Die physiologische Relevanz von ADAM17 in der Darmkarzinogenere

Die physiologische Bedeutung von ADAM17 besteht in der irreversiblen proteolytischen Regulation von wichtigen Signalwegen wie dem EGFR Signalweg, wobei ADAM17 für die proteolytische Freisetzung von löslichen ErbB-Liganden wie Amphiregulin (AREG) verantwortlich ist. Lösliche EGFR Liganden binden an Rezeptoren der ErbB Rezeptor Tyrosinkinasefamilie, woraufhin sich Homo- oder Heterodimere der ErbB Rezeptoren bilden, welche durch Phosphorylierung aktiviert werden und intrazellulär u.a. Proliferationssignale weiterleiten. Die Expression von ADAM17, AREG und EGFR ist in Tumoren erhöht, was sich physiologisch durch signifikant verstärkte proteolytische Freisetzung von AREG auf intestinalen Epithelzellen äußert. Im Verlauf dieser Arbeit ließ sich dies in vitro bei humanen Kolorektalzelllinien, ex vivo in murinen 3D Organoidzellkulturen und in vivo in Gewebelysaten und Kolonkulturen von ADAM17 defizienten hypomorphen ADAM17ex/ex Mäusen zeigen. Um die pathophysiologische Relevanz von ADAM17 während der Darmkarzinogenese zu bestimmen, wurde im Rahmen dieser Arbeit zum einen ein entzündungsbasiertes Kolitis assoziiertes Darmkrebsmodell und zum anderen ein genetisch prädispositioniertes Modell mit hypomorphen ApcMin/+ ADAM17ex/ex Mäusen etabliert und analysiert. Die Mutation im Adenomatous polyposis coli (Apc) Gen hat eine Dysregulation des Wnt-Signalwegs zur Folge, was zur spontanen Entwicklung einer Vielzahl intestinaler Neoplasien führt. Zusammenfassend konnte in dieser Arbeit gezeigt werden, dass die ADAM17 Defizienz im CAC Mausmodell zu einer signifikant erhöhten Ausbildung von Karzinomen, assoziiert mit verstärkten Entzündungsmerkmalen, im Kolon führt. Bemerkenswerterweise zeigen die genetisch prädispositionierten ApcMin/+ Mäuse bei ADAM17 Defizienz eine signifikant reduzierte Tumoranzahl und verminderte Zellproliferation, die einheitlich geringgradigen Dysplasien entsprechen.One of the physiological roles of ADAM17 is the proteolytic regulation of important pathways like the EGFR (epidermal growth factor receptor) pathway. ADAM17 cleaves membrane bound ErbB (erythroblastosis oncogene B) ligands such as Amphiregulin (AREG). The soluble ligands bind to receptors of the ErbB receptor tyrosine kinase family and trigger phosphorylation of both homo- or heterodimers of the ErbB receptors. Phosphorylation of ErbB receptors has been shown to activate intracellular signals such as proliferation. Expression and activation of ADAM17, AREG and EGFR is highly upregulated during tumorigenesis, which leads to increased shedding of AREG on intestinal epithelial cells as presented in this thesis. This effect was shown in vitro using human colorectal cancer cells, ex vivo in an established 3D murine organoid culture system and in vivo using tissue lysates and colon cultures from ADAM17 deficent hypomorphic ADAM17ex/ex mice. To identify the pathophysiological relevance of the previous results, the effect of ADAM17 deficiency on tumor formation was investigated in vivo in murine colitis associated cancer (CAC) as a model for inflammation associated colorectal cancer. Further a genetically predisposed colorectal cancer model was chosen, whereby ApcMin/+ mice crossbred with hypomorphic ADAM17ex/ex mice were generated and evaluated in this work. The mutated Adenomatous polyposis coli (Apc) gene results in dysregulation of the Wnt signaling pathway, which leads to a spontaneous development of multiple intestinal neoplasia (Min) in this mouse model. In summary, tumor formation is altered in ADAM17 deficiency CAC mouse model and hypomorphic ADAM17ex/ex mice developed higher numbers of carcinoma coupled with increased intestinal inflammation. Remarkably, the genetically predisposed ApcMin/+ mice deficient for ADAM17 showed a significantly reduced tumor number, diminished cell proliferation and low grade dysplasi

