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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2015); 20151020-20151023; Berlin; DOCPO21-918 /20151005/
    Publication Date: 2015-10-06
    Keywords: implant ; electric ; stimulation ; monopolar ; femur neck ; fracture ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
    Keywords: EXPRESSION ; CELL LUNG-CANCER ; GENE ; IDENTIFICATION ; N-MYC ; SOLID TUMORS ; ONCOGENIC MUTATIONS ; HIGH-RISK NEUROBLASTOMA ; ANAPLASTIC LYMPHOMA KINASE ; ACTIVATING MUTATIONS
    Abstract: Treatment for neuroblastoma, the most common extracranial childhood tumor, spans a broad range of aggressiveness that mirrors the risk profiles of disease subtypes, with high-risk neuroblastoma still presenting a clinical challenge. Currently, most patients with relapsed neuro-blastoma die of disease and present a major challenge for treatment. New therapeutic options are urgently needed to improve patient survival. Activating mutations in the gene encoding the anaplastic lymphoma kinase (ALK) remain the most frequent druggable mutations identified in neuroblastomas to date. Preclinical data support an oncogene addiction of neuroblastoma cells to mutated ALK and demonstrate that ALK inhibitory therapy strongly combats tumor models. Most recently, pediatric phase I testing has been completed for the first approved ALK inhibitor, Crizotinib, showing very encouraging antitumoral results in neuroblastoma patients. Subsequently, an international phase I study with the second generation ALK inhibitor, LDK-378, will be launched that makes ALK inhibitory therapy also available to pediatric patients in Germany.
    Type of Publication: Journal article published
    PubMed ID: 24166094
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  • 3
    Keywords: APOPTOSIS ; CANCER ; GROWTH ; GENE-EXPRESSION ; STEM-CELLS ; CENTRAL-NERVOUS-SYSTEM ; neuroblastoma ; N-MYC ; BRAIN-TUMORS ; TUMOR-SUPPRESSOR
    Abstract: Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25348795
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  • 4
    Keywords: RECEPTOR ; CANCER ; GENES ; ASSOCIATION ; PHENOTYPE ; HETEROGENEITY ; N-MYC ; SIGNATURES ; ALK ; DNA METHYLATION DATA
    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 26121086
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  • 5
    Keywords: RECEPTOR ; EXPRESSION ; IN-VITRO ; SYSTEM ; DIFFERENTIATION ; TUMOR-GROWTH ; NERVE ; CULTURES ; PATHOLOGY CLASSIFICATION ; GLIAL GROWTH-FACTORS
    Abstract: In neuroblastoma, the most common solid tumor of childhood, excellent prognosis is associated with extensive Schwann cell (SC) content and high-level expression of the neurotrophin receptor, NTRK1/TrkA, which is known to mediate neuroblastoma cell differentiation. We hypothesized that both stromal composition and neuroblastic differentiation are based on bidirectional neuroblastoma-SC interaction. Reanalysis of microarray data from human SY5Y neuroblastoma cells stably transfected with either NTRK1 or NTRK2 revealed upregulation of the mRNA for the SC growth factor, NRG1, in NTRK1-positive cells. Media conditioned by NTRK1-expressing neuroblastoma cells induced SC proliferation and migration, while antibody-based NRG1 neutralization significantly decreased these effects. Vice versa, NRG1-stimulated SC secreted the NTRK1-specific ligand, NGF. SC-conditioned medium activated the NTRK1 receptor in a neuroblastoma cell culture model conditionally expressing NTRK1 and induced differentiation markers in NTRK1-expressing cells. NTRK1 induction in neuroblastoma xenografts mixed with primary SC also significantly reduced tumor growth in vivo. We propose a model for NTRK1-mediated and NRG1-dependent attraction of adjacent SC, which in turn induce neuroblastic differentiation by secretion of the NTRK1-specific ligand, NGF. These findings have implications for understanding the mature and less malignant neuroblastoma phenotype associated with NTRK1 expression, and could assist the development of new therapeutic strategies for neuroblastoma differentiation.
    Type of Publication: Journal article published
    PubMed ID: 25361003
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  • 6
    Keywords: APOPTOSIS ; EXPRESSION ; INHIBITION ; NEUROBLASTOMA-CELLS ; CELL-CYCLE ; PHOSPHORYLATION ; TNF-ALPHA ; MYCN ; NEGATIVE BREAST-CANCER ; CDK1
    Abstract: Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.
