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Wilisch-Neumann A.,Otto Von Guericke University of Magdeburg | Kliese N.,Otto Von Guericke University of Magdeburg | Pachow D.,Otto Von Guericke University of Magdeburg | Warnke J.-P.,Paracelsus Hospital | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells. Experimental Design: We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times. Results: avb5 was the predominantly expressed integrin heterodimer in meningiomas, whereas avb3 was mainly detected in tumor blood vessels. Application of up to 100 mg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One mg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. Adaily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P=0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05). Conclusions: These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention. © 2013 American Association for Cancer Research.


Simoes-Wust A.P.,Paracelsus Hospital | Jeschke E.,Havelhoehe Research Institute | Mennet M.,Weleda AG | Schnelle M.,Weleda AG | And 2 more authors.
Forschende Komplementarmedizin | Year: 2012

Background: The use of preparations from Bryophyllum pinnatum for tocolysis (or to arrest labor) is supported by observations obtained mainly at empirical level, but also by preclinical experiments performed with uterus strips and myometrium cell lines. Furthermore, a retrospective matched-pair study revealed good tolerability and effectiveness. In anthroposophic medicine, however, Bryophyllum species are used for a broad spectrum of diagnoses. Here, we characterize the prescribing pattern of Bryophyllum preparations in a network of anthroposophic physicians in Germany. Methods: 38 primary-care physicians in Germany participated in the EvaMed network, a multi-center observational study. They documented anonymized prescriptions, diagnoses and demographic data (age and gender) for each consecutive patient between 01.01.2004 and 01.01.2010. Diagnoses were coded according to the 10th revision of the International Classification of Diseases (ICD-10). In the present analysis, all prescriptions of any Bryophyllum preparation in the resulting data bank were identified and the corresponding diagnoses were analyzed retrospectively. Results: A total of 4,038 prescriptions of Bryophyllum preparations were identified in the EvaMed data bank. A variety of preparations could be found, 77.7% of which were prepared from Bryophyllum plants exclusively and 22.5% were combinations. Bryophyllum preparations were often prescribed to treat 'mental and behavioral disorders' (ICD-10 F00-F99, 35.7%) and 'diseases of the skin and subcutaneous tissue' (L00-L99, 16.0%), followed by 'symptoms, signs, and abnormal clinical and laboratory findings, not elsewhere classified diseases' (R00-R99, 15.2%) and 'diseases of the nervous system' (G00-G99, 9.7%). Conclusion: By revealing the use of Bryophyllum preparations in so many other indications than preterm delivery, our data clearly show the urgent need to conduct additional clinical trials. © 2012 S. Karger AG, Basel.


Giordano F.A.,German Cancer Research Center | Sorg U.R.,Heinrich Heine University Düsseldorf | Appelt J.-U.,German Cancer Research Center | Lachmann N.,Hannover Medical School | And 10 more authors.
Human Gene Therapy | Year: 2011

Gene transfer of mutant O6-methylguanine-DNA-methyltransferase (MGMTP140K) into hematopoietic stem cells (HSCs) protects hematopoiesis from alkylating agents and allows efficient in vivo selection of transduced HSCs. However, insertional mutagenesis, high regenerative stress associated with selection, and the genotoxic potential of alkylating drugs represent considerable risk factors for clinical applications of this approach. Therefore, we investigated the long-term effect of MGMTP140K gene transfer followed by repetitive, dose-intensive treatment with alkylating agents in a murine serial bone marrow transplant model and assessed clonality of hematopoiesis up to tertiary recipients. The substantial selection pressure resulted in almost completely transduced hematopoiesis in all cohorts. Ligation-mediated PCR and next-generation sequencing identified several repopulating clones carrying vector insertions in distinct genomic regions that were ∼9kb of size (common integration sites). Beside polyclonal reconstitution in the majority of the mice, we also detected monoclonal or oligoclonal repopulation patterns with HSC clones showing vector insertions in the Usp10 or Tubb3 gene. Interestingly, neither Usp10, Tubb3, nor any of the genes located in common integration sites have been linked to clonal expansion in previous preclinical or clinical gene therapy trials. However, a considerable number of these genes are involved in DNA damage response and cell fate decision pathways following cytostatic drug application. Thus, in summary, our study advocates ligation-mediated PCR and next generation sequencing as an effective and reliable method to identify gene products associated with clonal survival in specific experimental settings such as chemoselection using alkylating agents. © 2011 Mary Ann Liebert, Inc.


