Use of preclinical and early clinical data for dose selection of a selective estrogen receptor modulator toremifene in treatment of breast cancer

In development of human medicines, it is important to predict early and accurately enough the disease and patient population to be treated as well as the effective and safe dose range of the studied medicine. This is pursued by using preclinical research models, clinical pharmacology and early clinical studies with small sample sizes. When successful, this enables effective development of medicines and reduces unnecessary exposure of healthy subjects and patients to ineffectice or harmfull doses of experimental compounds. Toremifene is a selective estrogen receptor modulator (SERM) used for treatment of breast cancer. Its development was initiated in 1980s when selection of treatment indications and doses were based on research in cell and animal models and on noncomparative clinical studies including small number of patients. Since the early development phase, the treatment indication, the patient population and the dose range were confirmed in large comparative clinical studies in patients. Based on the currently available large and long term clinical study data the aim of this study was to investigate how the early phase studies were able to predict the treatment indication, patient population and the dose range of the SERM. As a conclusion and based on the estrogen receptor mediated mechanism of action early studies were able to predict the treatment indication, target patient population and a dose range to be studied in confirmatory clinical studies. However, comparative clinical studies are needed to optimize dose selection of the SERM in treatment of breast cancer.

The role of reelin in the development and evolution of the cerebral cortex

Reelin is an extracellular matrix protein that is defective in reeler mutant mice and plays a key role in the organization of architectonic patterns, particularly in the cerebral cortex. In mammals, a "reelin signal" is activated when reelin, secreted by Cajal-Retzius neurons, binds to receptors of the lipoprotein receptor family on the surface of cortical plate cells, and triggers Dab1 phosphorylation. As reelin is a key component of cortical development in mammals, comparative embryological studies of reelin expression were carried out during cortical development in non-mammalian amniotes (turtles, squamates, birds and crocodiles) in order to assess the putative role of reelin during cortical evolution. The data show that reelin is present in the cortical marginal zone in all amniotes, and suggest that reelin has been implicated in the evolution of the radial organization of the cortical plate in the synapsid lineage leading from stem amniotes to mammals, as well as in the lineage leading to squamates, thus providing an example of homoplastic evolution (evolutionary convergence). The mechanisms by which reelin instructs radial cortical organization in these two lineages seem different: in the synapsid lineage, a drastic amplification of reelin production occurred in Cajal-Retzius cells, whereas in squamates, in addition to reelin-secreting cells in the marginal zone, a second layer of reelin-producing cells developed in the subcortex. Altogether, our results suggest that the reelin-signaling pathway has played a significant role in shaping the evolution of cortical development.

News in the age of empire : two war scandals

This thesis argues that the motivations underpinning the mainstream news media have fundamentally changed in the 21 sl century. As such, the news is no longer best understood as a tool for propaganda or agenda setting; instead it seems that the news is only motivated by the flow of global network capitalism. The author contrasts the work of Noam Chomsky and Edward S. Herman with that of Gilles Deleuze. Chomsky and Herman's 'Propaganda Model' has been influential within the fields of media studies and popular culture. The 'propaganda model' states that the concentration of ownership of the media has allowed the media elite to exert a disproportionate amount of influence over the mass media. Deleuze, on the other hand, regards the mass media as being yet another cog within the global capitalist mechanism, and is therefore separate from ideology or propaganda. The author proposes that 'propaganda' is no longer a sufficient word to describe the function of the news as terms like 'propaganda' imply some form of national sovereignty or governmental influence. To highlight how the news has 'changed from an instrument of propaganda to an instrument of accumulation, the author compares and contrasts the· coverage of the Abu Ghraib Prison Scandal with that of the Haditha Civilian Massacre. Although similar in nature, the author proposes that the Abu Ghraib Prison Scandal received a disproportionate amount of coverage within the mainstream press because of its exciting and sensational nature.

La microfinance au coeur d'une géographie du genre renouvelée au Mexique?

