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Fecker L.F.,ChariteUniversitatsmedizin Berlin | Stockfleth E.,ChariteUniversitatsmedizin Berlin | Braun F.K.,ChariteUniversitatsmedizin Berlin | Rodust P.M.,ChariteUniversitatsmedizin Berlin | And 4 more authors.
Journal of Investigative Dermatology | Year: 2010

Actinic keratosis (AK) occurs on sun-exposed skin and may progress to invasive squamous cell carcinoma (SCC). As for its topical treatment, diclofenac/hyaluronic acid (HA) has been recently approved. The NSAID diclofenac is an inhibitor of COX-2; however, its mode of action in cutaneous epithelial cancer cells is largely unknown. Here, the effects of diclofenac/HA were investigated in relation to death ligand-mediated apoptosis (TNF-α, TRAIL, and CD95 activation). Whereas diclofenac/HA only moderately induced apoptosis by itself, it resulted in pronounced enhancement of death ligand-mediated apoptosis in sensitive SCC cell lines (3/4). Apoptosis was associated with activation of initiator caspases of the extrinsic pathway (caspase-8/caspase-10) . Furthermore, death ligand and diclofenac/HA-mediated apoptosis were blocked by the same caspase inhibitors, indicating related pathways. The proapoptotic effects of diclofenac/HA appeared independent of the p53 pathway. Also, upregulation of death receptors appeared less important; however, strong downregulation of c-FLIP isoforms was seen after diclofenac/HA treatment. The crucial role of c-FLIP was proven through overexpression and knockdown experiments. Thus, induction of apoptosis appears to be highly characteristic of the mode of action of diclofenac/HA, and the therapeutic effect may be related to sensitization of neoplastic keratinocytes for death ligand-induced apoptosis. © 2010 The Society for Investigative Dermatology.


Luftner D.,ChariteUniversitatsmedizin Berlin | Niepel D.,Amgen
Supportive Care in Cancer | Year: 2016

Purpose: The aim of this study is to provide an overview of the potential barriers to uptake of bone-targeted agents for the prevention of skeletal-related events (SREs) in patients with breast cancer and bone metastases. Methods: A top-line literature review was conducted to identify trends in and barriers to initiating bone-targeted therapy in patients with metastatic breast cancer. Results: The majority of patients with bone metastases that are secondary to breast cancer clearly benefit from treatment with a bone-targeted agent such as the RANK ligand inhibitor denosumab or the bisphosphonate zoledronic acid, because both delay the onset of SREs. Evidence suggests, however, that these agents are not being used in these patients as per European guideline recommendations. Conclusions: Adoption of a number of behavioral changes may help to overcome barriers to earlier initiation of treatment with bone-targeted agents in these patients. This includes raising awareness of the guidelines that are available for bone-targeted therapies, providing physician and patient education on the appropriate use of these agents, and highlighting to physicians the importance of early treatment and regular monitoring for adverse events. Earlier initiation of treatment should help to reduce the risk of SREs and thus lessen the burden that these debilitating skeletal complications place on patients and healthcare systems. © 2016, Springer-Verlag Berlin Heidelberg.


Elgeti T.,ChariteUniversitatsmedizin Berlin | Tzschatzsch H.,ChariteUniversitatsmedizin Berlin | Hirsch S.,ChariteUniversitatsmedizin Berlin | Krefting D.,ChariteUniversitatsmedizin Berlin | And 4 more authors.
Magnetic Resonance in Medicine | Year: 2012

Vibration synchronized magnetic resonance imaging of harmonically oscillating tissue interfaces is proposed for cardiac magnetic resonance elastography. The new approach exploits cardiac triggered cine imaging synchronized with extrinsic harmonic stimulation (f = 22.83 Hz) to display oscillatory tissue deformations in magnitude images. Oscillations are analyzed by intensity threshold-based image processing to track wave amplitude variations over the cardiac cycle. In agreement to literature data, results in 10 volunteers showed that endocardial wave amplitudes during systole (0.13 ± 0.07 mm) were significantly lower than during diastole (0.34 ± 0.14 mm, P < 0.001). Wave amplitudes were found to decrease 117 ± 40 ms before myocardial contraction and to increase 75 ± 31 ms before myocardial relaxation. Vibration synchronized magnetic resonance imaging improves the temporal resolution of magnetic resonance elastography as it overcomes the use of extra motion encoding gradients, is less sensitive to susceptibility artifacts, and does not suffer from dynamic range constraints frequently encountered in phase-based magnetic resonance elastography. © 2011 Wiley Periodicals, Inc.


