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Featured researches published by Cornelius Knabbe.


Analytical and Bioanalytical Chemistry | 2009

Current applications and future trends of molecular diagnostics in clinical bacteriology

Jan Weile; Cornelius Knabbe

Molecular diagnostics of infectious diseases, in particular, nucleic-acid-based methods, are the fastest growing field in clinical laboratory diagnostics. These applications are stepwise replacing or complementing culture-based, biochemical, and immunological assays in microbiology laboratories. The first-generation nucleic acid assays were monoparametric such as conventional tests, determining only a single parameter. Improvements and new approaches in technology now open the possibility for the development of multiparameter assays using microarrays, multiplex nucleic acid amplification techniques, or mass spectrometry, while the introduction of closed-tube systems has resulted in rapid microbial diagnostics with a subsequently reduced contamination risk. Whereas the first assays were focused on the detection and identification of microbial pathogens, these new technologies paved the way for the parallel determination of multiple antibiotic resistance determinants or to perform microbial epidemiology and surveillance on a genetic level.


Journal of Clinical Microbiology | 2004

Use of DNA Microarrays for Rapid Genotyping of TEM Beta-Lactamases That Confer Resistance

Verena Grimm; Satoshi Ezaki; Milorad Susa; Cornelius Knabbe; Rolf D. Schmid; Till T. Bachmann

ABSTRACT Standard clinical procedures for pathogen resistance identification are laborious and usually require 2 days of cultivation before the resistance can be determined unequivocally. In contrast, clinicians and patients face increasing threats from antibiotic-resistant pathogenic bacteria in terms of their frequencies and levels of resistance. A major class of microbial resistance stems from the occurrence of beta-lactamases, which, if mutated, can cause the severe extended-spectrum beta-lactamase (ESBL) or inhibitor-resistant TEM (IRT) phenotype, which cause resistance to extended-spectrum cephalosporins, monobactams, and beta-lactamase inhibitors. We describe an oligonucleotide microarray for identification of the single nucleotide polymorphisms (SNPs) of 96% of the TEM beta-lactamase variants described to date which are related to the ESBL and/or IRT phenotype. The target DNA, originating from Escherichia coli, Enterobacter cloacae, and Klebsiella pneumoniae cells isolated from clinical samples, was amplified and fluorescently labeled by PCR with consensus primers in the presence of cyanine 5-labeled nucleotides. The total assay, including PCR, hybridization, and image analysis, could be performed in 3.5 h. The microarray results were validated by standard clinical procedures. The microarray outperformed the standard procedures in terms of assay time and the depth of information provided. In conclusion, this array offers an attractive option for the identification and epidemiologic monitoring of TEM beta-lactamases in the routine clinical diagnostic laboratory.


Annals of the New York Academy of Sciences | 2006

TGF-Beta Signaling in Breast Cancer

Miriam Buck; Cornelius Knabbe

Abstract:u2002 The antiestrogen tamoxifen is one of the most successful drugs in the endocrine treatment of breast cancer and significantly reduces the risk of recurrence and death. Antiestrogens act by inhibiting the production of growth‐stimulatory factors as well as by activating peptides with growth‐inhibitory effects like transforming growth factor‐ beta (TGF‐β). In hormone‐responsive breast cancer cells treatment with antiestrogens leads to the conversion of TGF‐β1 into a biologically active form. Expression of TGF‐β2 and TGF‐β receptor (TβR) II is induced via a transcriptional mechanism involving p38 MAP kinase. Inhibition of p38 abolishes antiestrogen‐dependent growth inhibition. However, the role of TGF‐β in breast cancer progression is ambiguous, as it was shown to display both tumor‐suppressing and ‐enhancing effects. A polymorphism in the promoter of TGF‐β2 that enhances expression of the protein was associated with lymph node metastasis in breast cancer patients, pointing to a role of TGF‐β2 in the process of invasion. An immunohistochemical study on TβRI and TβRII expression in breast cancer tissues indicates that the estrogen receptor (ER) status of a tumor is an important marker and a potential mediator of the transition of TGF‐β from tumor suppressor to tumor promoter. In ER‐negative tumors, expression of TβRII was associated with a subset of tumors that appeared to be highly aggressive, leading to strongly reduced overall survival times. Further characterization of the influence of ER expression on TGF‐β signal transduction shows that ER‐α plays a crucial role in TGF‐β signaling.