Le développement des sociétés à travers le monde est influencé par des dynamiques de pouvoir social. D’une perspective de genre, les relations patriarcales ont contribué à la réorganisation du développement par un accès inégal aux ressources, à l’espace et à la mobilité. La société mexicaine, caractérisée par un fort patriarcat et une pauvreté endémique, a vu émerger de multiples outils de développement pour pallier aux inégalités de genre. Plus récemment, les programmes de microfinance sont devenus un instrument de choix pour lutter contre la marginalisation des femmes et les inégalités de genre. La littérature scientifique présente des lacunes au sujet de la nature des relations de genre dans les ménages qui bénéficient de la microfinance. Plusieurs études portent sur les impacts de la microfinance sur la vie des femmes, mais peu offrent une vision holistique considérant la microfinance comme un outil de développement capable de changer la nature spatiale des inégalités de genre. Cette recherche est basée sur une comparaison qualitative de deux études de cas de groupes de microfinance de San Miguel Tenextatiloyan et d’Émilio Carranza, deux communautés de la Sierra Norte de Puebla (Mexique). Son objectif principal est d’évaluer le degré selon lequel les programmes de microfinance ont changé la place des femmes dans la société. Pour répondre à cette question, un portrait de l’organisation spatiale du genre sera tracé, puis, les impacts des programmes de microfinance sur la place des femmes dans les espaces domestiques, de travail et communautaires seront évalués. L’étude mène à la conclusion que les programmes de microfinance du CESDER n’ont pas beaucoup changé la place des femmes dans la société. La recherche dévoile plutôt que, dans un contexte de pauvreté, la microfinance stabilise les ménages et offre des lieux d’échange et de réseautage, mais elle n’offre pas aux femmes une véritable chance d’acquérir plus de contrôle sur leur vie. Deuxièmement, les résultats démontrent que les tâches associées à la reproduction sociale – largement assumée par les femmes - engendrent une barrière structurante à l’empowerment des femmes, un obstacle que la microfinance ne parvient pas entièrement à surmonter. Mots-clés : Géographie du genre, relations de pouvoir, développement, microfinance, spatialité, néolibéralisme, Mexique.

The Forgotten Side of Partisanship: Negative Party Identification in Four Anglo-American Democracies

Early studies of electoral behavior proposed that party identification could be negative as well as positive. Over time, though, the concept became mostly understood as a positive construct. The few studies that took negative identification into account tended to portray it as a marginal factor that went “hand-in-hand” with positive preferences. Recent scholarship in psychology reaffirms, however, that negative evaluations are not simply the bipolar opposite of positive ones. This article considers negative party identification from this standpoint, and evaluates its impact in recent national elections in Australia, Canada, New Zealand, and the United States. Our findings highlight the autonomous power of negative partisanship. They indicate as well that ideology has an influence on both positive and negative partisan identification.

Public Opinion and Global Justice

The concept of global justice has been developed to stress the worldwide implications of moral problems. Not much, however, has been written about the actual politics of global justice. This article focuses on public opinion and argues that attitudes about international redistribution are not a simple projection of attitudes about the domestic situation. In countries where domestic income redistribution is seen as an important priority, foreign aid is less popular; where this is less so, there is more concern for the fate of the poor in the South. Far from reflecting a lack of coherence in public opinion, these counterintuitive results need to be understood in connection with policy achievements in donor countries. The authors' empirical findings suggest that although the commitment to redistribute is stronger at the national level, relationships of solidarity do not stop at national boundaries. The achievement of justice at home in fact sustains justice abroad.

La presse satirique illustrée française et la colonisation (1829-1990)

- Thèse réalisée en cotutelle entre les Université de Montréal et Paris Ouest Nanterre la Défense. -Thèse construite à partir de logiciels libres et gratuits : Ubuntu, Lyx, LibreOffice, Zotero, The Gimp.