Convergence of financial systems in Europe : a research programme

Aus dem weiten Spektrum ökonomisch relevanter Fragen, die die europäische Integration und das Gesellschaftsrecht verbinden, soll hier diejenige herausgegriffen werden, ob sich die nationalen Corporate-Governance-Systeme in den großen europäischen Volkswirtschaften Deutschlands, Frankreichs und Großbritanniens unter dem Einfluß der europäischen Integration bereits aneinander angeglichen haben und ob es demnächst zu einer solchen Angleichung kommen wird. Unser Thema deckt nur einen Teil des Gesellschaftsrechts ab und geht zugleich hinsichtlich der angesprochenen rechtlichen Materie über das Gesellschaftsrecht hinaus, denn die Corporate Governance fügt sich nicht einfach in herkömmliche juristische Klassifikationen ein. Unser Vorhaben unterscheidet sich aber vor allem dadurch von einer juristischen Behandlung des Themas, daß primär ökonomische Mechanismen und Zusammenhänge angesprochen werden. Ökonomen betrachten die Corporate Governance im weiteren Kontext des Finanzsystems, denn das Corporate-Governance-System ist ein Teil des Finanzsystems eines Landes. Die Fragen, wie unterschiedlich die nationalen Systeme der Corporate Governance waren, ehe zu Beginn der 80er Jahre der Prozeß der Angleichung in Europa einsetzte, wie unterschiedlich sie heute noch sind, wie sehr sie sich somit bereits angeglichen haben und wie ein möglicher Angleichungsprozeß weitergehen könnte, sind deshalb ein Teil der weiteren Frage nach der Angleichung der Finanzsysteme in Europa. In diesem Beitrag konzentrieren wir uns aber nur auf Entwicklungen der 90er Jahre.This paper discusses whether, in which respects, and to what extent the corporate governance systems of Germany, the United Kingdom and France have already converged in the course of European economic integration, or are likely to converge in the foreseeable future. We present, and attempt to provide empirical support for, the proposition that, firstly, as far as legal and other regulation is concerned, a certain, though limited, degree of convergence is already visible today. Secondly, as far as the practice of corporate governance is concerned, there is less convergence; and thirdly, as far as the systemic properties of the national corporate governance systems are concerned, there is no convergence at all. In order to support our proposition, we first develop a methodology for describing and analysing corporate governance systems and for identifying their systemic properties, and then apply this methodology to the corporate governance systems of the three countries. The lack of systemic convergence so far seems to be due to the complementarity between the different elements of the respective national financial systems. The paper therefore concludes with the prediction that, if there is any substantial convergence of the corporate governance systems in Europe in the foreseeable future at all, it is not likely to be a smooth transition to a "middle of the road" position located somewhere between the present German and British corporate governance systems

Influence of Immune Status on the Airborne Colonization of Piglets with Methicillin-Resistant Staphylococcus aureus (MRSA) Clonal Complex (CC) 398

Colonized vertebrates including humans and pigs are to date the main reservoirs of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA). Currently, the mechanisms underlying colonization of pigs are not fully understood. We investigated the influence of piglet pre-immune status on airborne MRSA colonization. Three groups of MRSA-negative piglets were primed and exposed to airborne LA-MRSA (104 colony forming units (cfu)/m3) in an aerosol chamber for 24 h. One group was treated intramuscularly with dexamethasone (1 mg/kg body weight) to imitate weaning stress. The second group was exposed to bacterial endotoxin containing MRSA aerosol. Both conditions play a role in the development of multifactorial diseases and may promote MRSA colonization success. The third group served as control. The piglets' MRSA status was monitored for 21 days via swab samples. At necropsy, specific tissues and organs were analyzed. Blood was collected to examine specific immunological parameters. The duration of MRSA colonization was not extended in both treated groups compared to the control group, indicating the two immune-status influencing factors do not promote MRSA colonization. Blood sample analysis confirmed a mild dexamethasone-induced immune suppression and typical endotoxin-related changes in peripheral blood. Of note, the low-dose dexamethasone treatment showed a trend of increased MRSA clearance

Prevention and Treatment of Social Anxiety Disorder in Adolescents: Protocol for a Randomized Controlled Trial of the Online Guided Self-Help Intervention SOPHIE.