Benecke R.,University of Rostock | Heinze A.,Kiel Headache and Pain Center | Reichel G.,Paracelsus Hospital | Hefter H.,Heinrich Heine University Düsseldorf | Gobel H.,Kiel Headache and Pain Center
Pain Medicine | Year: 2011

Objective. This was a prospective, randomized, double-blind, placebo-controlled, 12-week, multicenter study to evaluate the efficacy and tolerability of fixed location injections of botulinum type A toxin (BoNT-A, Dysport) in predetermined injection sites in patients with myofascial pain syndrome of the upper back. Design. Patients with moderate-to-severe myofascial pain syndrome affecting cervical and/or shoulder muscles (10 trigger points, disease duration 6-24 months) and moderate-to-severe pain intensity were randomized to BoNT-A (N=81) or saline (N=72). Intervention. Patients received treatment into 10 predetermined fixed injection sites in the head, neck, and shoulder (40 units of BoNT-A per site or saline, a total of 400 units of BoNT-A). Outcome Measures. The primary efficacy outcome was the proportion of patients with mild or no pain at week 5 (responders). Secondary outcomes included changes in pain intensity and the number of pain-free days per week. Results. At week 5, 49% (37/76) of BoNT-A patients and 38% (27/72) of placebo patients had responded to treatment (P=0.1873). Duration of daily pain was reduced in the BoNT-A group compared with the placebo group from week 5, with statistically significant differences at weeks 9 and 10 (P=0.04 for both). Treatment was well tolerated. Conclusion. Fixed-location treatment with BoNT-A of patients with upper back myofascial pain syndrome did not lead to a significant improvement of the main target parameter in week 5 after treatment. Only in week 8 were significant differences found. Several secondary parameters, such as physicians' global assessment and patients' global assessment, significantly favored BoNT-A over placebo at weeks 8 and 12. Wiley Periodicals, Inc.


Hass H.G.,Paracelsus Hospital | Vogel U.,University of Tübingen | Scheurlen M.,University of Würzburg | Jobst J.,Matrigene GmbH
Anticancer Research | Year: 2016

Background. Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation. Materials and Methods: DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples. Results: Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADPribosylation factor-like 2 (ARL2)] and extracellular matrix remodelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, Gproteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis. Conclusion: It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.


PubMed | University of Tübingen, Paracelsus Hospital, University of Würzburg and Matrigene GmbH
Type: Journal Article | Journal: Anticancer research | Year: 2016

Hepatocellular carcinoma comprises of a group of heterogeneous tumors of different etiologies. The multistep process of liver carcinogenesis involves various genetic and phenotypic alterations. The molecular pathways and driver mutations involved are still under investigation.DNA micorarray technology was used to identify differentially expressed genes between human hepatocarcinoma and non-tumorous liver tissues to establish a unique specific gene-expression profile independent of the underlying liver disease. The validity of this global gene-expression profile was tested for its robustness against biopsies from other liver entities (cirrhotic and non-cirrhotic liver) by diagnosing HCC in blinded samples.Most of the consistently and strongly overexpressed genes were related to cell-cycle regulation and DNA replication [27 genes, e.g. cyclin B1, karyopherin alpha 2 (KPNA2), cyclin-dependent kinase 2 (CDC2)], G-protein depending signaling [e.g. Rac GTPase activating protein 1 (RACGAP1), Rab GTPase YPT1 homolog (RAB1), and ADP-ribosylation factor-like 2 (ARL2)] and extracellular matrix re-modelling or cytoskeleton structure [22 genes, e.g. serine proteinase inhibitor 1 kazal-type (SPINK1), osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), collagen type 1 alpha2 (COL1A2), integrin alpha6 (ITGA6), and metalloproteinase 12 (MMP12)]. Furthermore, significantly differentially expressed genes (e.g. calcium-binding proteins, G-proteins, oncofetal proteins) in relation to tumor differentiation were detected using gene-expression analysis.It is suggested that these significantly dysregulated genes are highly specific and potentially utilizable as prognostic markers and may lead to a better understanding of human hepatocarcinogenesis.


PubMed | University of Tübingen, Paracelsus Hospital, University of Würzburg and Praxis of Gastroenterology and Tumor Medicine
Type: Journal Article | Journal: Anticancer research | Year: 2015

The poor prognosis of hepatocellular carcinoma (HCC) and the lack of specific screening markers underline the need for new biomarkers for human hepatocarcinogenesis.We investigated 10 postulated biomarkers for HCC (AFP, GPC3, OPN, IGF1, HGF, SPINK1, KPNA, FUCA1, CgA, HSP90) with microarray gene expression analysis and real-time polymerase chain reaction (RT-PCR) in HCC tissues of different etiologies.Four candidate genes (FUCA1, HGF, IGF1, CgA) showed low median fold changes (fc) of expression compared to corresponding non-malignant liver tissues (fc range=0.2-0.8; maximum 15% of samples). The classic biomarker, alpha-fetoprotein (AFP), was significantly over-expressed (fc=2.4) in 30% of tumors. High tumor AFP expression was associated with significantly elevated serum AFP concentrations (>90% of cases). Five genes (OPN, SPINK1, GPC3, HSP90, KNPA2) showed significantly higher expression than AFP in 64% to 82% of samples (median fc range=2.9-8.3). RT-PCR analyses gave similar results.Unlike previous studies, our results did not confirm FUCA1, HGF, IGF1 or CgA as potential markers for HCC. In contrast, OPN, SPINK1, GPC3 and KNPA2 were significantly over-expressed in HCC tissues. These genes may be useful in developing future biomarkers and therapeutic strategies for HCC.