Influence of personality factors on the consumption of personal care products

This research was undertaken with the primary objective of explaining differences in consumption of personal care products using personality variables. Several streams of research reported were reviewed and a conceptual model was developed. Theories on the relationship between self concept and behaviour was reviewed and the need to use individual difference variables to conceptualize and measure the salient dimensions of the self were emphasized. Theories relating to social comparison, eating disorders, role of idealized media images in shaping the self-concept, evidence on cosmetic surgery and persuasibility were reviewed in the study. These came from diverse fields like social psychology, use of cosmetics, women studies, media studies, self-concept literature in psychology and consumer research, and marketing. From the review three basic dimensions, namely self-evaluation, self-awareness and persuasibility were identified and they were posited to be related to consumption. Several personality variables from these conceptual domains were identified and factor analysis confirmed the expected structure fitting the basic theoretical dimensions. Demographic variables like gender and income were also considered.It was found that self-awareness measured by the variable public self-consciousness explain differences in consumption of personal care products. The relationship between public self-consciousness and consumption was found to be most conspicuous in cases of poor self-, evaluation measured by self-esteem. Susceptibility to advertising also was found to explain differences in consumption.From the research, it may be concluded that personality variables are useful for explaining consumption and they must be used together to explain and understand the process. There may not be obvious and conspicuous links between individual measures and behaviour in marketing. However, when used in proper combination and with the help oftheoretical models personality offers considerable explanatory power as illustrated in the seventy five percent accuracy rate of prediction obtained in binary logistic regression.

Molekulare Mechanismen der cAMP-vermittelten Signaltransduktion

Zusammenfassung - Der sekundäre Botenstoff zyklisches Adenosinmonophosphat (cAMP) reguliert viele fundamentale zelluläre Prozesse wie Zellproliferation, Differenzierung, Energiemetabolismus und Genexpression. In eukaryotischen Zellen vermittelt die cAMP-abhängige Proteinkinase (PKA) die meisten biologischen Funktionen von cAMP. Die PKA besteht aus jeweils zwei regulatorischen (R) und katalytischen (C) Untereinheiten, die zusammen einen inaktiven Holoenzymkomplex bilden, der durch cAMP aktiviert wird. In dieser Arbeit wurde die Bindung von cAMP und cAMP-Analoga an die R Untereinheit der PKA unter funktionellen und mechanistischen Aspekten untersucht. Eine neue, auf Fluoreszenzpolarisation basierende Methode wurde entwickelt, um die Affinität von cAMP-Analoga in einem homogenen Ansatz schnell, reproduzierbar und nicht radioaktiv zu quantifizieren. Zur detaillierten Untersuchung des Bindungsmechanismus von cAMP und cAMP Analoga (Agonisten und Antagonisten) wurden thermodynamische Studien im direkten Vergleich mittels isothermaler Titrationskalorimetrie und kinetischen Analysen (Oberflächenplasmonresonanz, SPR) durchgeführt, wodurch thermodynamische Signaturen für das Bindungsverhalten der Nukleotide an die R Untereinheit der PKA erhalten werden konnten. Durch Interaktionsstudien an mutagenisierten R Untereinheiten wurde der intramolekulare Aktivierungsmechanismus der PKA in Bezug auf cAMP-Bindung, Holoenzymkomplex-Formierung und -Aktivierung untersucht. Die dabei erhaltenen Ergebnisse wurden mit zwei Modellen der cAMP-induzierten Konformationsänderung verglichen, und ein Aktivierungsmechanismus postuliert, der auf konservierten hydrophoben Aminosäuren basiert. Für in vivo Untersuchungen wurden zusammen mit Kooperationspartnern membranpermeable, fluoreszierende cAMP Analoga entwickelt, die Einblicke in die Dynamik der cAMP-Verteilung in Zellen erlauben. Neu entwickelte, Festphasen gebundene cAMP-Analoga (Agonisten und Antagonisten) wurden in einem (sub)proteomischen Ansatz dazu genutzt, natürliche Komplexe der R Untereinheit und des PKA-Holoenzyms aus Zelllysaten zu isolieren und zu identifizieren. Diese Untersuchungen fließen letztlich in einem systembiologischen Ansatz zusammen, der neue Einblicke in die vielschichtigen cAMP gesteuerten Netzwerke und Regulationsprozesse erlaubt.

