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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA); 20111005-20111008; München; DOC11gma237 /20110926/
    Publication Date: 2011-09-26
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Keywords: NF-KAPPA-B ; BREAST-CANCER ; TARGET ; MUTATIONS ; HEMATOPOIETIC STEM-CELLS ; ACUTE MYELOGENOUS LEUKEMIA ; RAPAMYCIN ; AML ; MEK INHIBITION ; CONSTITUTIVE PHOSPHORYLATION
    Abstract: In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9(+)/FLT3-ITD+ xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9(+) and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9(+) samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML.
    Type of Publication: Journal article published
    PubMed ID: 25322685
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  • 3
    Abstract: Tumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression profiling revealed their similarity to primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD). Therapeutically adverse characteristics were reversible, as resistant, dormant cells became sensitive to treatment and started proliferating when dissociated from the in vivo environment. Our data suggest that ALL patients might profit from therapeutic strategies that release MRD cells from the niche.
    Type of Publication: Journal article published
    PubMed ID: 27916615
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Zeitschrift für Medizinische Ausbildung; VOL: 30; DOC9 /20130221/
    Publication Date: 2013-03-01
    Description: Purpose: Blogging is an increasingly popular method of sharing and reflecting on experiences of medical students in the World Wide Web with a potentially global learning community. The authors are not aware of studies that specifically examined blogs by medical students and thus for the first time investigated the type of experiences and impressions that emerged from these blogs with relevance for medical students and medical educators.Method: This was a qualitative study. Initially 75 blogs were identified. 33 blogs with a total of 1228 English and 337 German blog entries met the inclusion criteria and were analyzed. We started with line-by-line coding and switched to focused coding using constant comparative analysis to create a categorical framework for blogs.Results: Medical students use blogs to write and reflect about a large variety of issues related to medical school. Major emerging themes included the preparation for written and oral high-stakes exams, experiences during clinical rotations, dealing with distressing situations during medical school, and social life of students beyond medical school. Conclusions: Our findings suggest that blogs are a potentially useful tool for medical students to reflect on their experiences during medical school as well as for medical educators to better understand how students perceive their time in medical school. The educational benefit of blogging might even be increased if trained medical educators would help to facilitate meaningful and targeted discussions emerging from blog entries and comment on students' learning challenges with the chance to reach a large community of learners.
    Description: Einleitung: Bloggen ist eine unter Medizinstudierenden zunehmend verbreitete Methode, Erfahrungen über das Internet mit einer weltweiten "Learning Community" auszutauschen. Trotz intensiver Recherche sind den Autoren keine Studien bekannt, in denen spezifisch Blogs von Medizinstudierenden qualitativ analysiert wurden. Im Folgenden werden Kategorien und Themen aus diesen Blogeinträgen beschrieben und ihre medizindidaktische Bedeutung für Medizinstudierende und Lehrende diskutiert.Methoden: In der vorliegenden qualitativen Studie wurden ursprünglich 75 von Medizinstudierenden verfasste Blogs identifiziert. 33 Blogs mit insgesamt 1228 englischen und 337 deutschen Einträgen erfüllten die Einschlusskriterien und wurden analysiert. Mit Hilfe einer komparativen Analysemethode wurden die Blogeinträge zunächst Zeile für Zeile und anschließend fokussiert kodiert. Die emergierenden Themen und Unterthemen wurden in übergeordneten Kategorien zusammengefasst.Ergebnisse: Medizinstudierende verwenden Blogs, um über eine große Vielfalt an Erfahrungen während des Medizinstudiums zu berichten und diese zu reflektieren. Vorbereitung auf schriftliche und mündliche Examina, Erfahrungen während klinischer Praktika, der Umgang mit belastenden Situationen während des Studiums und das Sozialleben jenseits des Studiums waren Hauptthemen.Schlussfolgerung: Unsere Ergebnisse weisen darauf hin, dass Blogs für Medizinstudierende möglicherweise hilfreich sind, um Erfahrungen zu reflektieren. Zusätzlich können Lehrende auf diesem Weg wertvolle Einblicke in die studentische Wahrnehmung der medizinischen Ausbildung erhalten.Die Bedeutung von Blogs in der medizinischen Ausbildung könnte durch gezieltes Kommentieren von Blogeinträgen durch Lehrende erhöht werden. Von diesem Dialog könnte auch eine örtlich unabhängige "Learning Community" profitieren.
    Keywords: Blogging ; medical student ; qualitative ; undergraduate ; medical education ; Bloggen ; Medizinstudent ; qualitativ ; Erfahrungen ; Medizinstudium ; ddc: 610
    Language: English
    Type: article
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  • 5
    Publication Date: 2018-03-15
    Description: Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis—a major source of recurrent vascular events—have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)–signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2–CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of β3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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