo. Oral administration of PS-341 had anti-inflammatory effects in a model of Streptococcal cell wall-induced polyarthritis and liver inflammation in rats. The attenuation of inflammation in this model was associated with an inhibition of IκBα degradation and NF-κB-dependent gene expression. These experiments clearly demonstrate that the ubiquitin–proteasome pathway and NF-κB play important roles in regulating chronic inflammation and that, as predicted, proteasome inhibition has an anti-inflammatory effect.

Twenty-first aminoacyl-tRNA synthetase–suppressor tRNA pairs for possible use in site-specific incorporation of amino acid analogues into proteins in eukaryotes and in eubacteria

Two critical requirements for developing methods for the site-specific incorporation of amino acid analogues into proteins in vivo are (i) a suppressor tRNA that is not aminoacylated by any of the endogenous aminoacyl-tRNA synthetases (aaRSs) and (ii) an aminoacyl-tRNA synthetase that aminoacylates the suppressor tRNA but no other tRNA in the cell. Here we describe two such aaRS–suppressor tRNA pairs, one for use in the yeast Saccharomyces cerevisiae and another for use in Escherichia coli. The “21st synthetase–tRNA pairs” include E. coli glutaminyl-tRNA synthetase (GlnRS) along with an amber suppressor derived from human initiator tRNA, for use in yeast, and mutants of the yeast tyrosyl-tRNA synthetase (TyrRS) along with an amber suppressor derived from E. coli initiator tRNA, for use in E. coli. The suppressor tRNAs are aminoacylated in vivo only in the presence of the heterologous aaRSs, and the aminoacylated tRNAs function efficiently in suppression of amber codons. Plasmids carrying the E. coli GlnRS gene can be stably maintained in yeast. However, plasmids carrying the yeast TyrRS gene could not be stably maintained in E. coli. This lack of stability is most likely due to the fact that the wild-type yeast TyrRS misaminoacylates the E. coli proline tRNA. By using error-prone PCR, we have isolated and characterized three mutants of yeast TyrRS, which can be stably expressed in E. coli. These mutants still aminoacylate the suppressor tRNA essentially quantitatively in vivo but show increased discrimination in vitro for the suppressor tRNA over the E. coli proline tRNA by factors of 2.2- to 6.8-fold.

Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo

Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, α-myosin heavy chain promoter (α-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5–10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to β-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.

Women Leaders Resolving Conflict in Higher Education: A Feminist Epistemological Perspective

In an American postsecondary context, conflict is inherent (Gianneschi & Yanagiura, 2006; Valian, 1999). Successful navigation of conflict in the academy is vital for those who aspire to leadership positions (Nadler & Nadler, 1987; Walters, Stuhlmacher, & Meyer, 1998). Presently, however, women face significant barriers to achieving success in higher education administration, including gender expectations for conflict resolution behavior (Bartunek, 1992; Bowles, Babcock, & McGinn, 2005; Gayle, Preiss, & Allen, 2002). While a considerable body of literature exists for understanding gender negotiation, it remains rooted in a masculine paradigm (Kolb & Putnam, 2006; Shuter & Turner, 1997), and, as such, established theories lack a feminist epistemological perspective. Consequently, my primary research question is, How do women leaders experience and perceive conflict in the higher education work environment? I conduct a qualitative study that examines workplace conflict experiences of 15 women leaders from diverse personal and professional backgrounds. Hartsock's (1983) three-tiered gender-sensitive analysis of power, updated to include multicultural perspectives, serves as my theoretical framework. It is a lens through which I evaluate theories, finding multicultural organizational, higher education conflict, and gender negotiation theories most applicable to this study. The framework also creates the foundation upon which I build my study. Specifically, I determine that a feminist research method is most relevant to this investigation. To analyze data obtained through in depth interviews, I employ a highly structured form of grounded theory called dimensional analysis. Based on my findings, I co-construct with study participants a Feminist Conflict Process Theory and Flowchart in which initially the nature of the relationship, and subsequently the level of risk to the relationship, institution, or self, is evaluated. This study supports that which is observed in the conflict resolution practitioner literature, but is unique in its observation of factors that influence decisions within a dynamic conflict resolution process. My findings are significant to women who aspire to serve in leadership positions in higher education, as well as to the academy as a whole, for it expands our knowledge of women's ontological and epistemological perspectives on resolving conflict in postsecondary education.

Contributing Factors in Corporate America's Implementation of Policies and Procedures That Protect and Enhance the Work Experience for Gay, Lesbian, Bi-sexual and Transgender (GLBT) Employees: An Examination of Corporate GLBT Initiatives

Business organization executives today are routinely challenged to attract and retain key talent and employ innovative techniques to expand their consumer-base. Moreover, these executives have advanced their business initiatives to include workplace equality initiatives with a motivation to attract and retain key talent. In this research the author examined the contributing factors that lead executives in corporate America to implement Gay, Lesbian, Bisexual, and Transgender (GLBT) initiatives as business strategies. The case study methodology applied in this examination illustrated that the implementation of GLBT initiatives can increase a business organization's ability to attract and retain key talent, and increase employee work productivity while expanding the consumer base. Therefore, the business organization's competitive advantage in the marketplace is increased.

