Föderalismus in der Tschechoslowakei

Die slowakische Frage wurde bereits während des Ersten Weltkrieges Gegenstand der politischen Vertreter, die einer ersten Tschechoslowakischen Republik hoffnungsvoll entgegensahen. Auf Basis des Pittsburgh Agreement, welches wesentlich von der Doktrin des Selbstbestimmungsrechts der Völker beeinflusst war, wurde den slowakischen Vertretern im Ausland unter Beisein Masaryks das Recht auf eine eigene Verwaltung, ein eigenes Parlament und die eigene Gerichtsbarkeit innerhalb der Tschechoslowakei eingeräumt. In kulturellen Belangen sollte die slowakische Sprache neben der tschechischen als Amtssprache eingeführt werden. Als am 28. Oktober 1918 die erste Tschechoslowakische Republik ausgerufen wurde, war die Zustimmung zu diesem Staat auch seitens der Slowaken vor dem Hintergrund des Endes der Inkorporation in die ungarische Reichshälfte auf breiter Basis gegeben. Mit den unerfüllten Forderungen des Pittsburgh Agreement wuchs allerdings das Bestreben nach mehr Autonomie von Seiten der slowakischen Autonomisten, die sich in der Slowakischen Volkspartei um Pater Andrej Hlinka bündelten. In den Jahren 1919 und 1920 wurden die slowakischen Autonomiebestrebungen vom vorherrschenden Tschechoslowakismus und der einhergehenden Konzeption einer einheitlichen tschechoslowakischen Staatsnation verdrängt, die der Vorstellung von einer ethnisch konzipierten slowakischen Nation keinen Platz bot. Die Verfassung vom 29. Februar 1920 festigte die neue Staatsdoktrin. Zusätzlich dazu verstärkte die Einführung einer tschechoslowakischen Staatssprache, die Besetzung zahlreicher slowakischer administrativer Organe durch tschechische Beamten, sowie die Stationierung der tschechoslowakischen Armee auf slowakischem Gebiet das slowakische Bedürfnis nach Autonomie. Konstituierte sich die Tschechoslowakische Republik mit einer zentralistischen Verwaltung, so resultierte daraus das Ausbleiben einer Lösung der slowakischen Frage, wie sie von der Slowakischen Volkspartei eingefordert wurde. Auch eine Regierungsbeteiligung im Jahre 1927 beschied der Slowakischen Volkspartei keinen Erfolg. Lediglich in Verknüpfung mit dem Konfliktpotential, das von der zunehmenden politischen Agitation der Sudetendeutschen Partei Konrad Henleins und deren Verbindungen zum nationalsozialistischen Regime in Deutschland herrührte, gewann die slowakische Frage wieder zunehmend an Gewicht. Nach letzten gescheiterten Verhandlungsversuchen zwischen der tschechoslowakischen Regierung und der slowakischen Volkspartei bot sich für letztere nach dem Münchner Abkommen im September 1938 die Gelegenheit, ihre Forderung nach Autonomie gemäß des Pittsburgh Agreement noch einmal einzufordern. Bereits mit der Föderalisierung am 25. November 1938 wies die außenpolitische Situation sowie die Haltung einzelner radikaler Vertreter der Slowakischen Volkspartei, die mittlerweile als slowakische Einheitspartei jedweden Pluralismus unterband, in die Richtung eines souveränen slowakischen Staat, der letztlich auf Hitlers Gnaden am 14. März 1939 proklamiert wurde und das schnelle Ende der zweiten Tschechoslowakischen Republik nach sich zog. Nach den sechs Jahren der NS-Herrschaft, in denen das Protektorat Böhmen und Mähren neben dem formal souveränen nationalsozialistischen Vasallenstaat der Slowakei Bestand hatte, wurde der Status der Slowakei im Zuge des Kaschauer Programms im Jahre 1945 neu geregelt. Doch erst die nach der Verfassung der Sowjetunion von 1936 modellierte tschechoslowakische Verfassung von 1948 setzte die nunmehrigen sozialistischen Rahmenbedingungen, nach welchen die slowakische Frage geordnet wurde. Neben dem demokratischen Zentralismus und der Führungsrolle der Kommunistischen Partei sollte laut Artikel 1 der Verfassung die Diktion von zwei gleichberechtigten Brudervölkern gelten. Trotz angehender doktrinärer Abmilderungen nach dem Tode Stalins 1953, bot die Entstalinisierungsphase unter Chruščev keine realen Möglichkeiten, die slowakische Frage zu forcieren, die sich mittlerweile auf Forderungen nach nationalen Organen innerhalb eines asymmetrischen Staatsgebäudes sozialistisch-zentralistischer Prägung konzentrierte. Insbesondere die unter Antonin Novotný konzipierte Verfassung, welche die ČSR durch eine sozialistische ČSSR ersetzte, erwies sich als noch zentralistischer und