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  • 1
    Keywords: B ; SIGNATURES ; ORGANIZATION ; gene expression ; CLASSIFICATION ; EXPRESSION ; GENE ; GENE-EXPRESSION
    Type of Publication: Book chapter
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  • 2
    Abstract: Analysis of high-dimensional biomarker data is in general of exploratory nature and aims to discover or dissect subgroups of patients sharing a specific pattern of biomarker measurements. One major challenge is to extract the relevant markers from the extremely large pool of measured markers. Specific techniques such as grouping and ordering and dimension reduction allow to aggregate huge amounts of data into single meaningful graphics. These graphics can guide the direction of exploration during the analysis. We present graphical tools for unsupervised and supervised objectives based on gene expression data of multiple myeloma patients which are part of the MAQC-II project.
    Type of Publication: Book chapter
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  • 3
    Keywords: brain ; APOPTOSIS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; TYROSINE KINASE ; VITRO ; VIVO ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; RNA ; SURGERY ; LINES ; COMPLEX ; COMPLEXES ; MESSENGER-RNA ; INJECTION ; CELL-LINES ; SUPPRESSION ; TYROSINE KINASE INHIBITOR ; CANDIDATE GENE ; FORM ; TARGET ; gene expression ; resistance ; EFFICACY ; CELL-LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; PHENOTYPE ; POLYMERASE-CHAIN-REACTION ; sensitivity ; TARGETS ; cell lines ; STAT1 ; signaling ; ANNOTATION ; polymerase chain reaction ; CANDIDATE GENES ; EGFR ; KINASE INHIBITORS ; glioblastoma multiforme ; GLIOBLASTOMA-MULTIFORME ; ADULT-RAT ; USA ; KINASE INHIBITOR ; epidermal growth factor receptor ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; CANDIDATES ; POLYMERASE ; ASTROCYTES ; HUMAN GLIOMA-CELLS ; Genetic ; therapeutic ; THERAPEUTIC TARGET ; cellular response ; CELLULAR-RESPONSE ; TYROSINE ; Whole genome ; cRNA microarray ; erlotinib ; tyrosine kinase inhibition
    Abstract: Object. The authors have previously reported that erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on 9 human glioblastoma multiforme (GBM) cell lines in vitro and in vivo. These effects were independent of EGFR baseline expression levels, raising the possibility that more complex genetic properties form the Molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the present study was to determine candidate genes for mediating the cellular response of human GBMs to erlotinib. Methods. Complementary RNA obtained in cell lines selected to represent the sensitive, somewhat responsive, and resistant phenotypes were hybridized to CodeLink Human Whole Genome Bioarrays. Results. Expression analysis of 814 prospectively selected genes involved in major proliferation and apoptosis signaling pathways identified 19 genes whose expression significantly correlated with phenotype. Functional annotation analysis revealed that 2 genes (DUSP4 and STAT1) were significantly associated with sensitivity to erlotinib, and 10 genes (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, and TGFB3) were associated with resistance to erlotinib. Moreover, 5 genes (BDNF, CARD6, FOSL1, HSPA9B, and MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity. Gene expressions were confirmed by quantitative polymerase chain reaction. Conclusions. Based on an analysis of gene expressions in cell lines with sensitive, somewhat responsive, and resistant phenotypes, the authors propose candidate genes for GBM response to erlotinib. The 10 gene candidates for conferring GBM resistance to erlotinib may represent therapeutic targets for enhancing the efficacy of erlotinib against GBMs. Five additional genes warrant further investigation into their role as putative cotargets of erlotinib. (DOI: 10.3171/2008.9.JNS08551)
    Type of Publication: Journal article published
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  • 4
    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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  • 5
    Abstract: PURPOSE: With whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinal MRI have been of prognostic significance in symptomatic multiple myeloma (sMM). In this study, we investigated the prognostic significance of FLs in wb-MRI in patients with asymptomatic multiple myeloma (aMM). PATIENTS AND METHODS: Wb-MRI was performed in 149 patients with aMM. The prognostic significance of the presence and absence, as well as the number, of FLs for progression into sMM was analyzed. RESULTS: FLs were present in 28% of patients. The presence per se of FLs and a number of greater than one FL were the strongest adverse prognostic factors for progression into sMM (P 〈 .001) in multivariate analysis. A diffuse infiltration pattern in MRI, a monoclonal protein of 40 g/L or greater, and a plasma cell infiltration in bone marrow of 20% or greater were other adverse prognostic factors for progression-free survival in univariate analysis. CONCLUSION: We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.
