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Background: Definite diagnosis and therapeutic management of cholangiocarcinoma (CCA) remains a challenge. The aim of the current study was to investigate feasibility and potential impact on clinical management of targeted sequencing of intraductal biopsies.
Methods: Intraductal biopsies with suspicious findings from 16 patients with CCA in later clinical course were analyzed with targeted sequencing including tumor and control benign tissue (n = 55 samples). A CCA-specific sequencing panel containing 41 genes was designed and a dual strand targeted enrichment was applied.
Results: Sequencing was successfully performed for all samples. In total, 79 mutations were identified and a mean of 1.7 mutations per tumor sample (range 0–4) as well as 2.3 per biopsy (0–6) were detected and potentially therapeutically relevant genes were identified in 6/16 cases. In 14/18 (78%) biopsies with dysplasia or inconclusive findings at least one mutation was detected. The majority of mutations were found in both surgical specimen and biopsy (68%), while 28% were only present in biopsies in contrast to 4% being only present in the surgical tumor specimen.
Conclusion: Targeted sequencing from intraductal biopsies is feasible and potentially improves the diagnostic yield. A profound genetic heterogeneity in biliary dysplasia needs to be considered in clinical management and warrants further investigation.
Translational impact: The current study is the first to demonstrate the feasibility of sequencing of intraductal biopsies which holds the potential to impact diagnostic and therapeutical management of patients with biliary dysplasia and neoplasia.
Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation and accumulation of immature myeloblasts, which impair normal hematopoiesis. While this definition categorizes the disease into a distinctive group, the large number of different genetic and epigenetic alterations actually suggests that AML is not a single disease, but a plethora of malignancies. Still, most AML patients are not treated with targeted medication but rather by uniform approaches such as chemotherapy. The identification of novel treatment options likely requires the identification of cancer cell vulnerabilities that take into account the different genetic and epigenetic make-up of the individual tumors. Here we show that STK3 depletion by knock-down, knock-out or chemical inhibition results in apoptotic cells death in some but not all AML cell lines and primary cells tested. This effect is mediated by a premature activation of cyclin dependent kinase 1 (CDK1) in presence of elevated cyclin B1 levels. The anti-leukemic effects seen in both bulk and progenitor AML cells suggests that STK3 might be a promising target in a subset of AML patients.
Monoclonal antibodies (mAb) are promising therapeutics in multiple sclerosis and multiple new candidates have been developed, hence increasing the need for some agreement for preclinical mAb studies. We systematically analyzed publications of experimental autoimmune encephalomyelitis (EAE) studies showing effects of monoclonal antibodies. A PubMed search retrieved 570 records, out of which 122 studies with 253 experiments were eligible based on experimental design, number of animals and presentation of time courses of EAE scores. Analysis of EAE models, treatment schedules, single and total doses, routes of administration, and onset of treatment from pre-immunization up to 35 days after immunization revealed high heterogeneity. Total doses ranged from 0.1 to 360 mg/kg for observation times of up to 35 days after immunization. About half of experiments (142/253) used total doses of 10–70 mg/kg. Employing this range, we tested anti-Itga4 as a reference mAb at varying schedules and got no, mild or substantial EAE-score reductions, depending on the mouse strain and onset of the treatment. The result agrees with the range of outcomes achieved in 10 reported anti-Itga4 experiments. Studies comparing low and high doses of various mAbs or early vs. late onset of treatment did not reveal dose-effect or timing-effect associations, with a tendency towards better outcomes with preventive treatments starting within the first week after immunization. The systematic comparison allows for extraction of some “common” design characteristics, which may be helpful to further assess the efficacy of mAbs and role of specific targets in preclinical models of multiple sclerosis.
Objective: Most patients suffering with rheumatic diseases who undergo surgical treatment are receiving immune-modulating therapy. To determine whether these medications affect their outcomes a national registry was established in Germany by the German Society of Surgery (DGORh). Data from the first 1000 patients were used in a pilot study to identify relevant corisk factors and to determine whether such a registry is suitable for developing accurate and relevant recommendations.
Design and participants: Data were collected from patients undergoing surgical treatments with their written consent. A second consent form was used, if complications occurred. During this pilot study, in order to obtain a quicker overview, risk factors were considered only in patients with complications. Only descriptive statistical analysis was employed in this pilot study due to limited number of observed complications and inhomogeneous data regarding the surgery and the medications the patients received. Analytical statistics will be performed to confirm the results in a future outcome study.