Egyptian wheat

Wheat as the major cereal crop in Egypt is the core of the government's food security policy. But there are rapid losses of the genetic resources of the country as a result of ongoing modernization and development. Thus we compiled the largest possible number of Egyptian accessions preserved in the world gene banks. In the present study we collected nearly 1000 Egyptian wheat accessions. A part from the Triticum species of the Egyptian flora four species have been found, which were recorded for the first time T. turanicum, T. compactum, T. polonicum and T. aethiopicum. To classify the Egyptian wheat species using morphological studies, 108 accessions were selected. Thereafter, these accessions were cultivated and evaluated morphologically to confirm the validity of the classified species. During the morphological evaluation study, a new case was noticed for the number of glumes in one of the Egyptian wheat accessions. Three glumes per spikelet were observed in a branched spike. This led us to assess the phenomenon in all varieties with branching spikes within the genus Triticum. All varieties which have branching spikes at least in some spikletes have three glumes. We considered the case of the third glume as indicator for the domestication syndrome. Also, a new case of other forms of branching in the genus Triticum was investigated, which was a compromise between true and false-branching. We called it true-false branching. Comparative anatomical studies were carried out between Egyptian Triticum species to investigate the possibility of using anatomical features to classify the Egyptian wheat species. It was concluded that it is difficult to use anatomical features alone to differentiate between two Triticum species, especially when they belong to the same ploidy level. A key for the identification of Egyptian Triticum taxa was established.

Revisión sistemática de estudios descriptivos : tratamiento de fracturas diafisarias antebrazo en niños entre 6 y 12 años

El tratamiento de las fracturas de tercio medio de antebrazo en niños de 6-12 años es controversial, debido a las diferentes opciones de manejo que existen en la actualidad. Objetivo: realizar una revisión sistemática de la literatura para determinar cuál es el mejor tratamiento de las fracturas diafisiarias del tercio medio del antebrazo en niños de 6-12 años. Materiales y métodos: se realizó una búsqueda sistemática y ampliada de estudios descriptivos comparativos sobre los diferentes tratamientos para fracturas tercio medio antebrazo en niños de 6-12 años de edad. Resultados: se identificaron en total 16 artículos, seis de los cuales cumplieron los criterios de inclusión, con cinco diferentes opciones de tratamiento. No se encontraron diferencias en los resultados funcionales de los diferentes tipos de tratamiento y se evidencio un mayor número de complicaciones por angulación de las fracturas en los grupos de tratamiento con clavos endomedulares. Los estudios presentan sesgos de selección y hay varias diferencias en la medición de sus respectivos desenlaces. Conclusiones: la evidencia evaluada en esta revisión sistemática no permite determinar cuál es el mejor tratamiento para este tipo de fracturas, sin importar el tipo de material de osteosíntesis utilizado. Se requieren ensayos clínicos controlados que evalúen los diferentes tipos de tratamiento para poder determinar el mejor manejo de estas.

Los conceptos de salud financiera, riesgo y epidemiología en los estados financieros de las compañías del sector de extracción de petróleo crudo y gas natural en Colombia

El presente proyecto tiene como objeto identificar cuáles son los conceptos de salud, enfermedad, epidemiología y riesgo aplicables a las empresas del sector de extracción de petróleo y gas natural en Colombia. Dado, el bajo nivel de predicción de los análisis financieros tradicionales y su insuficiencia, en términos de inversión y toma de decisiones a largo plazo, además de no considerar variables como el riesgo y las expectativas de futuro, surge la necesidad de abordar diferentes perspectivas y modelos integradores. Esta apreciación es pertinente dentro del sector de extracción de petróleo y gas natural, debido a la creciente inversión extranjera que ha reportado, US$2.862 millones en el 2010, cifra mayor a diez veces su valor en el año 2003. Así pues, se podrían desarrollar modelos multi-dimensional, con base en los conceptos de salud financiera, epidemiológicos y estadísticos. El termino de salud y su adopción en el sector empresarial, resulta útil y mantiene una coherencia conceptual, evidenciando una presencia de diferentes subsistemas o factores interactuantes e interconectados. Es necesario mencionar también, que un modelo multidimensional (multi-stage) debe tener en cuenta el riesgo y el análisis epidemiológico ha demostrado ser útil al momento de determinarlo e integrarlo en el sistema junto a otros conceptos, como la razón de riesgo y riesgo relativo. Esto se analizará mediante un estudio teórico-conceptual, que complementa un estudio previo, para contribuir al proyecto de finanzas corporativas de la línea de investigación en Gerencia.

Entendiendo un programa de reparación: reconstrucción del proceso de creación e implementación de familias en su tierra – FEST– El caso del municipio de La Palma, Cundinamarca

A partir de la reconstrucción del proceso de creación e implementación del programa presidencial para la reparación a población desplazada Familias En Su Tierra, se exploran las dificultades y retos que enfrenta la Ley de Víctimas y Restitución de Tierras.