BACKGROUND Social anxiety symptoms are highly prevalent among adolescents and are associated with poor quality of life and low psychosocial functioning. If untreated, social anxiety often persists into adulthood and increases the risk for comorbid disorders. Therefore, early interventions for social anxiety to prevent negative long-term consequences are critical. However, adolescents rarely seek help and often avoid face-to-face psychotherapeutic interventions due to the perceived lack of autonomy and anonymity. Thus, online interventions represent a promising opportunity to reach adolescents who have social anxiety but do not seek help yet. OBJECTIVE This study aims to evaluate the efficacy, moderators, and mediators of an online intervention developed to reduce social anxiety in adolescents. METHODS A total of 222 adolescents aged 11-17 years with subclinical social anxiety (N=166) or with a diagnosis of social anxiety disorder (N=56) are randomly assigned to the online intervention or a care-as-usual control group. The 8-week guided online intervention is based on the Cognitive Model of Social Phobia and evidence-based online interventions for social anxiety adapted to the specific needs of adolescents. The care-as-usual group will be given access to the online intervention after the follow-up assessment. Participants are assessed at baseline, at 4 and 8 weeks post intervention, and at 3-month follow-up assessment on the primary outcome, that is, social anxiety, on secondary outcomes (eg, level of functioning, fear and avoidance, general anxiety, depression, quality of life, self-esteem, and negative effects of the intervention), on potential moderators (eg, therapy motivation, therapy expectancy, and satisfaction with the intervention), and potential mediators (eg, therapeutic alliance and adherence to the intervention). Data will be analyzed based on an intention-to-treat approach and both groups (intervention and care-as-usual) will be compared at each assessment time point. Furthermore, potential mechanisms of change and generalization of intervention effects on daily life are assessed using an ecological momentary assessment procedure that includes items on maintaining mechanisms of social anxiety, social context, and affect. Participants are prompted 3 times a day during the first 8 weeks of the study and again for 2 weeks following the follow-up assessment. RESULTS Recruitment is ongoing; initial results are expected in 2024. CONCLUSIONS Results are discussed considering the potential of online interventions as a low-threshold prevention and treatment option for adolescents with social anxiety and in light of current advances in dynamic modeling of change processes and mechanisms in early intervention and psychotherapy in adolescents. TRIAL REGISTRATION ClinicalTrials.gov NCT04782102; https://clinicaltrials.gov/ct2/show/NCT04782102. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/44346

Teroristické útoky jako politické příležitosti: Diskurzivní analýza německých parlamentních debat

Univerzita Karlova, Fakulta sociálních věd / Smetanovo nábřeží 6, 110 01 Praha 1 [email protected], tel: 222 112 111 www.fsv.cuni.cz V Praze dne 09.06.2021 Jméno a příjmení studenta: Stefanie Schmidt Identifikační číslo studenta: 80760757 Identifikační číslo studia: 486229 Jazyk práce: angličtina Název práce v jazyce práce: Terrorist Attacks as "Policy Windows": A Discourse Network Analysis of German Parliamentary Debates Název práce v českém jazyce: Teroristické útoky jako politické příležitosti: Diskurzivní analýza německých parlamentních debat Vedoucí práce: PhDr. Vít Střítecký, M.Phil., Ph.D. Oponent práce: prof. Volker Schneider, Dr. Abstract in English is not available.Katedra bezpečnostních studiíDepartment of Security StudiesFakulta sociálních vědFaculty of Social Science