Clinical Cancer Research | 2004

Prognostic Significance of Transforming Growth Factor β Receptor II in Estrogen Receptor-Negative Breast Cancer Patients

Miriam B. Buck; Peter Fritz; Juergen Dippon; Gerhard Zugmaier; Cornelius Knabbe

Purpose: The role of transforming growth factor β (TGF-β) in breast cancer is ambiguous; it can display both tumor suppressing and enhancing effects. Activation of the TGF-β signal transduction system is subject to hormonal regulation. This study was conducted to further analyze the role of TGF-β receptors in breast cancer and to evaluate their significance as prognostic markers. Experimental Design: Expression of TGF-β receptor I (TβRI) and TGFβ receptor II (TβRII) was retrospectively analyzed by immunohistochemistry in 246 breast cancer patients. Results: Expression of TβRI was strongly correlated with tumor size (P < 0.001) and nodal status (P = 0.012) but only weakly with overall survival (P = 0.056). In contrast, TβRII was prognostic for overall survival in univariate analysis (P = 0.0370). In estrogen receptor (ER) -negative patients TβRII expression was correlated with highly reduced overall survival (P = 0.0083). In multivariate analysis TβRII proved to be an independent and highly significant prognostic marker with a hazard ratio of 6.8. Simultaneous loss of both ER and TβRII was associated with longer overall survival times comparable with those of ER-positive patients. Conclusions: The results of this exploratory study show that TβRII is an independent, highly significant prognostic indicator for overall survival in ER-negative patients. In addition our results are supportive of a mechanism of breast cancer progression in which a selective loss of the tumor inhibitory action of TGFβ takes place, whereas tumor- promoting aspects remain intact.


Cellular Physiology and Biochemistry | 2002

Excessive Transcription of the Human Serum and Glucocorticoid Dependent Kinase hSGK1 in Lung Fibrosis

Simone Waerntges; Karin Klingel; Cora Weigert; Sophie Fillon; Miriam B. Buck; Erwin Schleicher; Hans-Peter Rodemann; Cornelius Knabbe; Reinhard Kandolf; Florian Lang

The excessive matrix deposition in lung fibrosis is thought to be due to enhanced formation and activity of TGFβ1, which stimulates synthesis and inhibits degradation of matrix proteins. The cellular mechanisms triggered by TGFβ1 are still incompletely understood. Recently, a novel transcriptional target of TGFβ1 has been identified, i.e. the human serum and glucocorticoid dependent kinase hSGK1. The present study has been performed to explore whether TGFβ1 stimulates hSGK1 transcription in lung fibroblasts and whether lung fibrosis is associated with enhanced hSGK1 expression. As evident from Northern Blotting, TGFβ1 strongly upregulates hSGK1 in human lung fibroblasts, an effect partially reversed by p38-kinase inhibitor SB203580. In situ hybridization experiments reveal that in intact lung tissue hSGK1 is expressed in single type II alveolar pneumocytes and macrophages. In contrast, in fibrotic lung tissue a dramatic upregulation of hSGK1 mRNA as well as a strong expression of hSGK1 protein is observed in epithelial cells and interstitial cells comprising macrophages and fibroblasts. In conclusion, in lung fibrosis, the serine/threonine kinase hSGK1 is upregulated, an effect at least partially accounted for by TGFβ1. The full effect of TGFβ1 requires the activation of p38 kinase.


