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  • 1
    Keywords: RISK ; EXPOSURE ; human ; MODEL ; MODELS ; STATISTICAL-ANALYSIS ; UNCERTAINTIES ; prevalidation study ; toxicokinetic ; TCDD ; UNCERTAINTY ; RISK ASSESSMENT
    Type of Publication: Book chapter
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  • 2
    Keywords: GENE-EXPRESSION ; INFORMATION ; PHASE-I ; gene expression ; DESIGN ; TRIAL ; PHASE ; SIGNATURE ; ONCOLOGY
    Type of Publication: Book chapter
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  • 3
    Keywords: Germany ; MODEL ; HYBRIDIZATION ; PATIENT ; prognosis ; chromosome ; DELETION ; IN-SITU ; COMPARATIVE GENOMIC HYBRIDIZATION ; NUMBER ; ABERRATIONS ; IN-SITU HYBRIDIZATION ; MUTATIONS ; PROBES ; EVOLUTION ; ABNORMALITIES ; FLUORESCENCE ; POOR-PROGNOSIS ; GLOBAL GENE-EXPRESSION ; MULTIPLE-MYELOMA ; CLUSTER ; CHROMOSOMES ; in situ hybridization ; multiple myeloma ; IV ; TREE MODELS ; cytogenetic ; cluster analysis ; EVENTS ; 11Q23 ; 14Q32 TRANSLOCATIONS ; 19Q ; CHROMOSOME-13 ; DOSE CHEMOTHERAPY ; HYPODIPLOIDY ; IgH rearrangement ; REARRANGEMENTS
    Abstract: To delineate multiple myeloma (MM) subgroups and their clonal evolution, we analyzed 81 newly diagnosed patients by interphase fluorescence in situ hybridization using a comprehensive probe set for 10 chromosomes and two IGH rearrangements. A median of 5 probes per patient displayed aberrant signal numbers (range, 1-10). Additional copies most frequently found were for 15q22, 19q13, 9q34, 11q23, and 1q21. Losses commonly observed were of 13q 14.3, 17p 13, and 22q 11. Predominance of gain or loss was quantified by a copy number score (CS) for each patient. Two peaks (CS = +3 and CS = 0) were found by plotting patient copy number scores over CS values corresponding to hyperdiploid and nonhyperdiploid MM. Cluster analysis revealed four major branches: (i) gain of 9q, 15q, 19q, and/or 11q; (ii) deletion of 13q and t(4; 14); (iii) t(11; 14); and (iv) gain of 1q. Statistical modeling of an oncogenetic tree indicated that early independent events were gain of 15q/9q and/or 11q, t(11; 14); deletion of 13q followed by t(4; 14); and gain of 1q. Aberrations of 17p13, 22q11, 8p12, and 6q21 were found as subsequent events. MM with gain of I q was delineated as a subentity with significantly higher beta-2-microglobulin and lower hemoglobin levels, indicating a poor prognosis. From our results, we propose a model of MM for clonal evolution. (c) 2005 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 16001433
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  • 4
    Keywords: EXPRESSION ; GROWTH ; GROWTH-FACTOR ; Germany ; SYSTEM ; HEPATOCELLULAR-CARCINOMA ; liver ; RISK ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; COMPLEX ; RESPONSES ; COMPLEXES ; IMMUNE-RESPONSES ; INDUCED APOPTOSIS ; REPRODUCIBILITY ; vimentin ; IMMUNE-RESPONSE ; TCDD ; sensitivity ; FLUORESCENCE ; CELL-MIGRATION ; lamin ; PROTEOMICS ; ACTIN CYTOSKELETON ; HEAT-SHOCK PROTEINS ; GEL-ELECTROPHORESIS ; SINGLE ; thymus ; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ; MOUSE-LIVER ; IMMUNE-SYSTEM ; biomarker ; SIGNATURE ; CHAPERONE ; 2-DE ; CALLITHRIX-JACCHUS ; LAMIN-A ; marmoset ; MOLECULAR CHAPERONES
    Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an ubiquitously distributed environmental pollutant. Health effects have been studied intensively, but low-dose effects are quite complex and not yet fully understood. In many studies. the immune system was identified as the most sensitive target. Here, we demonstrate changes of protein expression in liver and thymus of male marmosets (Callithrix jacchus) which were subjected to a single dose of a subcutaneous injection of 100 ng/kg body weight TCDD. Histopathological examination revealed myocardial fibrosis. but there, were no significant findings in pathology and histopathology of liver and thymus. In order to detect more subtle treatment-related changes, we performed a comparative proteomic investigation of