Knecht S.,Universitatsklinikum Munster | Hesse S.,ChariteUniversitatsmedizin Berlin | Oster P.,Geriatrisches Zentrum
Deutsches Arzteblatt | Year: 2011

Background: Stroke is becoming more common in Germany as the population ages. Its long-term sequelae can be alleviated by early reperfusion in stroke units and by complication management and functional restoration in early-rehabilitation and rehabilitation centers. Methods: Selective review of the literature. Results: Successful rehabilitation depends on systematic treatment by an interdisciplinary team of experienced specialists. In the area of functional restoration, there has been major progress in our understanding of the physiology of learning, relearning, training, and neuroenhancement. There have also been advances in supportive pharmacotherapy and robot technology. Conclusion: Well-organized acute and intermediate rehabilitation after stroke can provide patients with the best functional results attainable on the basis of our current scientific understanding. Further experimental and clinical studies will be needed to expand our knowledge and improve the efficacy of rehabilitation.


Christen M.,University of Zürich | Muller S.,ChariteUniversitatsmedizin Berlin
Current Topics in Behavioral Neurosciences | Year: 2015

Understanding how the “brain produces behavior” is a guiding idea in neuroscience. It is thus of no surprise that establishing an interrelation between brain pathology and antisocial behavior has a long history in brain research. However, interrelating the brain with moral agency—the ability to act in reference to right and wrong—is tricky with respect to therapy and rehabilitation of patients affected by brain lesions. In this contribution, we outline the complexity of the relationship between the brain and moral behavior, and we discuss ethical issues of the neuroscience of ethics and of its clinical consequences. First, we introduce a theory of moral agency and apply it to the issue of behavioral changes caused by brain lesions. Second, we present a typology of brain lesions both with respect to their cause, their temporal development, and the potential for neural plasticity allowing for rehabilitation. We exemplify this scheme with case studies and outline major knowledge gaps that are relevant for clinical practice. Third, we analyze ethical pitfalls when trying to understand the brain–morality relation. In this way, our contribution addresses both researchers in neuroscience of ethics and clinicians who treat patients affected by brain lesions to better understand the complex ethical questions, which are raised by research and therapy of brain lesion patients. © Springer-Verlag Berlin Heidelberg 2014.


Savvatis K.,ChariteUniversitatsmedizin Berlin | Pappritz K.,ChariteUniversitatsmedizin Berlin | Becher P.M.,University of Hamburg | Lindner D.,University of Hamburg | And 6 more authors.
Circulation: Heart Failure | Year: 2014

Background - CD4+ cells are implicated in the healing process after myocardial infarction (MI). We sought to investigate the role of interleukin-23 (IL-23) deficiency, a cytokine important in differentiation of CD4+ cells, in scar formation of the ischemic heart. Methods and Results - MI was performed in wild-type and IL23p19./. mice. Thirty-day mortality, hemodynamic function 4 days after MI and myocardial inflammation, and remodeling 4 and 30 days after MI were examined. Differentiation of fibroblasts from infarcted and noninfarcted hearts into myofibroblasts was examined under basal conditions and after stimulation with interferon-ã, IL-17á and IL-23. Interleukin-23p19./. mice showed higher expression of proinflammatory cytokines and immune cell infiltration in the scar early after MI compared with wild-type mice. A stronger interferon- ã/ Th1 reaction seemed to be responsible for the increased inflammation under IL-23 deficiency. Expression of á-smooth muscle actin (á-SMA), collagen I and III was significantly higher in the heart tissue and isolated cardiac fibroblasts 4 days after MI in the wild-type mice. Interleukin-23p19./. mice showed impaired healing compared with wild-type mice, as seen by significantly higher mortality because of ventricular rupture (40% higher after 30 days) and stronger left ventricular dilation early after MI. Stimulation of cardiac fibroblasts with interferon-ã, the main Th1 cytokine, but not with IL-23 or IL-17á, led to a significant downregulation of á-smooth muscle actin, collagen I and III and decreased migration and differentiation to myofibroblasts. Conclusions - IL-23 deficiency leads to increased myocardial inflammation and decreased cardiac fibroblast activation, associated with impaired scar formation and adverse remodeling after MI. © 2013 American Heart Association, Inc.


