Preventing the anti-angiogenic escape through the endothelial adhesome

αVβ3 integrin is a promising target for therapy due to its upregulation in angiogenic vasculature. However, Cilengitide, an αVβ3 integrin inhibitor (RGD mimetic), has failed late stage clinical trials due to lack of overall survival benefit. We have previously shown that depleting β3-integrin acutely in the mouse endothelium leads to smaller tumours in vivo, whereas constitutive depletion of endothelial expression of this molecule causes an increase in tumour angiogenesis. In the context of cancer therapy, long-term depletion or inhibition of β3-integrin is subject to treatment escape via unknown mechanisms of resistance. At the molecular level, much of the regulation of endothelial cell migration and adhesion, and therefore angiogenesis, occurs via the ‘adhesome’ – the sub-proteome present in focal adhesion complexes. We isolated and compared WT, β3-HET, β3-KO and αVβ3-inhibitor-treated adhesomes by mass spectrometry. Among approximately 300 proteins whose abundance significantly changed, three intermediate filament proteins were upregulated in the β3-integrin depleted adhesome, namely: nestin, plectin and vimentin. All three molecules are known to regulate integrins and play a role in angiogenesis. Given this upregulation of intermediate filaments in the adhesome, I set out to determine whether they are playing a differential role in angiogenesis depending on β3-integrin depletion. At first, I took an siRNA approach to determine the functional consequence of knocking down each target, but, overall, results from this approach were inconclusive. However, I observed that Withaferin A, an inhibitor of vimentin, impaired proliferation and migration of β3-HET, but not WT, endothelial cells. I then decided to look at the effects of Withaferin A on subcutaneous tumour growth in vivo, in combination with long-term endothelial-specific depletion of β3-integrin (via the β3-floxed Tie1.Cre model). The drug did not significantly inhibit tumour growth, but tumour angiogenesis was significantly reduced in the Cre +ve, and not in the Cre -ve background. Similarly, Withaferin A inhibited microvascular sprouting of β3-floxed Tie1.Cre +ve aortic rings, but not of Cre -ve rings. I also utilised pSico technology as an shRNA delivery system and observed impaired microvascular sprouting when depleting nestin. Additionally, I generated tdTomato-labelled nestin constructs which could be utilised to visualise nestin in vitro. Overall, the findings described in this thesis suggest co-targeting β3-integrin and intermediate filaments, such as those made up of vimentin, as an improved anti-angiogenic strategy

Specific problems of nursing patients suffering from Mayer-Rokitansky-Küster-Hauser syndrome

W pracy przedstawiono opis przypadku chorej z zespołem Mayera-Rokitansky'ego-Küstera-Hausera. Scharakteryzowano czynniki etiologiczne, obraz kliniczny, diagnostykę i metody leczenia. Szczególną uwagę zwrócono na specyficzne problemy pielęgnacyjne osób z tym zespołem.Introduction. This paper presents a case description of a woman suffering from Mayer-Rokitansky-Küster-Hauser Syndrome. The etiological factors, the clinical presentation as well as the diagnostics and methods of treatment were scrutinized in this paper. Special attention was devoted to specific problems of nursing patients suffering from that syndrome

Escolarização e trabalho infantojuvenil no Maciço do Morro da Cruz – Florianópolis, Santa Catarina, Brasil

A relação entre o trabalho precoce e a escolarização ainda é um tema central para pensar a equidade e a permanência de jovens no processo de escolarização no Brasil. Este artigo tem por objetivo refletir sobre a relação entre o trabalho infantojuvenil e a escolarização de estudantes matriculados em 10 escolaslocalizadas no Maciço do Morro da Cruz, território precário e periférico da ilha de Florianópolis, Santa Catarina, Brasil. Foi realizada análise documental dos Projetos Políticos Pedagógicos e Planos de Gestão das escolas participantes e, para isso, utilizamos os seguintes instrumentos de coleta de dados: questionário, entrevistas com grupos focais com crianças, adolescentes e jovens que começaram a trabalhar precocemente e observações diretas registradas em diário de campo. Os dados foram tabulados e analisados à luz das seguintes categorias: escolarização, trabalho, classe social, infância e juventude. Considera-se que parte dos estudantes abandonam ou se afastam sazonalmente da escola em função da necessidade precoce de trabalhar, fato esse que está entre os principais fatores que geram evasão e abandono escolar

Transcriptome responses to aluminum stress in roots of aspen (Populus tremula)

ABSTRACT: BACKGROUND: Ionic aluminum (mainly Al3+) is rhizotoxic and can be present in acid soils at concentrations high enough to inhibit root growth. Many forest tree species grow naturally in acid soils and often tolerate high concentrations of Al. Previously, we have shown that aspen (Populus tremula) releases citrate and oxalate from roots in response to Al exposure. To obtain further insights into the root responses of aspen to Al, we investigated root gene expression at Al conditions that inhibit root growth. RESULTS: Treatment of the aspen roots with 500 uM Al induced a strong inhibition of root growth within 6 h of exposure time. The root growth subsequently recovered, reaching growth rates comparable to that of control plants. Changes in gene expression were determined after 6 h, 2 d, and 10 d of Al exposure. Replicated transcriptome analyses using the Affymetrix poplar genome array revealed a total of 175 significantly up-regulated and 69 down-regulated genes, of which 70% could be annotated based on Arabidopsis genome resources. Between 6 h and 2 d, the number of responsive genes strongly decreased from 202 to 26, and then the number of changes remained low. The responses after 6 h were characterized by genes involved in cell wall modification, ion transport, and oxidative stress. Two genes with prolonged induction were closely related to the Arabidopsis Al tolerance genes ALS3 (for Al sensitive 3) and MATE (for multidrug and toxin efflux protein, mediating citrate efflux). Patterns of expression in different plant organs and in response to Al indicated that the two aspen genes are homologs of the Arabidopsis ALS3 and MATE. CONCLUSION: Exposure of aspen roots to Al results in a rapid inhibition of root growth and a large change in root gene expression. The subsequent root growth recovery and the concomitant reduction in the number of responsive genes presumably reflect the success of the roots in activating Al tolerance mechanisms. The aspen genes ALS3 and MATE may be important components of these mechanisms

