Topologien der Geschlechter : die Revision traditioneller Raumordnungen im Postfranquismus am Beispiel von Esther Tusquets, Carme Riera und Clara Janés

Die vorliegende Arbeit untersucht anhand von ausgewählten Romanen dreier zeitgenössischer spanischer Autorinnen – Esther Tusquets, Carme Riera und Clara Janés – exemplarisch, wie sich die soziokulturelle Raumordnung nach dem Ende der Franco-Diktatur in Spanien verändert hat und wie dies literarisch gestaltet wird. Zentrales Erkenntnisinteresse der Arbeit ist es, den Zusammenhang von Raumkonzeptionen und Weiblichkeitsdiskursen möglichst umfassend zu beleuchten; analysiert werden die Geschlechterrepräsentation im Raum und die geschlechts-spezifische Codierung von Räumen. Dabei werden zum einen traditionelle Paradigmen beschrieben, auf die die Romane teils Bezug nehmen, zum anderen stellt sich die Frage, welche Alternativen zur Verortung weiblicher Subjektivität und welche alternativen Raumordnungen der Geschlechter möglich sind. Hierfür werden verschiedene topologische Ansätze aus Literatur- und Kulturwissenschaft herangezogen. Wenn Raum nicht unabhängig vom wahrnehmenden Subjekt zu denken ist, wie die neuere kulturwissenschaftliche Theoriebildung veranschaulicht, dann stellt sich auch die Frage, wie das Paradigma weibliche/männliche Identität die Raumper-zeption und -konstruktion bestimmt. Für die Textanalyse relevante Aspekte sind etwa die Auswahl und Verknüpfung, die sensuelle Wahrnehmung und die sprachliche Ausgestaltung der Räume, die Positionierung und Interaktion der Figuren sowie Standort und Raumbezug der Erzählinstanz, gerade auch in ihrem strukturellen Zusammenhang mit anderen narrativen Elementen wie Figuren, Handlung und Zeit. Metafiktionale Raumfiguren fügen der Raumordnung der Texte eine weitere Bedeutungsebene hinzu. Die Arbeit ist folgendermaßen aufgebaut: Auf Einleitung, Forschungsbericht und ein methodologisches Kapitel folgt zunächst eine Überblicksdarstellung zu sozialen, kultur- und literaturgeschichtlichen Aspekten des Raumes, welche abschließend zu einer theoretischen Betrachtung der Analogisierung von Weiblichkeit und Raum zusammengeführt werden. Die hier diskutierten Figurationen des Weiblichen sollen die Komplexität des Zusammenhangs von Raum- und Geschlechterordnung aufzeigen und als Folie für die nachfolgenden Textanalysen dienen. Den Analysen der drei ausgewählten Romane vorgeschaltet ist ein Kapitel, in dem die Raumstrukturen in repräsentativen Texten von Autorinnen seit dem Bürgerkrieg (Laforet, Gaite, Rodoreda, Roig) zusammenfassend dargestellt werden. Die Vorstellung dieser Prätexte erlaubt es, die nachfolgend untersuchten Romane literaturgeschichtlich einzuordnen und Bezüge herzustellen. Für ein close reading wurden drei Romane von Autorinnen aus dem katalanischsprachigen Raum ausgewählt: Esther Tusquets, El mismo mar de todos los veranos (1978), Carme Riera, Una primavera per a Domenico Guarini (1981), Clara Janés, El hombre de Adén (1991). Alle drei Autorinnen haben sich an anderer Stelle zur Gender-Thematik geäußert, und das Thema weibliche Identität stellt einen roten Faden in ihrer Prosa dar. Das Korpus erlaubt einen Längsschnitt von der transición bis Anfang der neunziger Jahre, ein Zeitraum, in dem sich in Spanien tiefgreifende gesellschaftliche Veränderungen vollzogen haben, die gerade auch Frauen neue mentale und soziale Räume eröffnet haben. Für die Textanalysen werden idealtypisch drei Raumebenen unterschieden, die eng miteinander verknüpft sind: a) physische, lebensweltlich inspirierte Räume, die der Erzählung ihren äußeren Rahmen geben und als Handlungsräume bzw. erlebte Räume fungieren und teils symbolisch-metaphorischen Charakter haben; b) innere bzw. imaginäre Räume, die nur im Bewusstsein der Figur qua Imagination, als Erinnerungen oder Phantasien existieren; c) die metafiktionale Dimension des Textraums, die den Text selbst als bedeutungstragenden Raum anspricht, der narrative Funktion hat. Aufbauend auf einer Inventarisierung der verschiedenen Räume und raumbildenden Elemente in den untersuchten Romanen wird das Verhältnis von kulturell codiertem Handlungsraum, subjektiver Raumaneignung der Figuren und diskursiven Strategien des Textraums dargestellt und in Bezug zur Gender-Repräsentation gesetzt. Die Zusammenschau von Texten aus franquistischer Zeit mit den drei ausführlicher vorgestellten Romanen der siebziger bis neunziger Jahre zeigt, mit welchen literarischen Mitteln traditionelle Raumparadigmen des Geschlechterdiskurses subversiv entwertet und durch Umkodierung mit alternativen Bedeutungen aufgeladen werden bzw. wie versuchsweise neue Raumordnungen mit utopischem Charakter entworfen werden. So erschließen sich neue Gesichtspunkte nicht nur für die einzelnen Romane, sondern die aufgezeigten Querverbindungen erlauben Einblicke in spezifisch weibliche Traditionslinien innerhalb der spanischen Literaturgeschichte

Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy

Expression of Angiopoietin 1, 2 and Their Common Receptor Tie2 in Human Gastric Carcinoma: Implication for Angiogenesis

Angiogenesis, formation of new microvessels providing oxygen and nutrient supply, is essential for tumor growth. It is dependent on the production of angiogenic growth factors by tumor cells. Angiopoietin 1 (Ang-1) and 2 (Ang-2) and their common receptor, Tie2, are thought to be critical regulators of tumor angiogenesis. We examined expression of Ang-1, Ang-2, and their common receptor Tie2 mRNAs and proteins in gastric cancers using in situ hybridization and immunohistochemistry. We also investigated the relationship between their expression and differentiation of cancer cells, lymph node metastasis, tumor size, depth of cancer cell invasion, TNM staging and microvessel density (MVD). The expression of Ang-1, Ang-2, and Tie2 mRNA in cancer cells significantly correlated with the MVD (p<0.001, <0.001 and =0.019, respectively). Ang-1 and Tie2 positivity correlated with advanced gastric cancers (p<0.05) and larger cancers had higher positive rates of Ang-1, Ang-2, and Tie2 mRNA expression (p<0.001, =0.010 and =0.039, respectively). Significant positive correlations were also found between mRNA expression of Tie2 and those of Ang-1 and Ang-2 (p<0.01 and <0.001, respectively). These findings indicate that the expression of Ang-1 and Ang-2 is important for tumor angiogenesis, and suggest a possible role of autocrine/paracrine function of angiopoietin/Tie2 system in gastric cancer progression

Multimodality Imaging of Abnormal Vascular Perfusion and Morphology in Preclinical 9L Gliosarcoma Model

This study demonstrates that a dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) perfusion parameter may indicate vascular abnormality in a brain tumor model and reflects an effect of dexamethasone treatment. In addition, X-ray computed tomography (CT) measurements of vascular tortuosity and tissue markers of vascular morphology were performed to investigate the underpinnings of tumor response to dexamethasone.One cohort of Fisher 344 rats (N = 13), inoculated intracerebrally with 9L gliosarcoma cells, was treated with dexamethasone (i.p. 3 mg/kg/day) for five consecutive days, and another cohort (N = 11) was treated with equal volume of saline. Longitudinal DSC-MRI studies were performed at the first (baseline), third and fifth day of treatments. Relative cerebral blood volume (rCBV) was significantly reduced on the third day of dexamethasone treatment (0.65 ± .13) as compared to the fifth day during treatment (1.26 ±.19, p < 0.05). In saline treated rats, relative CBV gradually increased during treatment (0.89 ±.13, 1.00 ± .21, 1.13 ± .23) with no significant difference on the third day of treatment (p>0.05). In separate serial studies, microfocal X-ray CT of ex vivo brain specimens (N = 9) and immunohistochemistry for endothelial cell marker anti-CD31 (N = 8) were performed. Vascular morphology of ex vivo rat brains from micro-CT analysis showed hypervascular characteristics in tumors, and both vessel density (41.32 ± 2.34 branches/mm(3), p<0.001) and vessel tortuosity (p<0.05) were significantly reduced in tumors of rats treated with dexamethasone compared to saline (74.29 ± 3.51 branches/mm(3)). The vascular architecture of rat brain tissue was examined with anti-CD31 antibody, and dexamethasone treated tumor regions showed reduced vessel area (16.45 ± 1.36 µm(2)) as compared to saline treated tumor regions (30.83 ± 4.31 µm(2), p<0.001) and non-tumor regions (22.80 ± 1.11 µm(2), p<0.01).Increased vascular density and tortuosity are culprit to abnormal perfusion, which is transiently reduced during dexamethasone treatment

The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model

Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg−1) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities

Role of Src in angiopoietin 1-induced capillary morphogenesis of endothelial cells: Effect of chronic hypoxia on Src inhibition by PP2.