liver and thymus using a 2-D gel electrophoresis based proteomics approach. Fluorescence labeling and automated image analysis was used to enhance sensitivity and reproducibility. In both organs, distinct changes of protein expression were detected which were more pronounced in thymus. where the pattern of deregulated proteins could be clearly related to immune responses. In the thymus of treated animals. several toxicologically relevant factors were increased, including chaperones, glycerol-3-phosphate dehydrogenase.. and adseverin. Among others, vimentin, Ca-dependent protease and protein disulfide isomerase were downregulated. In the liver, transferrins, lamin A and HSP70 were upregulated, whereas thymidine phosphorylase (synonyms: endothelial cell growth factor, PD-ECGF, gliostatin) was significantly reduced. Comparative analysis
    Type of Publication: Journal article published
    PubMed ID: 15590107
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  • 5
    Keywords: EXPRESSION ; proliferation ; Germany ; liver ; GENE ; microarray ; PROTEIN ; PROTEINS ; MICE ; DNA ; hepatocytes ; TRANSGENIC MICE ; hepatocarcinogenesis ; MUTATION ; JUNCTIONS ; E-cadherin ; INCREASE ; secretion ; MICE LACKING ; gene targeting ; MOUSE-LIVER ; gap junctions ; function ; DEFICIENT ; Connexin32 ; CHANNELS ; ACTIN ; JUNCTION ; SUBUNIT PROTEIN ; connexin26 ; CONNEXIN32-DEFICIENT MICE
    Abstract: Gap junctions between murine hepatocytes are composed of two subunit proteins, connexin26 (Cx26) and connexin32 (Cx32). Previously, we found increased formation of chemically induced liver tumours but no increase in spontaneous development of preneoplastic hepatic foci in mice that lacked Cx32 and expressed decreased amounts of Cx26. In order to clarify this tumour-suppressive effect and to overcome embryonic lethality of constitutive Cx26-deficient mice, cell type-specific targeting of the Cx26 gene was performed. Mice with loxP-flanked Cx26 coding DNA were crossed with mice expressing the Cre recombinase exclusively in hepatocytes. Progeny mice lacking Cx26 in the liver were viable and fertile with no obvious signs of phenotypic alterations. To generate mice that totally lack gap junctional intercellular coupling, these mice were crossed with constitutive Cx32-deficient mice. We found no increase in spontaneously induced liver tumour formation in Cx26 and double deficient Cx26/Cx32 mice. Occasionally, double deficient livers exhibited morphological alterations, like amyloidosis, and a slightly increased basal proliferation rate of hepatocytes. Although the absence of gap junction channels led to altered expression of adhesion-related proteins like E-cadherin and actin, microarray analyses of total liver transcripts yielded only few differences between Cx26-deficient and double deficient livers compared to control samples. Our results suggest that total lack of gap junctional communication due to hepatocytic ablation of Cx26 and Cx32 does not drastically alter basal hepatocytic function and does not lead to increased spontaneous liver tumour formation. (c) 2006 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16740338
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  • 6
    Keywords: BLOOD ; Germany ; MODEL ; PERFUSION ; DIAGNOSIS ; IMAGES ; QUANTIFICATION ; VOLUME ; PATIENT ; BLOOD-FLOW ; blood flow ; FLOW ; MR ; MRI ; SIGNAL ; magnetic resonance imaging ; AGE ; WOMEN ; MEN ; MUSCLE ; PARAMETERS ; SKELETAL-MUSCLE ; ULTRASONOGRAPHY ; KINETICS ; sensitivity ; specificity ; BIOPSY ; ultrasound ; INCREASE ; replenishment kinetics ; analysis ; methods ; MYOPATHY ; muscle perfusion ; replenishment kinetics of microbubbles ; Sensitivity and Specificity ; EVALUATE ; UNIT ; myopathies ; MR-IMAGES ; contrast-enhanced ultrasound ; BIOPSIES ; DERMATOMYOSITIS ; INFLAMMATORY MYOPATHIES ; POLYMYOSITIS ; MYOSITIS ; SKELETAL-MUSCLE PERFUSION
