Studying normal and cancer stem cells in the kidney using 3D organoids and genetic mouse models

Organoide aus adulten Mäusen sind vielversprechende Modelle für die Nierenforschung. Ihre Charakterisierung wurde jedoch nicht auf ein zufriedenstellendes Niveau gebracht. Hier habe ich ein langfristiges 3D-Maus-Organoid (Tubuloid)-Modell etabliert und charakterisiert, das die Erneuerung und die Reparatur sowie die Architektur und die Funktionalität der adulten tubulären Epithelien rekapituliert. In der Zukunft wird das Modell detaillierte Untersuchungen der Trajektorien selbsterneuernder Zellen sowohl zur teilweisen Wiederherstellung der Niere als auch zur malignen Transformation der Niere ermöglichen. Das klarzellige Nierenzellkarzinom (ccRCC) ist der häufigste und aggressivste Nierenkrebs. Die Inaktivierung des Tumorsuppressorgens Von Hippel-Lindau (VHL) ist der Haupttreiber des ccRCCs. Zuvor hatten wir die Hochregulation der Wnt- und Notch-Signalübertragung in den CXCR4+MET+CD44+-Krebsstammzellen (CSC) aus primären humanen ccRCC-Tumoren identifiziert. Das Blockieren von Wnt und Notch in von Patienten stammenden Xenotransplantaten, Organoiden und nicht-anhaftenden Sphären unter Verwendung von niedermolekularen Inhibitoren beeinträchtigte die Selbsterneuerung der CSC und das Tumorwachstum. Um CSC-gesteuertes humanes ccRCC in genetischen Mausmodellen nachzuahmen, begann ich mit der Erzeugung von zwei Doppelmausmutanten; β-Catenin-GOF; Notch-GOF und Vhl-LOF; β-Catenin-GOF. Sowohl die β-Catenin-GOF; Notch-GOF Mausmutante als auch die Vhl-LOF; β-Catenin-GOF Mausmutante entwickelten innerhalb einiger Monate schwere Krankheitssymptome. Überraschenderweise beobachtete ich weder Tumore oder Tumorvorläuferläsionen noch höhere Zellproliferationsraten in den mutierten Nieren. Weitere Analysen ergaben, dass die Mausmutanten Merkmale chronischer Nierenerkrankung (CKD) aufwiesen.Adult mouse organoids are promising models for kidney research. However, their characterization has not been pushed forward to a satisfying level. Here, I have generated and characterized a long-term 3D mouse organoid (tubuloid) model, which recapitulates renewal and repair, and the architecture and functionality of the adult tubular epithelia. In the future, the model will allow detailed investigations of trajectories of self-renewing cells towards both the partial recreation and malignant transformation of the kidney. Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive kidney cancer. Inactivation of the Von Hippel-Lindau (VHL) tumor suppressor gene is the major driver of ccRCC. Earlier, we identified the upregulation of Wnt and Notch signaling in CXCR4+MET+CD44+ cancer stem cells (CSCs) from primary human ccRCCs. Blocking Wnt and Notch in patient-derived xenografts, organoids and non-adherent spheres using small-molecule inhibitors impaired self-renewal of CSCs and tumor growth. To mimic CSC-governed human ccRCC in genetic mouse models, I started from the generation of two double mouse mutants; β-catenin-GOF; Notch-GOF and Vhl-LOF; β-catenin-GOF. Surprizingly, I observed neither tumors or tumor precursor lesions nor higher cell proliferation rates in the mutant kidneys. Further analyses revealed that the mutant mice displayed features of chronic kidney disease (CKD). Thus, β-catenin-GOF; Notch-GOF and Vhl-LOF; β-catenin-GOF mouse mutants did not develop kidney tumors under the given experimental conditions

Long-term correlations between the development of rail transport and the economic growth of the German Reich (1872-1913)

Purpose: This study is part of the trend of researching new economic history using econometric analysis (the new economic history paradigm), still not very popular in Europe and the world (outside the USA and UK). The main purpose of the article was to use the Granger cointegration test to confirm the long-term correlations between the level of economic growth and the development of the German Reich railways. Design/Methodology/Approach: In the field of theoretical analysis, a review of international literature on the study of the interdependence of economic growth and the development of transport, including rail transport, was carried out. The empirical analysis was based on available statistical data for the period of 1872–1913. Econometric methods were used, including: stationary test using ADF and KPSS tests, Engle-Granger cointegration test, as well as the analysis of the impulse response function. Findings: The results of the research received confirm that there was a long-term correlation between the level of economic growth in Germany (expressed as Net National Product (NNP) and the level of rail freight symbolizing the development of railways. Practical Implications: The Granger causality test allows the elimination of economic variables that are not in a causal relationship, which in turn leads to a better explanation of the studied economic phenomenon. A special case in VAR auto-regression models when the analysed time series are integrated in the first degree I(1). Originality/Value: Considering the importance of transport for the economy, it is particularly important to examine whether the development of transport had an impact on the level of economic growth, and whether economic growth led to the development of the transport industry, and perhaps this relationship was two-way. The obtained results are the foundation for the construction of vector-autoregressive models (VAR) and the study of long-term relationships.peer-reviewe

