A country with non-existent unemployment: The special characteristics of the Czech labour market. OSW Report July 2019

The low unemployment rate in the Czech Republic is an effect of a number of structural and political factors which have generated a certain economic potential. This potential was achieved when external stimuli occurred in the form of economic boom, which has been visible especially since 2014. The policy adopted by each of the Czech governments during the recent recession and stagnation was of great significance, alongside the support for the economic policy through actions taken by the National Bank of the Czech Republic (above all the low interest rate policy and interventions on the currency market). One of the reasons why the unemployment rate in the Czech Republic continues to be low is the relatively low labour costs and the high level of the country’s industrialisation where the automotive industry, which heavily relies on the market situation, has an essential share. So-called ‘assembly plants’, i.e. industrial plants generating numerous jobs with low added value, also play an important role in reducing the scale of unemployment. A great number of such plants have been created in effect of investment incentives over the past twenty years (the wave reached its peak in 1998–2007). They were often created with the intention of reducing unemployment. At the same time, the Czech Republic, a developed country heavily reliant on exports, is extremely sensitive to changes in the economic situation in Europe. The Czech economy is particularly strongly influenced by the situation in other EU member states, which are the outlet for almost 85% of the Czech exports. Germany is a major player in this context as it accounts for a third of Czech exports and a quarter of its imports, and has engaged its capital fairly intensively in the Czech Republic

Frustration and hope: Slovakia after Kuciak’s murder. OSW Point of View Number 75, July 2019

The murders of the investigative journalist Ján Kuciak and his fiancée in February 2018 became the catalyst for the civic outrage that has brought about significant changes on the Slovak political scene. This has mainly affected the long-ruling party Smer- SD and its leader Robert Fico, who resigned as prime minister under public pressure. However, the main opposition forces have benefited from the protests to only a small degree, as large sections of society perceive the opposition leaders as unreliable. New political projects have benefited from the social agitation, primarily the Progressive Slovakia party, co-founded by Zuzana Čaputová who won the presidential election in March on a wave of slogans calling for the repair of the state and the restoration of justice. The outgoing President Andrej Kiska is also forming his own political party with a centrist agenda

Integration of NMR and SAXS with Atomistic Simulations for Characterizing the Structure and Dynamics of Multi-Domain Proteins

In the seven decades since the first atomic-level structures of biomolecules were determined, the development and application of novel research methods has led to an advanced understanding of biological functions at the molecular level. In addition to experimental methods, key advances have been spurred by computer simulations, which provide an in silico representation of accumulated prior knowledge of biomolecular structure and dynamics. These models can be used both (i) as a complement to experimental results, filling in the gaps where experimental information is not accessible, and (ii) as complete representations, directing future research. Critically, the validity of either application depends on the accuracy of the models used. In this work, I aspired to combine computational and experimental methods to characterize the structure and dynamics of the flexibly linked two-domain protein MoCVNH3. In Chapter 1 I describe my motivation, and the suspected simulation artifacts observed in our preliminary simulations, which led me to investigate how accurately simulation models represent salt bridge interactions. Chapter 2 details my comparison of current models (“force fields”), for which significant variation but consistent overstabilization of salt bridges was discovered. This work motivated the development of a new force field, AMBER ff15ipq, which corrects, to some degree, the overstabilization and introduces extensive improvements, described in Chapter 3. Finally, in Chapter 4, I applied this new force field in simulations of MoCVNH3, for which I collected extensive experimental data leading to the determination of a structural ensemble. I validated the simulations against the experimental data set, and identified further directions for improvement. Overall, the work presented here demonstrates the power of integrating experimental and computational methods

Wirksamkeit der adjuvanten Strahlentherapie bei regionalen Lymphknotenmetastasen des malignen Melanoms