The β3-integrin endothelial adhesome regulates microtubule-dependent cell migration

Integrin β3 is seen as a key anti-angiogenic target for cancer treatment due to its expression on neovasculature, but the role it plays in the process is complex; whether it is pro- or anti-angiogenic depends on the context in which it is expressed. To understand precisely β3's role in regulating integrin adhesion complexes in endothelial cells, we characterised, by mass spectrometry, the β3-dependent adhesome. We show that depletion of β3-integrin in this cell type leads to changes in microtubule behaviour that control cell migration. β3-integrin regulates microtubule stability in endothelial cells through Rcc2/Anxa2-driven control of active Rac1 localisation. Our findings reveal that angiogenic processes, both in vitro and in vivo, are more sensitive to microtubule targeting agents when β3-integrin levels are reduced

Fairness at Trial: The Impact of Procedural Justice and Other Experiential Factors on Criminal Defendants' Perceptions of Court Legitimacy in Poland

A large body of research supports the procedural justice hypothesis that quality of treatment matters more than outcomes for institutional legitimacy. How fairness matters across legal institutions and geographic settings remains an open question, however. This article uses a survey of criminal defendants to test the factors associated with perceived legitimacy of courts in Poland, a country whose judiciary is currently subject to intense political contestation. The findings confirm the primacy of procedural justice, while also illustrating the influence of instrumental performance factors such as time and court organization. This suggests that in contexts of political transition with disputed legal institutions, citizens’ contact with procedurally fair, operationally efficient institutions can support the legitimacy of authorities and strengthen the rule of law

Profit as a category of commercial law, balance law and tax law

Celem niniejszego opracowania jest prezentacja i analiza wybranych rozwiązań prawnych z zakresu prawa handlowego, bilansowego oraz prawa podatkowego dotyczących kategorii zysku. Uzasadnieniem wyboru przedmiotu badań i refleksji nad uniwersalną kategorią zysku jest brak spójności systemowej wspomnianych regulacji prawnych. Zasadne jest sformułowanie podstawowego problemu badawczego, jakim są wzajemne relacje pomiędzy przepisami prawa handlowego, bilansowego i podatkowego regulującymi kategorię zysku oraz tego konsekwencje w różnych sytuacjach społecznych. Istotna jest również kwestia wskazania granic, jakie stawiają te regulacje prawne w zakresie kształtowania obrazu sytuacji finansowej podmiotów sprawozdawczych, w tym przypadku spółek kapitałowych. Przede wszystkim wiąże się to z udzieleniem odpowiedzi na pytanie, w jaki sposób prawo podatkowe wpływa na stosowanie rozwiązań przyjętych w przepisach prawa handlowego i bilansowego. Wydaje się, że mimo braku hierarchicznego podporządkowania, przepisy prawa podatkowego mogą w pewnych sytuacjach mieć dominujące znaczenie.The aim of the paper is to present and analyse some of the legal solutions in the area of commercial, balance and tax law, which refer to the category of profit. A reason to choose the subject for the study and reflection over a universal category of profit is a lack of systemic coherence of the mentioned legal regulations. It is relevant to formulate a research problem in terms of mutual relationships between regulations of commercial, balance and tax law, which apply to profit category and its consequences in various social situations. It seems essential to state the limits which are established by the regulations in the field of building of an image of the reporting entities’ (limited companies) financial situations. Mostly, it refers to answering the question how tax law influences applying solutions assumed by regulations of commercial and balance law. It seems that despite a lack of hierarchic subjection, tax law regulations may be of dominant sense in some situations

Obama and McCain with Lightsabers. Politicians in the Age of Cultural Convergence

W artykule przedstawiono sposób, w jaki polityk-celebryta funkcjonuje we współczesnej, transmedialnej rzeczywistości. Autor przybliża teorię oraz kontrowersje związane z wykorzystywaniem kultury masowej w dyskursie publicznym. Uznaje, że zrozumienie powyższego mechanizmu wymaga uzupełnienia o teorię aktywnej konsumpcji informacji przez współczesnych odbiorców. Przedstawia w związku z tym zagadnienie kultury konwergencji, zakładającej nieustanną interakcję mediów różnego rodzaju. Kwestie teoretyczne uzupełnia przykład wykorzystania nawiązań do „Gwiezdnych Wojen” w dyskursie politycznym.The paper presents the manner in which a celebrity politician functions in contemporary transmedia reality. The author describes the theory and controversies associated with the use of popular culture in public discourse and claims that understanding of its mechanism requires including the theory of active consumption of information by contemporary audiences. Therefore, the paper focuses also on the issue of convergence culture, which involves constant interaction of various types of media. Theoretical issues are complemented with an example of the use of „Star Wars” references in political discourse