    Type of Publication: Journal article published
    PubMed ID: 26029996
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  • 7
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    German Medical Science; Düsseldorf, Köln
    In:  Hypertonie 2005; 29. Wissenschaftlicher Kongress der Deutschen Hochdruckliga; 20051123-20051125; Berlin; DOC05hochP22 /20060808/
    Publication Date: 2006-08-09
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  22. Jahrestagung der Retinologischen Gesellschaft; 20090626-20090627; Berlin; DOCRG2009-53 /20090629/
    Publication Date: 2009-07-07
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 9
    ISSN: 1432-055X
    Keywords: Schlüsselwörter Zerebrale Durchblutung ; Hirnvenöse Sättigung ; Arteriovenöse Sauerstoffgehaltsdifferenz ; Key words Cerebral blood flow ; Cerebral venous oxygen saturation ; Arteriovenous oxygen content difference
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract The arteriovenous oxygen content difference (avDO2) of the brain is dependent on O2 consumption (CMRO2) and cerebral blood flow (CBF). With unchanging arterial O2 content, avDO2 is inversely related to cerebral venous O2 saturation (SO2). Measurement of SO2 in the jugular bulb not only provides information about the O2 balance of the brain, but may give an important estimation of CBF if a clinically useful correlation is proven. The aim of the present study was to verify this aspect. Methods. Sixty-two male patients undergoing coronary revascularisation were investigated. The study was approved by the local Ethical Committee and each patient gave written informed consent on the preoperative day. At four points during the perioperative course arterial and cerebral venous SO2 and CBF were measured. Cerebral venous blood was sampled from a catheter in the superior bulb of the right internal jugular vein. CBF was measured using the argon wash-in technique. All sampled data were pooled and evaluated. Results. As expected from theory, cerebral venous SO2 and avDO2 showed a close linear relationship (r=−0.892). However, only a weak hyperbolic relationship was found between cerebral venous SO2 and CBF. In addition, no direct correlation between CMRO2 and SO2 in the jugular bulb could be demonstrated. Conclusions. In this clinical study, a close relationship between cerebral venous SO2 and CBF was not found. This was primarily due to the high variability of cerebral O2 uptake. Changes in cerebral venous SO2 may therefore not be used as an estimate of perioperative changes in CBF.
    Notes: Zusammenfassung In der klinischen Routine stellt die Bestimmung der Hirndurchblutung häufig ein Problem dar. Leichter meßbar ist die arteriovenöse Sauerstoffgehaltsdifferenz (avDO 2 ) des Gehirns, die abhängig ist von dessen O 2 -Verbrauch (CMRO 2 ) und dem zerebralen Blutfluß (CBF). Bei gleichbleibendem Sauerstoffangebot ist die avDO 2 umgekehrt proportional zur hirnvenösen O 2 -Sättigung (ShvO 2 ). Damit erlaubt die Bestimmung der hirnvenösen Sättigung nicht nur eine Aussage über die Sauerstoffausschöpfung des Gehirns, sondern könnte bei einer konstanten O 2 -Aufnahme eine Einschätzung des CBF ermöglichen. In der vorliegenden Untersuchung wurde an 62 männlichen Patienten im Alter von 41–60 Jahren im Rahmen von aorto-koronaren Bypassoperationen dieser Zusammenhang untersucht. Zu vier definierten Meßpunkten wurden die arterielle und hirnvenöse Sauerstoffsättigung sowie die zerebrale Durchblutung gemessen. Die erhaltenen Werte wurden gepoolt. Es konnte eine lineare Abhängigkeit zwischen der avDO 2 und ShvO 2 bestätigt werden; eine hinreichend enge Verknüpfung zwischen ShvO 2 und CBF lag unter diesen klinischen Bedingungen jedoch nicht vor. Die Ursache lag in der hohen Variabilität des CMRO 2 . Ohne Kenntnis der CMRO 2 dürfen aus Sättigungsänderungen keine Rückschlüsse auf perioperative Veränderungen der Hirndurchblutung gezogen werden.