Results: Complications occurred in 26 patients and were distributed equally among the different types of surgeries. Twenty one of these patients were receiving immune-modulating therapy at the time, while five were not. Infections were observed in 2.3% of patients receiving and in 5.1% not receiving immunosuppression.
Conclusions: Due to the low number of cases, inhomogeneity in the diseases and the treatments received by the patients in this pilot study, it is not possible to develop standardised best-practice recommendations to optimise their care. Based on this observation we conclude that in order to be suitable to develop accurate and relevant recommendations a national registry must include the most important and relevant variables that impact the care and outcomes of these patients.
Ich hatte im Wintersemester 1968 in Frankfurt mit dem Pharmaziestudium angefangen. Das pharmazeutische Institut lag ja damals in der Georg-Voigt-Straße, also nicht weit entfernt vom Zentrum der Studentenunruhen, dem Uni-Hauptgebäude mit der Aula. Daher haben wir einiges von den Protesten mitbekommen. ...
Über die Bedeutung des geistigen Erbes von 68 wird 50 Jahre später trefflich gestritten. Mögen die politischen Ideen des Aufbruchs und das daran anknüpfende Handeln heute für Kontroversen sorgen, so erfreut sich hingegen der Sound der Revolution, der damals zum Ärger orthodoxer Kommunisten ganz klar von der Rockmusik dominiert wurde, einer nahezu ungebrochenen Begeisterung: Das "»Weiße Album" der Beatles, "Electric Ladyland" von Jimi Hendrix oder "Beggars Banquet" von den Rolling Stones, alle 68 erschienen, werden heute mehr denn je bewundert. Im Zeichen einer grassierenden "Retromania" (Simon Reynolds) gewinnt der mit Mythen und Heldengeschichten aufgeladene Sound der Vergangenheit mit zunehmendem zeitlichen Abstand sogar noch an Bedeutung. In ihrer Frühphase ist die Popmusik noch ein Wettstreit verschiedener Stile, Techniken und auch Bands. Ihre steigende gesellschaftliche Akzeptanz lässt aber spätestens in den 70er Jahren Zweifel laut werden an ihrer weiterhin behaupteten und auch inszenierten Widerständigkeit.
Das Private ist politisch! – 68 war der Slogan eine auf Ganze gerichtete Perspektive der Kritik und ein Impuls für die Revolutionierung des Alltagslebens: Es ging bei den Diskussionen und Analysen um die "Weltherrschaft des Kapitals" und den Zusammenhang von Faschismus und Kapitalismus immer zugleich um die Manifestationen von Herrschaft und Unterdrückung in den Kapillaren des Alltäg lichen. In den Blick gerieten dabei nicht zuletzt die Autoritätsstrukturen der bürgerlichen Familie und damit die (im Sinne marxistischer Gesellschaftsanalyse) sogenannte "Nebenwidersprüche" des Privaten: das Verhältnis der Geschlechter, Fragen von Liebe und Sexualität, Kindererziehung, Eigentumsfragen und Besitzdenken. Der Slogan wurde darüber hinaus zum Leitspruch der Frauenbewegung, die vor Augen führt, wie politisch das Private gerade in Fragen von Nachwuchs und Alltagsorganisation ist. ...
In den zahlreichen Beiträgen zum "Jubeljahr der 1968er-Bewegung" kommen oft ehemalige Aktive, Historikerinnen und Experten zu Wort. Doch wie blicken eigentlich Aktivistinnen und Aktivisten des 21. Jahrhunderts auf diese Zeit zurück? Dieser Frage hat sich ein zweijähriges Forschungsprojekt am Institut für Politikwissenschaft der Goethe-Universität gewidmet.
Weg mit den Talaren! Hoch die Doktorhüte! : vom Wandel der Zeremonialität an deutschen Universitäten
(2018)
"Unter den Talaren – Muff von 1000 Jahren": Dieser Slogan steht wie kaum ein anderer für die Aufbruchstimmung der 68er-Generation. Damit zielten die Hamburger Studenten auf das Verschweigen der NS-Vergangenheit ab, anschließend ging es aber auch den Talaren selbst an den Kragen. Seit einigen Jahren wird im zeremoniellen Raum der Universitäten vielfach experimentiert: Die Fächer bilden eine jeweils eigene Feierkultur aus – auf der Suche nach einem Übergang von der Universität in das berufliche Leben.