versagte den Slowaken durch eine neue Kreiseinteilung weitere Kompetenzen. Erst als die planwirtschaftlichen Misserfolge während der 1960er Jahre spürbarer und Novotnýs Position umstrittener wurde, gelang es einer reformorientierten Bewegung in der KPČ Fuß zu fassen. Die weitere Zuspitzung im Kampf um die Parteiführung resultierte in der Absetzung Novotnýs und der Ernennung Dubčeks als Vorsitzender der KPČ, die auch von Brežnev gebilligt wurde. Durch Dubčeks Vorsitz wurde eine Reformperiode eingeläutet, die mitunter auch eine Lösung der slowakischen Frage mittels Föderalisierung anstrebte. Durch die jähe militärische Intervention der Sowjetunion im August 1968 wurde das Reformprogramm Dubčeks beendet. Lediglich die Föderalisierung, die in den Monaten zuvor unter Gustav Husák konzipiert worden war, konnte mit dem 1. Jänner 1969 ratifiziert werden. Abgesehen vom nominellen Umbau der ČSSR in eine Tschechische Sozialistische Republik und eine Slowakische Sozialistische Republik sowie einigen strukturellen Veränderungen blieb die führende Rolle der KPČ unangetastet und damit die Föderalisierung dem demokratischen Zentralismus angepasst und untergeordnet.Through the theoretical approach to divergent principles of federalism this historical survey deals with the Slovak question and its altering process in time. Hence starting with a detailed analyses for the years of 1919 and 1920 according to the political reports of the Austrian official delegates in Prague and Bratislava, the Slovak question could be characterized as the major political expression and program of Andrej Hlinkas’ Slovak Peoples Party. The Slovak Peoples Party stood in for the autonomist solution of Czecho-Slovak relationships within a decentralized Czechoslovak state referring to the Pittsburgh Agreement of 1918. Whereas during the years of 1919 and 1920 the Slovak question remained unsolved, a radicalisation process within the Slovak Peoples Party started in the early 1930’s that tended towards Slovak sovereignty. Boosted by the Munich Agreement of September 1938 the Slovak Peoples Party urged their Czech counterparts to ratify the autonomy law of 1938, thus creating the second Czecho-Slovak republic. This Czecho-Slovak Republic existed only until March 14th 1939, the day Dr. Tiso proclaimed a sovereign Slovak republic that was politically close linked to the Hitler Regime. When the Slovak territory was again incorporated by the Czechoslovak government lead by the former republican government in exile and the communist party, the Slovak question of autonomy was unclear again. After the seizure of power by the communist party and the installation of a socialist regime in 1948 the Slovak question lost its significance under the democratic centralist rule of the communist party. Lacking national organs even on the party level, the Slovak National Council was further deprived of power by the socialist constitution under Antonin Novotný in 1960. As a response to the economic crisis throughout the 1960’s and Novotný’s repressive leadership, reformist politicians like Dubček gained support. Novotný was finally impeached and replaced by Dubček in January 1968. It was through the reform program that the Slovak question in terms of a federalization returned on the political agenda. When the Soviet Union ended the reform plans by a military intervention in August 1968, the federalization survived as the only part of the reform program. Though legislatively approved on October 28th 1968 and ratified on January 1st 1969, the federalization was limited to marginal structural changes. In creating a Czech Socialist Republic and a Slovak Socialist Republic the leading role of the Czechoslovak Communist Party and its underlying centralism remained untouched. Moreover it was further strengthened by Gustav Husák as the leading figure of the party throughout the following years. Focussing on two divergent principles of federalism – in terms of a republican on the one hand, and a Marxist-Leninist concept on the other hand – the Slovak question underwent essential transformations, which were obstructed by different regimes that stood for different federalist premises. Nevertheless the Slovak question of 1968 reactivated unsolved anti-Czech and anti-Slovak resentments that rooted in a Czechoslovak republican past