Tuvia S.,Chiasma | Atsmon J.,Tel Aviv University | Teichman S.L.,Chiasma | Katz S.,Chiasma | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Oral administration of a novel octreotide formulation enabled its absorption to the systemic circulation, exhibiting blood concentrations comparable to those observed with injected octreotide and maintaining its biological activity. Objectives: The aim of the study was to determine oral octreotide absorption and effects on pituitary GH secretion compared to sc octreotide injection. Design: Four single-dose studies were conducted in 75 healthy volunteers. Intervention: Oral doses of 3, 10, or 20 mg octreotide and a single sc injection of 100-g octreotide were administered. Main Outcome Measure: We measured the pharmacokinetic profile of orally administrated octreotide and the effect of octreotide on basal and stimulated GH secretion. Results: Both oral and sc treatments were well tolerated. Oral octreotide absorption to the circulation was apparent within 1 h after dose administration. Escalating oral octreotide doses resulted in dose-dependent increased plasma octreotide concentrations, with an observed rate of plasma decay similar to parenteral administration. Both 20 mg oral octreotide and injection of 0.1 mg sc octreotide resulted in equivalent pharmacokinetic parameters [mean peak plasma concentration, 3.77 ± 0.25 vs. 3.97 ± 0.19 ng/ml; mean area under the curve, 16.2 ± 1.25 vs. 12.1 ± 0.45 hxng/ml); and median time ≥0.5 ng/ml, 7.67 vs. 5.88 h, respectively). A single dose of 20 mg oral octreotide resulted in basal (P < 0.05) and GHRH-stimulated (P < 0.001) mean GH levels suppressed by 49 and 80%, respectively. Conclusions: The results support an oral octreotide alternative to parenteral octreotide treatment for patients with acromegaly. Copyright © 2012 by The Endocrine Society.


Sinn M.,ChariteUniversitatsmedizin Berlin
British Journal of Cancer | Year: 2014

Background:Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods:CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results:High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions:Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.British Journal of Cancer advance online publication, 14 October 2014; doi:10.1038/bjc.2014.495 www.bjcancer.com. © 2014 Cancer Research UK


Storm C.,ChariteUniversitatsmedizin Berlin | Nee J.,ChariteUniversitatsmedizin Berlin | Roser M.,German Heart Center Berlin | Jorres A.,ChariteUniversitatsmedizin Berlin | Hasper D.,ChariteUniversitatsmedizin Berlin
Emergency Medicine Journal | Year: 2012

Objective: Therapeutic hypothermia has proved effective in improving outcome in patients after cardiac arrest due to ventricular fibrillation (VF). The benefit in patients with non-VF cardiac arrest is still not defined. Methods: This prospective observational study was conducted in a university hospital setting with historical controls. Between 2002 and 2010 387 consecutive patients have been admitted to the intensive care unit (ICU) after cardiac arrest (control n=186; hypothermia n=201). Of those, in 175 patients the initial rhythm was identified as non-shockable (asystole, pulseless electrical activity) rhythm (control n=88; hypothermia n=87). Neurological outcome was assessed at ICU discharge according to the Pittsburgh cerebral performance category (CPC). A follow-up was completed for all patients after 90 days, a Kaplan-Meier analysis and Cox regression was performed. Results: Hypothermia treatment was not associated with significantly improved neurological outcome in patients resuscitated from non-VF cardiac arrest (CPC 1-2: hypothermia 27.59% vs control 18.20%, p=0.175). 90-Day Kaplan-Meier analysis revealed no significant benefit for the hypothermia group (log rank test p=0.82), and Cox regression showed no statistically significant improvement. Conclusions: In this cohort patients undergoing hypothermia treatment after non-shockable cardiac arrest do not benefit significantly concerning neurological outcome. Hypothermia treatment needs to be evaluated in a large multicentre trial of cardiac arrest patients found initially to be in non-shockable rhythms to clarify whether cooling may also be beneficial for other rhythms than VF.


Audebert H.J.,ChariteUniversitatsmedizin Berlin | Fiebach J.B.,ChariteUniversitatsmedizin Berlin
Current Neurology and Neuroscience Reports | Year: 2015

In acute stroke, imaging provides different technologies to demonstrate stroke subtype, tissue perfusion and vessel patency. In this review, we highlight recent clinical studies that are likely to guide therapeutic decisions. Clot length in computed tomography (CT) and clot burden in MR, imaging of leptomeningeal collaterals and indicators for active bleeding are illustrated. Imaging-based concepts for treatment of stroke at awakening and pre-hospital treatment in specialized ambulances offer new potentials to improve patient outcome. © 2015, Springer Science+Business Media New York.

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