Journal of Clinical Microbiology | 2004

Development and Validation of a Diagnostic DNA Microarray To Detect Quinolone-Resistant Escherichia coli among Clinical Isolates

Xiaolei Yu; Milorad Susa; Cornelius Knabbe; Rolf D. Schmid; Till T. Bachmann

ABSTRACT The incidence of resistance against fluoroquinolones among pathogenic bacteria has been increasing in accordance with the worldwide use of this drug. Escherichia coli is one of the most relevant species for quinolone resistance. In this study, a diagnostic microarray for single-base-mutation detection was developed, which can readily identify the most prevalent E. coli genotypes leading to quinolone resistance. Based on genomic sequence analysis using public databases and our own DNA sequencing results, two amino acid positions (83 and 87) on the A subunit of the DNA gyrase, encoded by the gyrA gene, have been identified as mutation hot spots and were selected for DNA microarray detection. Oligonucleotide probes directed against these two positions were designed so that they could cover the most important resistance-causing and silent mutations. The performance of the array was validated with 30 clinical isolates of E. coli from four different hospitals in Germany. The microarray results were confirmed by standard DNA sequencing and were in full agreement with phenotypic antimicrobial susceptibility testing.


AIDS | 2002

Human herpesvirus 8-derived viral Il-6 induces Ptx3 expression in Kaposi's sarcoma cells

Mariam Klouche; Norbert H. Brockmeyer; Cornelius Knabbe; Stefan Rose-John

Objective To analyse if human herpesvirus 8 (HHV8)-derived viral interleukin-6 (vIL-6) has the capacity to activate Kaposis sarcoma (KS) cells to elicit a local acute-phase response. Design Proinflammatory activation of KS cells was compared using vIL-6, human IL-6, as well as the complex of human IL-6 with the soluble IL-6 receptor, and expression of the novel acute-phase protein pentraxin-3 (PTX3) was analysed. Methods We established primary KS cell cultures from patients with AIDS-associated and classical KS and expressed recombinant HHV8-derived vIL-6 in COS-7 cells. Expression of PTX3 by vIL-6-stimulated KS cell cultures was analysed by quantitative real-time reverse transcriptase–polymerase chain reaction. Mitogenic effects of vIL-6 on the KS cells of distinct aetiology were compared by [3H]thymidine incorporation. Results We show that vIL-6 induced a marked and sustained expression of the novel acute-phase protein PTX3 in human primary KS cell cultures. vIL-6 directly activated KS cells, which uniquely expressed gp130, the signal-transducing subunit of the IL-6 receptor, but were negative for the IL-6-binding unit (IL-6R). In contrast, human IL-6 did not stimulate KS cells in the absence of the full IL-6R. Expression of PTX3 messenger RNA increased by more than 25-fold in vIL-6-stimulated KS cells after 24 h. Particularly after extended incubation with the virokine, vIL-6 mediated a pronounced mitogenic effect on KS cells. Conclusion The induction of an extrahepatic acute-phase response by vIL-6-activated KS cells may contribute to local tissue damage and the attraction of inflammatory cells, and add to a more aggressive phenotype.


BMC Cancer | 2006

Smad4-expression is decreased in breast cancer tissues: a retrospective study

Christina Stuelten; Miriam B. Buck; Juergen Dippon; Anita B. Roberts; Peter Fritz; Cornelius Knabbe