Bei unserer Untersuchung handelte es sich um eine retrospektive Studie, deren Ziel es war, den Nutzen der adjuvanten Strahlentherapie nach einer Lymphknotendissektion bei Patienten mit malignen Melanomen und Lymphknotenmetastasen zu evaluieren. Aus diesem Grund verglichen wir die Gruppe von 42 Patienten, die sich einer adjuvanten Bestrahlung nach der Lymphknotendissektion unterzogen haben, mit einer Kontrollgruppe, bei der nur eine Dissektion durchgeführt wurde (matched pairs). Vorraussetzung für die Aufnahme in unser Patientenkollektiv war eine positive Histologie der Dissektats, kein zweites Malignom, keine Fernmetastasen und die Durchführung der Operation und der Bestrahlung in unserer Universitätsklinik. Die Bestrahlung der 42 Patienten fand mit Einzeldosen von 1,8-3 Gy statt. Sie wurde 3-5 mal pro Woche bis zu einer Gesamtdosis von 46-55 Gy verabreicht, insgesamt über eine Zeitspanne von 2-6 Wochen. Zunächst untersuchten wir in unserer Kontrollgruppe den Einfluss von: Geschlecht, Alter, Lokalisation des Primärtumors, Dicke, Clark Level, Histologie, TNM Stadium, befallenen LK in dem Dissektat, Kapselperforation, Zeitspanne zwischen dem Primärtumor und dem Auftreten der Lymphknotenmetastasen auf die regionäre Rezidivrate und die Überlebenszeit. Statistisch konnte keine Abhängigkeit zwischen diesen Einflussfaktoren und den Zielgrößen (regionäre Rezidivrate und Überlebenszeit) nachgewiesen werden. Nur die Daten bezüglich der Anzahl der befallenen Lymphknoten waren nah an der Signifikanz (p=0,09). Als nächstes haben wir unseren beiden Gruppen bezüglich der regionären Lymphknotenrezidivraten, die Rezidivraten und die Überlebensraten verglichen. In den Gruppen wurden im Verlauf der Studie jeweils 9 Lymphknotenrezidive im OP-Bereich beobachtet. Die regionäre 2- bzw. 5-Jahres-Rezidivfreiheitsrate betrug in der Bestrahlungsgruppe 81% bzw. 70%. Ähnlich sahen die Zahlen in der Kontrollgruppe aus ( 76% bzw. 72%), so daß man bezüglich der regionären Lymphknotenrezidive keinen Unterschied feststellen konnte (p=0,75 ). Auch in der Frage nach der allgemeinen Rezidivfreiheit waren keine Unterschiede zu finden. In der Bestrahlungsgruppe lagen die 2- bzw. 5- Jahres-Rezidivfreiheitsraten bei 48% bzw. 37%, in der Kontrollgruppe lagen sie bei 44% bzw. 39% (p=0,74). Schließlich haben wir den Einfluss der Bestrahlung auf die Überlebensrate geprüft, aber auch hier waren die Therapiearme gleich wirksam (p=0,35). Die 2- bzw. 5-Jahres-Überlebensrate lag in der Bestrahlungsgruppe bei 58% bzw. 47% vs. 58% bzw. 38% in der Kontrollgruppe. Bezüglich der Nebenwirkungsrate stellte sich die Strahlentherapie als eine gut verträgliche Therapie dar, die Nebenwirkungen (Ödeme, Beweglichkeitseinschränkungen und Sensibilitätseinschränkungen) glichen den der alleinigen Dissektion. Strahlenbedingte Fibrosen kamen nur bei 3 Patienten von 42 vor. Aus unserer Studie geht hervor, daß die Strahlentherapie in unserer Klinik, so wie sie beim malignen Melanom durchgeführt wurde, keine besseren Ergebnisse im Vergleich zu der alleinigen Lymphknotendissektion aufwies. Weder die regionäre Rezidivfreiheit noch die Überlebensrate konnten durch die Bestrahlung verbessert werden. Möglicherweise wäre eine Bestrahlung mit höheren Einzeldosen wirksamer

Downstream and Intermediate Interactions of Synovial Sarcoma-Associated Fusion Oncoproteins and Their Implication for Targeted Therapy

Synovial sarcoma (SS), an aggressive type of soft tissue tumor, occurs mostly in adolescents and young adults. The origin and molecular mechanism of the development of SS remain only partially known. Over 90% of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of SS18-SSX1 or SS18-SSX2 fusion genes. In recent years, several reports describing direct and indirect interactions of SS18-SSX1/SSX2 oncoproteins have been published. These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis. Additional research efforts are required to fully explore the protein-protein interactions of SS18-SSX oncoproteins and the pathways that are regulated by these partnerships for the development of effective targeted therapy

New Tanaidacea (Crustacea: Peracarida) from the Gulf of Guinea

publishedVersio

Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]

peer-reviewedIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie) (MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www. gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R)

A Sarcoma at the Site of Previous Extravasation of Adriamycin

We report the case of a 66-year-old man presenting with a high-grade pleomorphic sarcoma at the left elbow 16 years after the extravasation of adriamycin given for a malignant ifbrous histiocytoma of the tibia.We suggest that this sarcoma originated in a multistep way over many years, out of the chronic inflammatory tissue that developed due to a non-specific cellular damage at the nuclear level, interfering with normal cell replication necessary for normal healing tissue healing. As a result, the non-healed chronic inflammatory tissue transformed over several years into a preneoplastic mesenchymal tumour and later into a high-grade pleomorphic sarcoma