    Abstract: Objective To evaluate prospectively contrast-enhanced ultrasound (CEUS) in patients suspected of having dermatomyositis or polymyositis. Methods In 35 patients (23 women, 12 men; mean age, 51 years +/- 16 years) who were suspected of having dermatomyositis or polymyositis, perfusion in clinically affected skeletal muscles was quantified with contrast-enhanced intermittent power Doppler ultrasound. By applying a modified model that analyzed the replenishment kinetics of microbubbles, the perfusion-related parameters blood flow, local blood volume and blood flow velocity were measured. Findings were compared with muscle biopsy appearances and with the results of MRI that was performed with a 1.5-Tesla unit. Receiver operating characteristic analysis was performed and optimum thresholds for diagnosis of myositis were determined. Results Eleven patients had histologically confirmed dermatomyositis or polymyositis and showed significantly higher blood flow velocity (P = .01 for dermato- and P 〈 .001 for polymyositis), blood flow (P 〈 .001 for dermato- and polymyositis), and blood volume (P = .007 for dermato- and P 〈 .001 for polymyositis) on contrast-enhanced ultrasound than those who did not have myositis. An increase in signal intensity on T2-weighted MR images was found in all patients with myositis. MRI had a sensitivity, specificity, positive (PPV), and negative predicting values (NPV) of 100%, 88%, 77%, and 100% for diagnosis of myositis, respectively. CEUS blood flow was the best ultrasound measure for diagnosis of dermato- or polymyositis with sensitivity, specificity, PPV, and NPV of 73%, 91%, 80%, and 88%, respectively. Conclusions Increased skeletal muscle perfusion measured by CEUS could serve as an additional measurer for the diagnosis of an inflammatory myopathy
    Type of Publication: Journal article published
    PubMed ID: 17219033
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  • 7
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; GENE ; GENE-EXPRESSION ; gene expression ; MONONUCLEAR-CELLS ; cord blood ; ADULT ; PROFILES ; EXPRESSION PROFILES ; lipopolysaccharide ; PROFILE ; expression profile
    Type of Publication: Journal article published
    PubMed ID: 17700033
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  • 8
    Keywords: SURVIVAL ; Germany ; MODEL ; MODELS ; INFORMATION ; RISK ; GENE ; microarray ; prognosis ; BIOLOGY ; ASSOCIATION ; VARIANTS ; BREAST-CANCER ; MICROARRAY DATA ; NUMBER ; REQUIRES ; PREDICTION ; REGRESSION ; VARIANT ; model selection ; development ; survival analysis ; GENE-EXPRESSION SIGNATURE ; SURVIVAL PREDICTION ; ADAPTIVE LASSO ; High dimensions ; NONCONCAVE PENALIZED LIKELIHOOD ; ORACLE PROPERTIES ; Penalized proportional hazards ; Predictive accuracy ; PROBABILITIES ; PROPORTIONAL HAZARDS MODEL ; VARIABLE SELECTION
    Abstract: The Cox proportional hazards regression model is the most popular approach to model covariate information for survival times. In this context, the development of high-dimensional models where the number of covariates is much larger than the number of observations (p 〉〉 n) is an ongoing challenge. A practicable approach is to use ridge penalized Cox regression in such situations. Beside focussing on finding the best prediction rule, one is often interested in determining a subset of covariates that are the most important ones for prognosis. This could be a gene set in the biostatistical analysis of microarray data. Covariate selection can then, for example, be done by L-1-penalized Cox regression using the lasso (Tibshirani (1997). Statistics in Medicine 16, 385-395). Several approaches beyond the lasso, that incorporate covariate selection, have been developed in recent years. This includes modifications of the lasso as well as nonconvex variants such as smoothly clipped absolute deviation (SCAD) (Fan and Li (2001). Journal of the American Statistical Association 96, 1348-1360; Fan and Li (2002). The Annals of Statistics 30, 74-99). The purpose of this article is to implement them practically into the model building process when analyzing