Analysis of the interdependence between the economic growth and the development of the railway sector

Purpose: The authors directly formulated the ‘research hypothesis’ as the interdependence between economic growth and the volume of rail freight. It is a very valid question of primary importance not only to economic historians, but also to development economists. Approach/Methodology/Design: Econometric modelling was used to set out the factors of Germany’s economic growth between 1872 and 1913, with a particular focus on the importance of railways. While analysing many determinants of German economic growth, the authors also took into account the t time variable, which made possible the practical application of the theorem by Frisch-Waugh with the generalization of Stone. Findings: Considering these results, it can be confirmed that the railways, being a symbol of the era, and also a leading sector of the German economy, however, played an important role in shaping the modern economy and multiplying Germany’s social well-being. It can be considered as one of the causes of economic growth. On the other hand, the high economic growth rate of the German Reich was an important factor determining the development of transport. The obtained results are the basis for the construction of vector-autoregressive models (VAR) including the error correction model (ECM) and long-term relationship research. Practical Implications: A systematic, quantitative inquiry on the impact of railway expansion on economic growth would most likely contribute not only to better understanding of economic history but could also shed light on the foundations of the recent monetary theory. Originality/Value: Considering the importance of transport for the economy, it is particularly important to examine whether the development of transport had an impact on the level of economic growth, and whether economic growth led to the development of the transport industry, and perhaps was bidirectional relationships.peer-reviewe

Public-private partnership : development and dilemmas for the future from the point of view of the public partner

PURPOSE: The aim of this article was to evaluate the development of public-private partnership in Poland. The author also tried to determine the reasons for the still small number of such projects in Poland, also analyzing the results of his own research.APPROACH/METHODOLOGY/DESIGN: A literature review in the field of PPP was used, including available statistics and surveys.FINDINGS: The results of the research show the perspectives and dilemmas of PPP development in Poland, but also barriers and necessary changes in the future.PRACTICAL IMPLICATIONS: Public-private partnership in contemporary conditions, including the problems of financing public tasks by central and local authorities, may become the engine of economic development (including local), the basis for modernization, a factor in increasing competitiveness, including improving the quality of life of citizens. It is legitimate to learn about the principles of public-private partnership functioning in broad social circles in order to promote its development, both at the central, regional and local (e.g. municipal) level.ORIGINALITY/VALUE: Public-private partnership is still an unpopular form of cooperation, hence the analysis of its development, including the inhibitory factors, is crucial for its future and universality. Own research is an additional advantage emphasizing the originality.peer-reviewe

Protective customs duty: the achievements of classical school and historical German school as exemplified by Germany's iron and steel industry