    Type of Publication: Journal article published
    PubMed ID: 20177023
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  • 6
    Abstract: BACKGROUND: Chromosomal abnormalities have been shown to play a major role in disease evolution of multiple myeloma. Specific changes in interphase cells can be detected by fluorescent in situ hybridization, which overcomes the problem of the lack of dividing cells required for conventional cytogenetics. DESIGN AND METHODS: We analyzed the prognostic value of 12 frequent chromosomal abnormalities detected by fluorescent in situ hybridization in a series of patients (n=315) with newly diagnosed, symptomatic multiple myeloma. All patients underwent frontline autologous stem cell transplantation according to the GMMG-HD3- or GMMG-HD4-trial protocols or analogous protocols. RESULTS: Univariate statistical analyses revealed that the presence of del(13q14), del(17p13), t(4;14), +1q21 and non-hyperdiploidy was associated with adverse progression-free and overall survival rates independently of the International Staging System (ISS) classification. Multivariate analyses showed that only t(4;14) and del(17p13) retained prognostic value for both progression-free and overall survival. According to the presence or absence of t(4;14) and del(17p13) and the patients' International Staging System classification, the cohort could be stratified into three distinct groups: a group with a favorable prognosis [absence of t(4;14)/del(17p13) and ISS I], a group with a poor prognosis [presence of t(4;14)/del(17p13) and ISS II/III] and a group with an intermediate prognosis (all remaining patients). The probabilities of overall survival at 5 years decreased from 72% in the favorable prognostic group to 62% (hazard ratio 2.4; P=0.01) in the intermediate and 41% (hazard ratio 5.6; P〈0.001) in the poor prognostic groups. CONCLUSIONS: These results have implications for risk-adapted management for patients with multiple myeloma undergoing high-dose chemotherapy followed by autologous stem cell transplantation and suggest that new treatment concepts are urgently needed for patients who belong to the poor prognosis group. As targeted therapies evolve, different treatment options might have variable success, depending on the underlying genetic nature of the clone.
    Type of Publication: Journal article published
    PubMed ID: 20220069
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  • 7
    Keywords: brain ; tumor ; Germany ; neoplasms ; TOOL ; HYBRIDIZATION ; DIFFERENTIATION ; TUMORS ; MARKER ; BIOLOGY ; IN-SITU ; AMPLIFICATION ; AGE ; ABERRATIONS ; FISH ; CENTRAL-NERVOUS-SYSTEM ; pathology ; CHILDREN ; BEHAVIOR ; CHROMOSOMES ; FEATURES ; brain tumor ; BRAIN-TUMORS ; PRIMITIVE NEUROECTODERMAL TUMORS ; LOCUS ; diagnostic marker ; ABUNDANT NEUROPIL ; TRUE ROSETTES ; 19q13 ; Embryonal brain tumor ; Ependymoblastoma ; ETANTR ; Molecular diagnosis ; WHO classification of CNS tumors
    Abstract: Ependymoblastoma (EBL) and embryonal tumor with abundant neuropil and true rosettes (ETANTR) are very aggressive embryonal neoplasms characterized by the presence of ependymoblastic multilayered rosettes typically occurring in children below 6 years of age. It has not been established whether these two tumors really comprise distinct entities. Earlier, using array-CGH, we identified a unique focal amplification at 19q13.42 in a case of ETANTR. In the present study, we investigated this locus by fluorescence in situ hybridization in 41 tumors, which had morphologically been diagnosed as EBL or ETANTR. Strikingly, FISH analysis revealed 19q13.42 amplifications in 37/40 samples (93%). Among tumors harboring the amplification, 19 samples were identified as ETANTR and 18 as EBL. The three remaining tumors showed a polysomy of chromosome 19. Analysis of recurrent/metastatic tumors (n = 7) showed that the proportion of nuclei carrying the amplification was increased (up to 80-100% of nuclei) in comparison to the corresponding primary tumors. In conclusion, we have identified a hallmark cytogenetic aberration occurring in virtually all embryonal brain tumors with ependymoblastic rosettes suggesting that ETANTR and EBL comprise a single biological entity. FISH analysis of the 19q13.42 locus is a very promising diagnostic tool to identify a subset of primitive neuroectodermal tumors with distinct morphology, biology, and clinical behavior