Profile of neratinib and its potential in the treatment of breast cancer

The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compounds that bind irreversibly to the adenosine triphosphate binding pocket of HER receptors have been developed. One of these compounds, neratinib, has passed preclinical phases and is currently undergoing various clinical trials. This manuscript reviews the preclinical as well as clinical data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clinical activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s)

Automotive styling: Supporting engineering-styling convergence through surface-centric knowledge based engineering

The emotional impression a car imprints on a potential buyer is as equally important for its commercial success as fulfilling functional requirements. Hence, to create a positive emotional impression of a vehicle, great effort is put into a car's styling process. One of the key aspects during the early stages of the automotive design process is the convergence of styling and engineering design. While requirements stemming from engineering design are usually characterised by quantitative values, styling requirements are rather qualitative in nature. Converging these two requirement types is laborious. The present publication focuses on supporting this process through Knowledge Based Engineering. This is achieved by introducing a method which enables the designer to intuitively regard functional requirements during the styling phase. Moreover, the method improves the process of technical requirement checks regarding the shape and orientation of styling surfaces which exceed conventional package verifications

Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models

BACKGROUND: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear.METHODS: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays.RESULTS: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab.CONCLUSION: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.</p

Neue Literatur

Neue LiteraturPeter Hunziker: Medien, Kommunikation und GesellschaftHermann Boventer: Pressefreiheit ist grenzenlos Ottmar Fuchs: Kirche, Kabel, KapitalWolfgang Hoffinann-Riem (Hrsg.): Neue Medienstrukturen neue Sportberichterstattung?Frauke Höbermann: Der Gerichtsbericht in der LokalzeitungPatrick Roessler: Dallas und die Schwarzwaldklini

Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models

Background: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear. Methods: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays. Results: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. Conclusion: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients

Mechanisms and effects of the heterogeneous response of CAIX to hypoxia

Breast cancer is the most common cancer in females and several molecular subtypes have been described. However, intra-tumour heterogeneity exists and is associated with evolution of cancer metastasis and therapy resistance. The presence of regions of low oxygen (hypoxia) is associated with poor prognosis and the hypoxic microenvironment is also associated with resistance to current therapeutic strategies. Moreover, hypoxia and metabolite deficiency can alter the tumour microenvironment and drive heterogeneity. The pH regulating enzyme carbonic anhydrase IX (CAIX) is strongly induced under hypoxic conditions and its overexpression is likewise associated with poor therapeutic outcome. In a previous study, taking advantage of the membranous localization of CAIX, it was shown that under hypoxia a CAIX positive and CAIX negative population is present in MCF7 cells. RNA sequencing suggested an enrichment of stem cell markers in the CAIX positive population as well as a potential symbiotic relationship between these two subpopulations. In this study MCF7CAIX positive and negative populations were further investigated. Additionally, CAIX positive and negative populations were also found in HCT116 cells and subsequently established as stable cell populations. Both population show similar levels of induction of the hypoxia induced transcription factor HIF-1. The underlying mechanism of CAIX regulation was confirmed to rely on epigenetic modifications, as it could be shown that HIF-1 binding to the CAIX promoter is decreased in the CAIX negative population. To investigate the interaction of CAIX positive and negative cells in 3D models, stably labelled cells using either mCherry of GFP were generated. Upon mixing the two populations in a 1:1 ratio an initially even mix of the cells was observed in the spheroid. However, at a 72 h time point CAIX positive cells moved more towards the centre of the spheroid. This was inhibited by knockdown or pharmacological inhibition of CAIX. A key factor in migration and invasion are metalloproteinases/peptidases (MMPs). We found that MMP14 was upregulated in CAIX positive cells in 2D and 3D models, indicating an underlying mechanism for the re-localisation seen. Analysis of co-culture experiments using 2D a trans-well system revealed that under hypoxia the number of the CAIX positive population was increased in the presence of CAIX negative cells but not vice versa. A similar effect was seen using conditioned media, pointing to a secreted factor. Using a FRET based intracellular sensor to measure lactate levels it could be shown that lactate was higher in the CAIX negative cells. After spiking of the media during live imaging the CAIX positive cells quickly absorbed and retained lactate. In comparison, the CAIX negative cells initially showed an uptake of the metabolite, which was followed by a much quicker release. During co-culture, lactate levels in the conditioned media of CAIX negative cells were higher. Incubation of CAIX positive cells with this conditioned media decreased lactate levels, indicating lactate uptake by the cells. Moreover, knockdown of LDHA and/or B decreased the survival benefit CAIX positive cells had from CAIX negative cells. Another metabolic pathway showing marked differences between the two populations was lipid droplet formation. Under hypoxia CAIX positive cells showed an increased production of lipid droplet in comparison to CAIX negative cells and this was partly due to fatty acid uptake. In line with this, mRNA levels of the fatty acid transporter CD36 as well as some members of the FAB proteins were higher in the CAIX positive cells. Following a previous report showing that lipid droplets formed under hypoxia provide a survival benefit upon re-oxygenation, it was confirmed that CAIX positive cells grew indeed better in this set-up. Therefore, the results suggest a metabolic symbiosis between the CAIX positive and negative populations based on a lactate shuttle and differential uptake of fatty acids. Of wider significance, these findings show that tumours are heterogeneous in the response to hypoxia and that cell populations interact with each other in a symbiotic manner. This highlights the need for a better utilisation and combination of biomarkers to assess metabolic pathways and a better stratification of tumours. Moreover, this work highlights a potential effect of therapeutics addressing metabolic symbiosis.</p