Perceived sexism as a health determinant in Spain

OBJECTIVES: The goals of the present study are to explore the association between perceived sexism and self-perceived health, health-related behaviors, and unmet medical care needs among women in Spain; to analyze whether higher levels of discrimination are associated with higher prevalence of poor health indicators and to examine whether these relationships are modified by country of origin and social class. MATERIALS AND METHODS: The study is based on a cross-sectional design using data from the 2006 Spanish Health Interview Survey. We included women aged 20-64 years (n = 10,927). Six dependent variables were examined: four of health (self-perceived health, mental health, hypertension, and having had an injury during the previous year), one health behavior (smoking), and another related to the use of the health services (unmet need for medical care). Perceived sexism was the main independent variable. Social class and country of origin were considered as effect modifiers. We obtained the prevalence of perceived sexism. Logistic regression models, adjusted for potential confounders, were fitted to study the association between sexism and poor health outcomes. Results: The prevalence of perceived sexism was 3.4%. Perceived sexism showed positive and consistent associations with four poor health outcomes (poor self-perceived health, poor mental health, injuries in the last 12 months, and smoking). The strength of these associations increased with increased scores for perceived sexism, and the patterns were found to be modified by country of origin and social class. CONCLUSION: This study shows a consistent association between perceived sexism and poor health outcomes in a country of southern Europe with a strong patriarchal tradition.

The evolution of gender inequality in tourism employment in Spain

Evolución de la desigualdad por género del empleo turístico en España. Si bien la inversión en capital laboral femenino en la industria turística ha aumentado en los últimos años y parece que la discriminación en el acceso a puestos directivos ha descendido, se siguen produciendo diferentes situaciones de desigualdad. La mujer mantiene un salario por debajo del hombre y han aparecido nuevas formas de segregación ocupacional entre hombres y mujeres e incluso entre las propias mujeres: la división entre trabajo a tiempo parcial y completo es un buen ejemplo de este proceso. La hipótesis que se plantea este trabajo es que esa combinación entre tiempo de trabajo remunerado (ámbito público) y no remunerado (ámbito privado, doméstico) es un obstáculo que provoca el acceso de los varones a empleos hasta ahora "femeninos"; así mismo, se observará la calidad del empleo turístico desde la perspectiva de género.

Mixed Public-Private Enterprises in Europe: Economic Theory and an Empirical Analysis of Italian Water Utilities. Bruges European Economic Research (BEER) Papers 4/July 2006

Mixed enterprises, which are entities jointly owned by the public and private sector, are spreading all over Europe in local utilities. Well aware that in the vast majority of cases the preference of local authorities towards such governance structure is determined by practical reasons rather than by the ambition to implement new regulatory designs (an alternative to the typical “external” regulation), our purpose is to confer some scientific value to this phenomenon which has not been sufficiently investigated in the economic literature. This paper aims at proposing an economic analysis of mixed enterprises, especially of the specific configuration in which the public partner acts as controller and the private one (or “industrial” partner) as service provider. We suggest that the public service concession to mixed enterprises could embody, under certain conditions, a noteworthy substitute to the traditional public provision and the concession to totally private enterprises, as it can push regulated operators to outperform and limit the risk of private opportunism. The starting point of the entire analysis is that ownership allows the (public) owner to gather more information about the actual management of the firm, according to property rights theory. Following this stream of research, we conclude that under certain conditions mixed enterprises could significantly reduce asymmetric information between regulators and regulated firms by implementing a sort of “internal” regulation. With more information, in effect, the public authority (as owner/controller of the regulated firm, but also as member of the regulatory agency) can stimulate the private operator to be more efficient and can monitor it more effectively with respect to the fulfilment of contractual obligations (i.e., public service obligations, quality standards, etc.). Moreover, concerning the latter function, the board of directors of the mixed enterprise can be the suitable place where public and private representatives (respectively, welfare and profit maximisers) can meet to solve all disputes arising from incomplete contracts, without recourse to third parties. Finally, taking into account that a disproportionate public intervention in the “private” administration (or an ineffective protection of the general interest) would imply too many drawbacks, we draw some policy implications that make an equitable debate on the board of the firm feasible. Some empirical evidence is taken from the Italian water sector.

Growth, convergence and trade: The services sector in India’s states

India’s success story in services is well documented at the national level, but similar literature does not exist for India’s states. In this paper, we bridge this gap in research by looking at India’s services growth at the sub-national level and in doing so, also challenge existing literature by arguing that this growth has positive implications for income distribution. We find that even as per capita income is not converging across India’s states, per capita services are; evidence is provided both in terms of traditional measures of sigma- and beta-convergence and more recent panel unit root tests. A more disaggregated analysis of services sectors reveals convergence in railways, public administration and financial services. Finally, a Jensen & Kletzer (2005) approach to determining tradability provides evidence of most services being “traded” across India’s states, suggesting the role of such trade in the services growth and convergence story.

In the Supreme Court of the United States, October term, 1980, Héctor García, petitioner v. Alton V.M. Gloor ... [et al.], respondents : on writ of certiorari to the United States Court of Appeals for the Fifth Circuit : petition for writ of certiorari /

At head of title: no.

To eliminate employment discrimination : a sequel : the Federal civil rights enforcement effort--1977 : a report /

A sequel to v. 5 of its The Federal civil rights enforcement effort--1974.

Código de las leyes, decretos y acuerdos que sobre administración de justicia se ha dictado la Provincia de Mendoza.

Binder's title: Registro oficial, Mendoza.

Documentos producidos en la competencia suscitada por el poder ejecutivo a la Corte suprema de justicia, sobre el nombramiento de jueces interinos, ante el Congreso nacional.

Chiefly correspondence between the Corte suprema of Bolivia and the Ministerio de justicia y fomento.