Cło wychowawcze jest ciągle ważnym narzędziem polityki handlowej dotyczącym ochrony rozwijających się rodzimych (krajowych) nowych dziedzin gospodarki (przemysłu). Mimo powszechnej krytyki ze strony nurtu klasycznego w ekonomii, należy uznać, że poglądy reprezentowane przez szkoły będące w opozycji, w tym niemieckiej szkoły historycznej i Friedricha Lista, mają swoje solidne podstawy i nie mogą być ignorowane nawet we współczesnej gospodarce. Model ekonomiczny z uwzględnieniem polityki ceł wychowawczych jest właściwy metodologicznie, natomiast może być trudny w realizacji w warunkach realnej gospodarki. Zakładając jednak, że cło wychowawcze jest narzędziem tymczasowym, a docelowym etapem wolna wymiana handlowa, może ono przynieść wymierne korzyści zarówno dla kraju, jak i dobrobytu społecznego świata. Autor zobrazował poglądy ekonomistów szkoły klasycznej i neoklasycznej oraz szkoły niemieckiej odnoszące się do oceny wpływu ceł wychowawczych z wykorzystaniem dobrobytu społecznego. Posłużył się również przykładami liczbowymi dotyczącymi ochrony przemysłu w Wielkiej Brytanii i Niemczech. Ważnym elementem była analiza polityki celnej Niemiec obejmująca przemysł hutniczy w XIX i początkach XX wieku.The protective customs duty is still an important tool for the protection of trade policy of developing domestic (national) sectors of the economy (industry). In spite of widespread criticism from the classical school of economics, one should admit that the views of its opponents, including the German historical school have a sound basis and cannot be ignored, even in the contemporary economy. The founder of the school, Friedrich List, argues that the protection of an infant industry is necessary for countries at early stages of industrialization. Although the economic model involving protective custom duties is methodologically correct, it can be difficult to implement in a real economy. Assuming, however, that the protective customs duty is a temporary tool, and that free trade is the ultimate aim, it is likely to bring tangible benefits for both the country and the social welfare of the [email protected]ł Ekonomiczny, Zachodniopomorski Uniwersytet Technologiczny w SzczecinieAdebahr H., Maennig W. 1987 Außenhandel und Weltwirtschaft, Duncker & Humblot, Berlin.Bahadir S. 1984 Theorien und Strategien der regionalen Wirtschaftsintegration von Entwicklungsländern, Duncker & Humblot, Berlin.Bairoch P. 1993 Economics and World History – Myths and Paradoxes, Wheatsheaf, Brighton.Bairoch P. 1982 Industrialization Levels from 1750 to 1980, ,,Journal of European Economic History”, 11.Buzek J. 1933 Rozbudowa techniczna żelazo-hutnictwa polskiego w ostatnich 10 latach na tle rozwoju hutnictwa w ogóle, Wydawnictwo E. Mirek i Spółka, Sosnowiec.Capie F. 1994 Tariffs and growth: some illustrations from the world economy, 1850-1940, Manchester University Press, Manchester.Dawson W. H. 1904 Protection in various countries: Germany, King & Son Orchard House Westminster, London.Dormois J. P. Lains P. 2006 Classical Trade Protectionism 1815-1914, Taylor & Francis e-Library.Kicking Away the Ladder: The “Real” History of Free Trade, FPIF Special Report, Chang Chang H., December 2003, dokument elektroniczny, tryb dostępu: [http://www.ilocarib.org.tt/trade/documents/economic_policies/SRtrade2003.pdf, data wejścia: 15.12.2014].Kestner F. 1902 Die deutschen Eisenzölle 1879-1900, [in:] Staats- und socialwissenschaftliche Forschungen, G. Schmoller (ed.), Bd. 21, z. 3, Wydawnictwo Druncker und Humblot, Leipzig.Krugman P. R. Obstfeld M. 1997 Międzynarodowe stosunki gospodarcze, Wydawnictwo Naukowe PWN, Warszawa.Kuliszer J. 1961 Powszechna historia gospodarcza średniowiecza i czasów nowożytnych, t. II, KiW, Warszawa.Kutz M. 1974 Deutschlands Aussenhandel, Deutschlands Aussenhandel von der Französischen Revolution bis zur Gründung des Zollvereins 1787-1833. Eine statistische Strukturuntersuchung zur vorindustriellen Zeit, Franz-Steiner-Verlag, Wiesbaden.Lampe M. 2008 Bilateral Trade Flows in Europe, 1857-1875. A new dataset, [in:] Research in Economic History, A. Field, G. Clark, W. Sundstrom (eds.), JAI Press, Bingley.McKee S. 1934 Papers on Public Credit, Commerce and Finance, Colombia University Press, New York.Meisner M. 1929 Die Versorgung der Weltwirtschaft mit Eisen und Stahl 1860 bis 1926, Ferdinand Enke Verlag, Stuttgart.Mitchell B. 1988 British Historical Statistics, Cambridge University Press, Cambridge.Myszczyszyn J. 2013 Wpływ kolei żelaznych na wzrost gospodarczy Niemiec 1840-1913, Wydawnictwo Uniwersytetu Łódzkiego, Łódź.Ohlin B. 1933 Interregional and International Trade, Harvard University Press, Cambridge.Ricardo D. 1957 Zasady ekonomii politycznej i opodatkowania, Wydawnictwo Naukowe PWN, Warszawa.Rynarzewski T. Zielińska-Głębocka A. 2006 Międzynarodowe stosunki gospodarcze. Teoria wymiany i polityki handlu międzynarodowego, Wydawnictwo Naukowe PWN, Warszawa.Rynarzewski T. 2003 Cło wychowawcze i cło optymalne w teorii i praktyce polityki handlu międzynarodowego, Ruch Prawniczy, Ekonomiczny i Socjologiczny, Rok LXV/1.Smith A. 1954 Badania nad naturą i przyczynami bogactwa narodów, Wydawnictwo Naukowe PWN, Warszawa.Viner J. 1953 International trade and economic development, Clarendon, Oxford.3(75)759

A preliminary analysis of the relationship between economic growth and selected innovativeness indicators on the example of four European Union countries

PURPOSE: The article aimed to determine the general relationships between economic growth and development and selected innovativeness indicators in two countries belonging to the leaders of innovativeness in comparison with two countries of Central and Eastern Europe representing moderate innovators.DESIGN/METHODOLOGY/APPROACH: Cluster analysis (agglomeration method), elements of descriptive statistics, correlation calculus, and the ADF test were used to study the stationarity of the variables initially.FINDINGS: The results have shown that the analyzed innovativeness indicators have fluctuated to varying degrees, although in many cases, Poland and Hungary demonstrated high rates of growth, which could suggest a catching-up effect. Although the correlation coefficients between the levels of economic growth and development and the analyzed innovativeness variables were in many cases significant (usually positive), stationarity tests showed that the variables are in the vast majority non-stationary, which is a reason for further research when trying to build an econometric model.PRACTICAL IMPLICATIONS: A general analysis of the data indicated that the following stages of the study would require an expansion to include a cointegration account and determine the interrelationship of variables in both the short and long term, using autoregressive models.ORIGINALITY/VALUE: Preliminary analysis of economic growth factors using descriptive statistics and correlation coefficients for selected countries (Sweden, the Netherlands, Poland, Hungary) based on available source data from OECD.peer-reviewe

Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients

Dendriticâ cellâ based immunotherapy evokes potent antiâ tumor immune responses in CD105+ human renal cancer stem cells

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138877/1/mc22697.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138877/2/mc22697_am.pd

The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development