    Type of Publication: Journal article published
    PubMed ID: 20407781
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  • 8
    Keywords: EXPRESSION ; tumor ; IDENTIFICATION ; PROGRESSION ; OVARIAN-CANCER ; PROGNOSTIC-FACTORS ; CHILDHOOD MEDULLOBLASTOMA ; STEM-CELL ; BREAST-CANCER CELLS ; INFLUENCES ZYXIN LOCALIZATION
    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 20924110
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  • 9
    Abstract: Multiple myeloma (MM) is proposed to consist of two main pathogenetic groups. Although hyperdiploid MM (HD) is characterized by multiple trisomies of odd chromosomes, in nonhyperdiploid MM (NHD), one of the recurrent primary immunoglobulin heavy chain (IGH) translocations and deletion of chromosome 13 can frequently be found. In this study, we analyzed gene-expression profiles of patients with previously untreated MM. Fifty-four genes were significantly differentially expressed between the two groups. NPM1 was upregulated in HD. The differential expression of 25 genes, including NPM1 and 13 ribosomal protein genes, was validated using a published gene expression data set. The overexpression of NPM1 in HD was further confirmed by quantitative real-time PCR and Western blotting. NPM1 was significantly overexpressed in HD as the result of a gain of chromosome 5. Insertions into exon 12 of NPM1 were not detected. NPM1 was localized to the nucleoli of MM cells. Furthermore, HD was associated with an overexpression of ribosomal protein genes, independent of their localization on the trisomic or other chromosomes. Our results indicate that the gain of chromosome 5 might play an important role in the pathogenesis of HD.
    Type of Publication: Journal article published
    PubMed ID: 20073075
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  • 10
    Keywords: ANGIOGENESIS ; CANCER ; PERFUSION ; DISEASE ; MICROCIRCULATION ; magnetic resonance imaging ; bone marrow ; LOCALIZATION ; PARAMETERS ; functional MRI ; MULTIPLE-MYELOMA ; DIFFUSION ; ONCOLOGY ; INFILTRATION ; SPINE ; AGE-RELATED-CHANGES ; cellularity
    Abstract: Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool for quantification of cellularity in the investigated area. Recently published examples cover breast cancer, CNS tumors, head and neck cancer, gastrointestinal cancer, prostate cancer as well as hematologic malignancies. Purpose: To investigated the influence of age, sex, and localization of the investigated region on findings of DCE-MRI and DWI. Material and Methods: DCE-MRI-parameters amplitude A and exchange rate constant kep as well as the DWI-parameter ADC of the bone marrow of the lumbar vertebral column of 30 healthy individuals covering the typical range of age of tumor patients were evaluated. ADC was calculated using b=0 and a maximal b value of either 400 or 750 s/mm(2). Results: Amplitude A of DCE-MRI decreased with age (P = 0.01) and amplitude A, exchange rate constant kep as well as ADC based on b = 400 s/mm(2) and b = 750 s/mm(2,) respectively, decreased significantly from the first to the fifth lumbar vertebra with P = 0.02, P = 0.05, P = 0.003, and P = 0.002, respectively. Conclusion: Quantitative parameters of functional imaging techniques in bone marrow are influenced by the age of the examined individual and the anatomical location of the investigated region
    Type of Publication: Journal article published
    PubMed ID: 21498370
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