Duschek S.,Ludwig Maximilians University of Munich | Hellmann N.,Ludwig Maximilians University of Munich | Merzoug K.,Paracelsus Hospital | Reyes del Paso G.A.,University of Jaén | Werner N.S.,Ludwig Maximilians University of Munich
Pain Medicine | Year: 2012

Objective. Functional transcranial Doppler sonography (fTCD) enables reliable quantification of cerebral blood flow modulation during neural activation processes. Its high-time resolution, relatively simple technical arrangement, and low costs could make fTCD a useful tool in the investigation of brain activity underlying pain experience in fundamental and clinical research. The present pilot study explored the suitability of this technique to investigate cerebral hemodynamics during the processing of experimental heat pain. Design. In 46 healthy subjects, blood flow velocities in the anterior cerebral arteries (ACA) and middle cerebral arteries (MCA) of both hemispheres were recorded, while heat stimuli of 45 and 47°C were applied to their left forearms (stimulus duration 20seconds). Subjective sensory and affective pain intensities were assessed using visual analog scales. Results. A biphasic right dominant blood flow increase arose in the ACA and MCA with maxima around 5 and 15seconds after stimulus onset. The response was stronger under stimulation with 47°C with respect to 45°C, and the magnitude of the late response component correlated positively with sensory and affective pain intensity under the 45°C condition. Conclusions. The findings suggest that fTCD measurements prove sensitive both to different levels of physical intensity of painful stimuli and to interindividual differences in nociceptive responding. fTCD may be a valuable tool in clinical pain research, for instance, when it comes to quantifying the temporal dynamics of exaggerated nociceptive responses in chronic pain, or evaluating treatment effects on nociceptive processing. © 2012.


Fleischer M.,University of Leipzig | Kessler R.,University of Leipzig | Klammer A.,Paracelsus Hospital | Warnke J.-P.,Paracelsus Hospital | Eschrich K.,University of Leipzig
Genes Chromosomes and Cancer | Year: 2011

Loss of heterozygosity (LOH) on chromosome arm 10p is very common in high-grade gliomas and is, among others, concentrated on the region 10p14-p15. Presence of multiple tumor suppressor genes is assumed, but until now only Krüpple-like transcription factor 6 (KLF6) has been suggested as possible target of LOH in this region. On the basis of the fact that the splice variant 4 (UBI2K4) of the PFKFB3 gene, located in 10p15.1, inhibits the anchorage-independent growth of U87 glioblastoma cells, we hypothesized that PFKFB3 is a target gene of LOH in glioblastomas. In this study, we analyzed 40 glioblastomas for LOH in 10p15, including the PFKFB3 and KLF6 loci, by PCR-based microsatellite analysis. We detected LOH of PFKFB3 in 55% (22/40) of glioblastomas. LOH of KLF6, mapped 2.5 cM telomerically to the PFKFB3 locus, was not stringently correlated to the PFKFB3 LOH. The allelic deletion of PFKFB3 resulted in a decrease of PFKFB3 mRNA level accompanied by a lower PFKFB3 protein level. The expression of growth-inhibiting splice variant UBI2K4 was effectively reduced in glioblastomas with PFKFB3 LOH and a positive correlation with overall PFKFFB3 expression was observed. The PFKFB3 LOH as well as the resulting low UBI2K4 expression level was associated with a poor prognosis of glioblastoma patients. We conclude that LOH on 10p14-p15 in glioblastomas targets PFKFB3 and in particular splice variant UBI2K4, a putative tumor suppressor protein in glioblastomas. © 2011 Wiley-Liss, Inc.


PubMed | Paracelsus Hospital and University of Munster
Type: Journal Article | Journal: Journal of orthopaedic surgery and research | Year: 2016

Two-stage revision (TSR) knee arthroplasty is an established treatment, but failure to control infection still occurs in 4-50% of cases. The aim of this study was to assess the infection eradication rate, risk factors for failure, and the clinical outcome after two-stage revision knee arthroplasty.This retrospective study included 59 patients who had undergone at least one two-stage revision procedure due to periprosthetic joint infection (PJI). Demographic data, comorbidities, types of implant, and complications were analyzed. Univariate and multivariate logistic regression analysis were used to identify risk factors for failure.The infections were controlled in 55 patients (93.2%). The follow-up period was 4.1 (2.7) years. Infection control was achieved after the first TSR in 42 patients (71.2%) and after the second TSR in 13 (76.5%). The percentage of arthrodesis procedures in patients with infection control increased from 16.75% after one TSR to 69.2% after two TSRs. Multivariate logistic regression analysis identified body mass index (BMI) (odds ratio 1.22; 95% confidence intervals, 1.07 to 1.40; p=0.004) and smoking (OR 21.52; 95% CI, 2.60 to 178.19; p=0.004) as risk factors for failure.Two-stage revision protocols can achieve acceptable results even after a second procedure. It is still unclear whether the choice of implant influences failure rates. Risk factors for failure after two-stage revision were identified. Studies with larger sample sizes are needed in order to support these findings and identify further risk factors. To reduce failure rates, programs should be established to treat or minimize risk factors in patients with PJI.

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