high-dimensional data with the Cox proportional hazards model. To evaluate penalized regression models beyond the lasso, we included SCAD variants and the adaptive lasso (Zou (2006). Journal of the American Statistical Association 101, 1418-1429). We compare them with "standard" applications such as ridge regression, the lasso, and the elastic net. Predictive accuracy, features of variable selection, and estimation bias will be studied to assess the practical use of these methods. We observed that the performance of SCAD and adaptive lasso is highly dependent on nontrivial preselection procedures. A practical solution to this problem does not yet exist. Since there is high risk of missing relevant covariates when using SCAD or adaptive lasso applied after an inappropriate initial selection step, we recommend to stay with lasso or the elastic net in actual data applications. But with respect to the promising results for truly sparse models, we see some advantage of SCAD and adaptive lasso, if better preselection procedures would be available. This requires further methodological research
    Type of Publication: Journal article published
    PubMed ID: 20166132
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  • 9
    Abstract: A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor beta Receptor I (TGF-betaR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-beta biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.
    Type of Publication: Journal article published
    PubMed ID: 21170314
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  • 10
    Keywords: IN-VITRO ; PROTECTION ; Germany ; human ; IN-VIVO ; MODEL ; MODELS ; TOXICITY ; VITRO ; VIVO ; RISK ; validation ; EQUIVALENT ; ASSAY ; RATES ; PROGNOSTIC FACTORS ; SAFETY ; PREDICTION ; RISK ASSESSMENT ; UNCERTAINTY ; biostatistics ; COSMETIC INGREDIENTS ; DIAGNOSTIC-TESTS ; EYE IRRITATION TESTS ; in vitro tests ; INTERLABORATORY VALIDATION ; OPERATING CHARACTERISTIC CURVES ; OPTIMAL CUTPOINTS ; OUTCOMES ; PREDICTIVE MODEL ; REGRESSION METHODOLOGY ; ROC ; ROC CURVES ; SELECTION ; sensitivity ; SHORT-TERM TESTS ; specificity ; toxicity testing ; VALIDITY
    Abstract: Statistical methods for the validation of toxicological in vitro test assays are developed and applied. Validation is performed either in comparison with in vivo assays or in comparison with other in vitro assays of established validity. Biostatistical methods are presented which are of potential use and benefit for the validation of alternative methods for the risk assessment of chemicals, providing at least an equivalent level of protection through in vitro toxicity testing to that obtained through the use of current in vivo methods. Characteristic indices are developed and determined. Qualitative outcomes are characterised by the rates of false-positive and false-negative predictions, sensitivity and specificity, and predictive values. Quantitative outcomes are characterised by regression coefficients derived from predictive models. The receiver operating characteristics (ROC) technique, applicable when a continuum of cut-off values is considered, is discussed in detail, in relation to its use for statistical modelling and statistical inference. The methods presented are examined for their use for the proof of safety and for toxicity detection and testing. We emphasise that the final validation of toxicity testing is human toxicity, and that the in vivo test itself is only a predictor with an inherent uncertainty. Therefore, the validation of the in vitro test has to account for the vagueness and uncertainty of the "gold standard" in vivo test. We address model selection and model validation, and a four-step scheme is proposed for the conduct of validation studies. Gaps and research needs are formulated to improve the validation of alternative methods for in vitro toxicity testing
    Type of Publication: Journal article published
    PubMed ID: 15595899
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