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Berlin Brandenburg

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  • 1
    Language: English
    In: The Journal of biological chemistry, 14 October 2016, Vol.291(42), pp.22136-22148
    Description: Mutations in the gene encoding phospholipase C-γ (PLCγ) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLCγ mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells. Enhanced "basal" activity of PLCγ in intact cells is shown using the pharmacologic Rac inhibitor EHT 1864 and the PLCγ mutation mediating Rac resistance to be caused by Rac-stimulated rather than by constitutively enhanced PLCγ activity. We suggest that R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2 Rerouting of the transmembrane signals emanating from BCR and converging on PLCγ through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients.
    Keywords: Rac (Rac Gtpase) ; Chronic Lymphocytic Leukemia ; Ibrutinib Resistance ; Leukemia ; Lymphoma ; Phosphatidylinositol Signaling ; Phospholipase C ; Drug Resistance, Neoplasm ; Leukemia, Lymphocytic, Chronic, B-Cell ; Mutation, Missense ; Neoplasm Proteins ; Phospholipase C Gamma ; Signal Transduction ; Rac Gtp-Binding Proteins ; Pyrazoles -- Pharmacology ; Pyrimidines -- Pharmacology
    E-ISSN: 1083-351X
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  • 2
    In: Nature, 2014
    Description: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Keywords: Medulloblastoma – Research ; Medulloblastoma – Health Aspects ; DNA Sequencing – Analysis ; Growth Factor Receptors – Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: 2012, Vol.7(9), p.e44401
    Description: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. ; CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. ; ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Computational Biology ; Neuroscience ; Pathology ; Neurological Disorders ; Biochemistry
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.4724-4724
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e66621
    Description: The emergence of high-throughput, next-generation sequencing technologies has dramatically altered the way we assess genomes in population genetics and in cancer genomics. Currently, there are four commonly used whole-genome sequencing platforms on the market: Illumina's HiSeq2000, Life Technologies'...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.3084-3084
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 7
    In: Transplantation, 2011, Vol.92(4), pp.477-485
    Description: BACKGROUND.: Obliterative bronchiolitis poses a primary obstacle for long-term survival of lung transplant recipients and manifests clinically as bronchiolitis obliterans syndrome (BOS). Establishing a molecular level screening method to detect BOS-related proteome changes before its diagnosis by forced expiratory volume surrogate marker criteria was the main objective of this study. METHODS.: Bronchoalveolar lavage was performed in 82 lung transplant recipients (48/34 with/without known BOS development) at different time points between 12 and 48 months after lung transplantation. A mass spectrometry-based method was devised to generate bronchoalveolar lavage fluid proteome profiles that were screened for BOS-specific alterations. Statistically significant marker peptides and proteins were identified and validated by in-gel digestion, tandem mass spectrometric sequencing, and quantitative immunoassays. RESULTS.: Among the panel of statistically significant markers were Clara cell protein, calgranulin A, human neutrophil peptides, and the antimicrobial agent histatin. To assess their clinical relevance, a highly sensitive and specific classifier model was developed. Positive BOS classification by monitoring of seven polypeptides correlated strongly with a significant decrease in BOS-free time. Thus, it was possible to detect high-risk patients early on in the pathogenetic process. CONCLUSIONS.: Monitoring the bronchoalveolar lavage fluid levels of seven polypeptides detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows a reliable prediction of early BOS using a Random Forest decision tree-based classifier model. The high accuracy of this robust model and its synergistic potential in combination with established forced expiratory volume-based diagnostics could make it an effective tool to supplement the current diagnostic regime after multicentric validation.
    Keywords: Leukocytes (Neutrophilic) ; Statistical Analysis ; Survival ; Forests ; Development ; Alveoli ; Mass Spectroscopy ; Antimicrobial Agents ; Obliterative Bronchiolitis ; Digestion ; Lung Transplantation ; Bronchus ; Risk Factors ; S100a8 Protein ; Risk Groups ; Lasers ; Bronchiolitis Obliterans ; Proteomics ; Immunoassays ; Alveoli ; Antimicrobial Agents ; Bronchus ; Development ; Digestion ; Forests ; Immunoassays ; Lasers ; Leukocytes (Neutrophilic) ; Lung Transplantation ; Mass Spectroscopy ; Risk Factors ; Risk Groups ; S100a8 Protein ; Statistical Analysis ; Survival ; Bronchiolitis Obliterans ; Obliterative Bronchiolitis ; Proteomics ; Transplantation;
    ISSN: 0041-1337
    E-ISSN: 15346080
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  • 8
    In: Nature, 2014, Vol.510(7506), p.537
    Description: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Keywords: Gene Expression Regulation, Neoplastic ; Gene Silencing ; DNA Methylation -- Genetics ; Medulloblastoma -- Genetics ; Sequence Analysis, DNA -- Methods;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 9
    In: Nature, 2016
    Description: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
    Keywords: Medulloblastoma -- Genetic Aspects ; Cancer Genetics -- Research ; Cancer Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 10
    Language: English
    In: Cancer Research, 07/01/2018, Vol.78(13 Supplement), pp.5109-5109
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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