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  • 10
    ISSN: 1432-055X
    Keywords: Schlüsselwörter PDE-III-Hemmer ; Hämodynamik ; Koronare Herzkrankheit ; Key words PDE-III-inhibitors ; Haemodynamics ; Ischaemic heart disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract At present, phosphodiesterase III inhibitors are commonly used for the treatment of low cardiac output states. Despite their positive inotropic and lusitropic effects, these drugs are still under discussion because of certain adverse effects like thrombopaenia, elevation of transaminases, abdominal disregulation, and excessive periphereal vasodilatation. As a consequence, more cardioselective phosphodiesterase inhibitors were developed with the aim of reducing these adverse effects. One of them, enoximone (Marion Merrell Dow, Fig. 1), an imidazole derivative, has nearly no influence on platelets and abdominal organ function. In addition, in many studies vasodilatation was found to be absent. Recently a new substance, R80122 (Janssen, Belgium, Fig. 1), was developed. First experimental studies showed high cardioselectivity of this substance. The aim of this study was to compare the haemodynamic effects of enoximone and R80122 in patients with ischaemic heart disease. Methods. This study was thoroughly discussed and approved by the local Ethics Committee; all patients gave written informed consent. Twenty male patients (Table 1) with normal left ventricular function who were about to undergo elective coronary artery bypass surgery were randomly allocated to receive a bolus of either 1.0 mg/kg enoximone or 0.3 mg/kg R80122 after induction of anaesthesia. Premedication consisted of 2 mg flunitrazepam orally the evening before and in the morning 1 h before operation. Anaesthesia was induced with 0.007 mg/kg fentanyl, 0.2 mg/kg etomidate, and 0.1 mg/kg pancuronium bromide and maintained by a continuous infusion of 0.02 mg/min fentanyl and 0.3 mg/min midazolam. After induction of anaesthesia haemodynamic measurements were performed and blood gas samples were taken preoperatively under steady-state conditions before and 5, 30, and 60 min after drug administration. Results. The results of both groups are shown in Table 2 as mean values with standard deviations. Individual changes of cardiac index (CI), mean arterial pressure (MAP), and systemic vascular resistance (SVR) are depicted in Fig. 2. Peak percentage changes of the haemodynamic parameters are shown in Fig. 3. Both substances improved cardiac function; 5 min after drug administration CI increased by 31% and 26%, respectively. This was accompanied by increases in stroke volume (13% and 14%, respectively) and heart rate (15% and 10%, respectively). At the same time, there were declines in SVR (38% and 36%, respectively) and MAP (19% and 21%, respectively). Although mean values of pulmonary arterial and wedge pressure decreased after drug administration, these changes were inconsistent and not of clinical relevance. There were no statistically significant differences between the haemodynamic effects of both substances at any time in this study. Conclusions. Both enoximone and R80122 showed the expected inotropic effects. Nevertheless, both substances have a distinct vasodilative effect, which leads to a decline in MAP. R80122 does not have higher cardioselectivity than enoximone.
    Notes: Zusammenfassung In dieser Untersuchung wurden die hämodynamischen Effekte einer Bolusinjektion von 1,0 mg/kg KG Enoximon bzw. 0,3 mg/kg KG R80122 bei jeweils 10 Patienten mit koronarer Herzkrankheit und normaler linksventrikulärer Funktion gemessen und miteinander verglichen. Die einzelnen Messungen erfolgten präoperativ nach Narkoseeinleitung unter steady state-Bedingungen. Der Herzindex stieg bereits 5 min nach Gabe des jeweiligen PDE-III-Hemmers maximal an, in der Enoximongruppe im Mittel um 31%, in der R80122-Gruppe im Mittel um 26% über die jeweiligen Ausgangswerte. Der Anstieg des Herzindex basierte bei beiden Gruppen sowohl auf einem Anstieg des Schlagvolumens, nach Enoximongabe im Mittel um 13%, nach Gabe von R80122 im Mittel um 14%, wie auch der Herzfrequenz, nach Enoximongabe im Mittel um 15%, nach Gabe von R80122 im Mittel um 10%. Gleichzeitig kam es zu einem Abfall des arteriellen Mitteldrucks, nach Enoximongabe im Mittel um 19%, nach Gabe von R80122 im Mittel um 21%. Ursache für den Abfall des arteriellen Mitteldrucks war in beiden Gruppen die Erniedrigung des peripheren Gefäßwiderstands, in der Enoximongruppe im Mittel um 38%, in der R80122-Gruppe im Mittel um 36%. Ein signifikanter Unterschied zwischen den hämodynamischen Parametern beider Gruppen lag zu keinem Meßzeitpunkt vor. Beide Substanzen zeigen in der vorgegebenen Dosierung vergleichbare hämodynamische Effekte, einen Anstieg von Herzindex, Herzfrequenz und Schlagvolumen bei gleichzeitigem Abfall des peripheren Gefäßwiderstands. Die in tierexperimentellen Untersuchungen nachgewiesene höhere Kardioselektivität von R80122 konnte unter den klinischen Bedingungen dieser Studie nicht nachgewiesen werden.
    Type of Medium: Electronic Resource
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