Signal transduction pathways leading to angiopoietin 1 (Ang1)-induced capillary morphogenesis by endothelial cells remain poorly defined. Angiogenic cellular responses by endothelial cells may be modulated in vivo by chronic hypoxia, such as that induced by tumors. Here, we studied Ang1-induced capillary morphogenesis in human umbilical-vein endothelial cells (HUVECs) cultured chronically under normoxic (21% oxygen) or hypoxic (1.5% oxygen) conditions. Downregulation of Src using a small interfering RNA (siRNA) inhibited Ang1-induced capillary morphogenesis of HUVECs cultured under both conditions by blocking cell spreading and protrusion. Ang1 upregulated the Src-dependent secretion of vascular endothelial growth factor-A (VEGF-A). Blockade of endogenous VEGF-A also inhibited Ang1-induced capillary morphogenesis. Addition of exogenous VEGF-A restored cell spreading and protrusion, leading to Ang1-induced capillary morphogenesis of Src siRNA-treated HUVECs, suggesting that Ang1-induced VEGF-A secretion through Src was required for capillary morphogenesis. PP2 inhibited both Ang1-induced capillary morphogenesis and Src activation in HUVECs cultured under normoxic conditions, but the PP2 activity was significantly impaired in HUVECs cultured under hypoxic conditions. Expression of multidrug resistance-associated protein 1 (MRP 1) was upregulated in hypoxic HUVECs, and treatment with MRP 1 siRNA restored the inhibitory action of PP2. Taken together, our results suggest that Ang1 induces capillary morphogenesis in HUVECs through Src-dependent upregulation of endogenous VEGF-A. Conditions of chronic hypoxia impaired the effect of PP2, possibly via MRP 1

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice

Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1−/−) mice. Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation

Antitumor effect of sFlt-1 gene therapy system mediated by Bifidobacterium Infantis on Lewis lung cancer in mice

Soluble fms-like tyrosine kinase receptor (sFlt-1) is a soluble form of extramembrane part of vascular endothelial growth factor receptor-1 (VEGFR-1) that has antitumor effects. Bifidobacterium Infantis is a kind of non-pathogenic and anaerobic bacteria that may have specific targeting property of hypoxic environment inside of solid tumors. The aim of this study was to construct Bifidobacterium Infantis-mediated sFlt-1 gene transferring system and investigate its antitumor effect on Lewis lung cancer (LLC) in mice. Our results demonstrated that the Bifidobacterium Infantis-mediated sFlt-1 gene transferring system was constructed successfully and the system could express sFlt-1 at the levels of gene and protein. This system could not only significantly inhibit growth of human umbilical vein endothelial cells induced by VEGF in vitro, but also inhibit the tumor growth and prolong survival time of LLC C57BL/6 mice safely. These data suggest that Bifidobacterium Infantis-mediated sFlt-1 gene transferring system presents a promising therapeutic approach for the treatment of cancer

Systemic inhibition of tumour angiogenesis by endothelial cell-based gene therapy

Angiogenesis and post-natal vasculogenesis are two processes involved in the formation of new vessels, and both are essential for tumour growth and metastases. We isolated endothelial cells from human blood mononuclear cells by selective culture. These blood outgrowth cells expressed endothelial cell markers and responded correctly to functional assays. To evaluate the potential of blood outgrowth endothelial cells (BOECs) to construct functional vessels in vivo, NOD-SCID mice were implanted with Lewis lung carcinoma cells subcutaneously (s.c.). Blood outgrowth endothelial cells were then injected through the tail vein. Initial distribution of these cells occurred throughout the lung, liver, spleen, and tumour vessels, but they were only found in the spleen, liver, and tumour tissue 48 h after injection. By day 24, they were mainly found in the tumour vasculature. Tumour vessel counts were also increased in mice receiving BOEC injections as compared to saline injections. We engineered BOECs to deliver an angiogenic inhibitor directly to tumour endothelium by transducing them with the gene for human endostatin. These cells maintained an endothelial phenotype and decreased tumour vascularisation and tumour volume in mice. We conclude that BOECs have the potential for tumour-specific delivery of cancer gene therapy

Tumour vascularization: sprouting angiogenesis and beyond

Tumour angiogenesis is a fast growing domain in tumour biology. Many growth factors and mechanisms have been unravelled. For almost 30 years, the sprouting of new vessels out of existing ones was considered as an exclusive way of tumour vascularisation. However, over the last years several additional mechanisms have been identified. With the discovery of the contribution of intussusceptive angiogenesis, recruitment of endothelial progenitor cells, vessel co-option, vasculogenic mimicry and lymphangiogenesis to tumour growth, anti-tumour targeting strategies will be more complex than initially thought. This review highlights these processes and intervention as a potential application in cancer therapy. It is concluded that future anti-vascular therapies might be most beneficial when based on multimodal anti-angiogenic, anti-vasculogenic mimicry and anti-lymphangiogenic strategies