N´-Aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazides: Novel inhibitors of cancer related protein kinases

Ausgehend von N´-(1H-Indol-3-ylmethyliden)-2-phenylcyclopropancarbohydrazid und 2-(1H-Indol-3-yl)-N´-(4-nitrobenzoyl)-2-oxoacetohydrazid, die auf Basis eines virtuellen Screenings als schwach potente, selektive Inhibitoren der c-MET Kinase identifiziert wurden, erfolgte im Rahmen dieser Arbeit die Synthese und Charakterisierung potentieller Proteinkinase-Hemmstoffe zum Aufbau einer fokussierten Substanzbibliothek. Durch systematische Modifizierung der Ausgangsverbindungen konnten N´-Aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazide entwickelt werden, die neben einer moderat erhöhten inhibitorischen Aktivität gegenüber der c-MET Kinase eine vielversprechende Inhibition der Kinasen IGF-1R, VEGFR-2, SRC und TRK-B zeigten. Die Einführung großer, lipophiler Substituenten in Position 4 des Aroylrestes hatte eine deutliche Steigerung der kinaseinhibitorischen Aktivität zur Folge. Eine zum Teil submikromolare Aktivität gegenüber IGF-1R, VEGFR-2, SRC und TRK-B zeigten mittels Mikrowellen-unterstützter Suzuki-Kupplung dargestellte Biphenyl-Strukturen. Die kinaseinhibitorische Aktivität dieser Verbindungen konnte um mehr als zwei Größenordnungen gegenüber den Ausgangsverbindungen verbessert werden. In einem SRC-spezifischen zellulären Phosphorylierungsassay zeigten die Verbindungen hingegen keine Aktivität. Des Weiteren wurden ausgewählte Verbindungen zur Bestimmung ihrer antiproliferativen Aktivität beim National Cancer Institute an ca. 60 tumorrelevanten Zelllinien getestet. Dabei konnte eine selektive Hemmung einzelner Lungen- bzw. Ovarialkrebszelllinien festgestellt werden.Within the scope of a virtual screening N´-(1H-indol-3-ylmethylidene)-2-phenylcyclopropanecarbohydrazide and 2-(1H-indol-3-yl)-N´-(4-nitrobenzoyl)-2-oxoacetohydrazide were identified as weak, but selective inhibitors of the c-MET kinase. In the course of this thesis potential kinase inhibitors related to these hit structures were synthesized and tested for their inhibitory activity to establish a focused library of structural diverse compounds. A structure modification campaign led to the discovery of N´-aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazides with slightly improved potency against the c-MET kinase. Moreover, a promising inhibitory activity against IGF-1R, VEGFR-2, SRC and TRK-B could be observed. The insertion of lipophilic substituents at the phenyl C-4 position caused a significant increase in inhibitory activity against IGF-1R, VEGFR-2, SRC and TRK-B. Most notably, biphenylic structures, which were prepared via microwave-promoted Suzuki-coupling reaction, demonstrated potent inhibition of IGF-1R, VEGFR-2, SRC and TRK-B with IC50-values in the submicromolar range. Thus, the inhibitory activity increased by two orders of magnitude compared to the hit structures. However, the compounds did not have effects in a SRC-specific cellular phosphorylation assay. Furthermore, selected compounds were tested at the National Cancer Institute for their antiproliferative activity towards approximate 60 cancer related cell lines. They exhibited a selective inhibition of particular lung- and ovarian cancer cell lines

Integrated psychological therapy: effectiveness in schizophrenia inpatient settings related to patients' age

Elderly people with schizophrenia often suffer from cognitive impairments, which affect their social functioning. Today, only a few therapy approaches for middle-aged and older patients are available. The Integrated Psychological Therapy (IPT) combines neurocognitive and social cognitive interventions with social skills approaches. The aim of this study was to evaluate (1) whether IPT is effective in younger patients (age < 40 years) and middle-aged patients (age ≥ 40 years) and (2) whether control conditions (treatment as usual or unspecific group activities) reveal some change in outcome depending on age