Mechanisms and effects of the heterogeneous response of CAIX to hypoxia

Breast cancer is the most common cancer in females and several molecular subtypes have been described. However, intra-tumour heterogeneity exists and is associated with evolution of cancer metastasis and therapy resistance. The presence of regions of low oxygen (hypoxia) is associated with poor prognosis and the hypoxic microenvironment is also associated with resistance to current therapeutic strategies. Moreover, hypoxia and metabolite deficiency can alter the tumour microenvironment and drive heterogeneity. The pH regulating enzyme carbonic anhydrase IX (CAIX) is strongly induced under hypoxic conditions and its overexpression is likewise associated with poor therapeutic outcome. In a previous study, taking advantage of the membranous localization of CAIX, it was shown that under hypoxia a CAIX positive and CAIX negative population is present in MCF7 cells. RNA sequencing suggested an enrichment of stem cell markers in the CAIX positive population as well as a potential symbiotic relationship between these two subpopulations. In this study MCF7CAIX positive and negative populations were further investigated. Additionally, CAIX positive and negative populations were also found in HCT116 cells and subsequently established as stable cell populations. Both population show similar levels of induction of the hypoxia induced transcription factor HIF-1. The underlying mechanism of CAIX regulation was confirmed to rely on epigenetic modifications, as it could be shown that HIF-1 binding to the CAIX promoter is decreased in the CAIX negative population. To investigate the interaction of CAIX positive and negative cells in 3D models, stably labelled cells using either mCherry of GFP were generated. Upon mixing the two populations in a 1:1 ratio an initially even mix of the cells was observed in the spheroid. However, at a 72 h time point CAIX positive cells moved more towards the centre of the spheroid. This was inhibited by knockdown or pharmacological inhibition of CAIX. A key factor in migration and invasion are metalloproteinases/peptidases (MMPs). We found that MMP14 was upregulated in CAIX positive cells in 2D and 3D models, indicating an underlying mechanism for the re-localisation seen. Analysis of co-culture experiments using 2D a trans-well system revealed that under hypoxia the number of the CAIX positive population was increased in the presence of CAIX negative cells but not vice versa. A similar effect was seen using conditioned media, pointing to a secreted factor. Using a FRET based intracellular sensor to measure lactate levels it could be shown that lactate was higher in the CAIX negative cells. After spiking of the media during live imaging the CAIX positive cells quickly absorbed and retained lactate. In comparison, the CAIX negative cells initially showed an uptake of the metabolite, which was followed by a much quicker release. During co-culture, lactate levels in the conditioned media of CAIX negative cells were higher. Incubation of CAIX positive cells with this conditioned media decreased lactate levels, indicating lactate uptake by the cells. Moreover, knockdown of LDHA and/or B decreased the survival benefit CAIX positive cells had from CAIX negative cells. Another metabolic pathway showing marked differences between the two populations was lipid droplet formation. Under hypoxia CAIX positive cells showed an increased production of lipid droplet in comparison to CAIX negative cells and this was partly due to fatty acid uptake. In line with this, mRNA levels of the fatty acid transporter CD36 as well as some members of the FAB proteins were higher in the CAIX positive cells. Following a previous report showing that lipid droplets formed under hypoxia provide a survival benefit upon re-oxygenation, it was confirmed that CAIX positive cells grew indeed better in this set-up. Therefore, the results suggest a metabolic symbiosis between the CAIX positive and negative populations based on a lactate shuttle and differential uptake of fatty acids. Of wider significance, these findings show that tumours are heterogeneous in the response to hypoxia and that cell populations interact with each other in a symbiotic manner. This highlights the need for a better utilisation and combination of biomarkers to assess metabolic pathways and a better stratification of tumours. Moreover, this work highlights a potential effect of therapeutics addressing metabolic symbiosis.</p