BackgroundAlthough transforming growth factor β (TGF-β) typically inhibits proliferation of epithelial cells, consistent with a tumor suppressor activity, it paradoxically also exhibits pro-metastatic activity in the later stages of carcinogenesis. Since tumors often display altered TGF-β signaling, particularly involving the Smad-pathway, we investigated the role of Smad4-expression in breast cancer.MethodsSmad4 expression was investigated by immunohistochemistry in formalin-fixed, paraffin-embedded tissue from 197 samples of primary breast cancer obtained between 1986 and 1998. The prognostic value of Smad4-expression was analyzed.ResultsSmad4 expression was found to be reduced in lobular and ductal breast carcinoma as compared to surrounding uninvolved lobular and ductal breast epithelia (p < 0.001, n = 50). Smad4-expression correlated positively with expression of TGF-β-receptor I (p < 0.001, n = 197) and TGF-β-receptor II (p < 0.001, n = 197), but showed no significant correlation with tumor size, metastases, nodal status, histological grade, histological type, or estrogen receptor expression. While not achieving statistical significance, there was a trend towards longer survival times in patients with Smad4 negative tumors.ConclusionAccording to the suggested role of Smad4 as a tumor suppressor we observed that expression of Smad4 is lower in human breast cancer than in surrounding breast epithelium. However, we also observed a trend towards longer survival times in Smad4-negative patients, indicating the complex role of TGF-β signaling in tumor progression.


Journal of Clinical Virology | 2002

Two-round rapid-cycle RT-PCR in single closed capillaries increases the sensitivity of HCV RNA detection and avoids amplicon carry-over

Dieter Ratge; B Scheiblhuber; O Landt; J Berg; Cornelius Knabbe

BACKGROUNDnFor the detection of hepatitis C virus (HCV) specific nucleic acids the polymerase chain reaction (PCR) is widely used. Rapid-cycle PCR is performed in glass capillaries with the LightCycler instrument and allows PCR including product analysis to be performed within a closed system in about 1 h. Thus, rapid-cycle PCR appears especially suitable for routine diagnostic applications. However, the volume of the PCR vessel is restricted to about 20 microl, which may limit the sensitivity of the PCR. To increase its sensitivity two-round or nested primer PCR protocols have been developed. In rapid-cycle PCR first-round PCR products are usually collected from the capillaries by centrifugation, a procedure prone to cross-contamination.nnnOBJECTIVESnDevelopment of a two-round rapid-cycle reverse transcription-polymerase chain reaction (RT-PCR) in single closed LightCycler capillaries for the sensitive detection of HCV RNA in serum or plasma.nnnSTUDY DESIGNnA set of two pairs of nested primers was selected. The first-round RT-PCR reaction mixture was separated from the second-round PCR mixture by silicone oil. Reverse transcription followed by the first-round PCR was performed. Then, the second-round mixture was combined with first-round products by a centrifugation step followed by second round PCR during which fluorescence intensities were recorded and used for quantification.nnnRESULTSnTo establish the sensitivity of this novel assay a serial dilution of HCV reference standard was used. In plasma samples about 100 IU/ml HCV were consistently detected using the high pure viral RNA kit for nucleic acid purification. This detection limit was found to be about 20 fold increased compared with single-round RT-PCR and corresponded to 3.4 IU of HCV per capillary. Using a panel of HCV genotype standards the novel assay exhibited similar sensitivity for all HCV genotypes. The applicability for clinical routine testing was demonstrated by examining 156 clinical samples.nnnCONCLUSIONnTwo-round RT-PCR with the LightCycler instrument using a single closed capillary throughout the procedure was found ideally suited for rapid (100 min), accurate and sensitive molecular diagnosis of active HCV infections. Since the capillaries remained closed during the procedure carry-over contamination was precluded.


Journal of Clinical Microbiology | 2009

Severe Cytomegalovirus-Associated Esophagitis in an Immunocompetent Patient after Short-Term Steroid Therapy

Jan Weile; Benjamin Streeck; Johannes Muck; Gerd Krebs; Karl-Heinz Jakobus; Cornelius Knabbe; Friedhelm Weber

ABSTRACT A case of severe human cytomegalovirus esophagitis after short-term corticosteroid therapy in a patient with no other apparent cause of immunodeficiency, such as human immunodeficiency virus infection, neoplasia, or previous organ transplantation, is described herein. The cytomegalovirus esophagus infection was successfully treated with ganciclovir.

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Jan Weile

Ruhr University Bochum

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Jan Weile

Ruhr University Bochum

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