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Sample records for expression signatures diagnose

  1. Motor current signature analysis method for diagnosing motor operated devices

    DOEpatents

    Haynes, Howard D.; Eissenberg, David M.

    1990-01-01

    A motor current noise signature analysis method and apparatus for remotely monitoring the operating characteristics of an electric motor-operated device such as a motor-operated valve. Frequency domain signal analysis techniques are applied to a conditioned motor current signal to distinctly identify various operating parameters of the motor driven device from the motor current signature. The signature may be recorded and compared with subsequent signatures to detect operating abnormalities and degradation of the device. This diagnostic method does not require special equipment to be installed on the motor-operated device, and the current sensing may be performed at remote control locations, e.g., where the motor-operated devices are used in accessible or hostile environments.

  2. A novel urinary metabolite signature for diagnosing major depressive disorder.

    PubMed

    Zheng, Peng; Chen, Jian-jun; Huang, Ting; Wang, Ming-ju; Wang, Ying; Dong, Mei-xue; Huang, Yuan-jun; Zhou, Lin-ke; Xie, Peng

    2013-12-06

    Major depressive disorder (MDD) is a prevalent and debilitating mental disorder. Yet, there are no objective biomarkers available to support diagnostic laboratory testing for this disease. Here, gas chromatography-mass spectrometry was applied to urine metabolic profiling of 126 MDD and 134 control subjects. Orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to identify the differential metabolites in MDD subjects relative to healthy controls. The OPLS-DA analysis of data from training samples (82 first-episode, drug-naïve MDD subjects and 82 well-matched healthy controls) showed that the depressed group was significantly distinguishable from the control group. Totally, 23 differential urinary metabolites responsible for the discrimination between the two groups were identified. Postanalysis, 6 of the 23 metabolites (sorbitol, uric acid, azelaic acid, quinolinic acid, hippuric acid, and tyrosine) were defined as candidate diagnostic biomarkers for MDD. Receiver operating characteristic analysis of combined levels of these six biomarkers yielded an area under the receiver operating characteristic curve (AUC) of 0.905 in distinguishing training samples; this simplified metabolite signature classified blinded test samples (44 MDD subjects and 52 healthy controls) with an AUC of 0.837. Furthermore, a composite panel by the addition of previously identified urine biomarker (N-methylnicotinamide) to this biomarker panel achieved a more satisfactory accuracy, yielding an AUC of 0.909 in the training samples and 0.917 in the test samples. Taken together, these results suggest this composite urinary metabolite signature should facilitate development of a urine-based diagnostic test for MDD.

  3. Digital gene expression signatures for maize development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome-wide expression signatures detect specific perturbations in developmental programs and contribute to functional resolution of key regulatory networks. In maize (Zea mays) inflorescences, mutations in the RAMOSA (RA) genes affect determinacy of axillary meristems and thus alter branching patt...

  4. Digital gene expression signatures for maize development.

    PubMed

    Eveland, Andrea L; Satoh-Nagasawa, Namiko; Goldshmidt, Alexander; Meyer, Sandra; Beatty, Mary; Sakai, Hajime; Ware, Doreen; Jackson, David

    2010-11-01

    Genome-wide expression signatures detect specific perturbations in developmental programs and contribute to functional resolution of key regulatory networks. In maize (Zea mays) inflorescences, mutations in the RAMOSA (RA) genes affect the determinacy of axillary meristems and thus alter branching patterns, an important agronomic trait. In this work, we developed and tested a framework for analysis of tag-based, digital gene expression profiles using Illumina's high-throughput sequencing technology and the newly assembled B73 maize reference genome. We also used a mutation in the RA3 gene to identify putative expression signatures specific to stem cell fate in axillary meristem determinacy. The RA3 gene encodes a trehalose-6-phosphate phosphatase and may act at the interface between developmental and metabolic processes. Deep sequencing of digital gene expression libraries, representing three biological replicate ear samples from wild-type and ra3 plants, generated 27 million 20- to 21-nucleotide reads with frequencies spanning 4 orders of magnitude. Unique sequence tags were anchored to 3'-ends of individual transcripts by DpnII and NlaIII digests, which were multiplexed during sequencing. We mapped 86% of nonredundant signature tags to the maize genome, which associated with 37,117 gene models and unannotated regions of expression. In total, 66% of genes were detected by at least nine reads in immature maize ears. We used comparative genomics to leverage existing information from Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) in functional analyses of differentially expressed maize genes. Results from this study provide a basis for the analysis of short-read expression data in maize and resolved specific expression signatures that will help define mechanisms of action for the RA3 gene.

  5. Three plasma metabolite signatures for diagnosing high altitude pulmonary edema

    PubMed Central

    Guo, Li; Tan, Guangguo; Liu, Ping; Li, Huijie; Tang, Lulu; Huang, Lan; Ren, Qian

    2015-01-01

    High-altitude pulmonary edema (HAPE) is a potentially fatal condition, occurring at altitudes greater than 3,000 m and affecting rapidly ascending, non-acclimatized healthy individuals. However, the lack of biomarkers for this disease still constitutes a bottleneck in the clinical diagnosis. Here, ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study plasma metabolite profiling from 57 HAPE and 57 control subjects. 14 differential plasma metabolites responsible for the discrimination between the two groups from discovery set (35 HAPE subjects and 35 healthy controls) were identified. Furthermore, 3 of the 14 metabolites (C8-ceramide, sphingosine and glutamine) were selected as candidate diagnostic biomarkers for HAPE using metabolic pathway impact analysis. The feasibility of using the combination of these three biomarkers for HAPE was evaluated, where the area under the receiver operating characteristic curve (AUC) was 0.981 and 0.942 in the discovery set and the validation set (22 HAPE subjects and 22 healthy controls), respectively. Taken together, these results suggested that this composite plasma metabolite signature may be used in HAPE diagnosis, especially after further investigation and verification with larger samples. PMID:26459926

  6. Three plasma metabolite signatures for diagnosing high altitude pulmonary edema

    NASA Astrophysics Data System (ADS)

    Guo, Li; Tan, Guangguo; Liu, Ping; Li, Huijie; Tang, Lulu; Huang, Lan; Ren, Qian

    2015-10-01

    High-altitude pulmonary edema (HAPE) is a potentially fatal condition, occurring at altitudes greater than 3,000 m and affecting rapidly ascending, non-acclimatized healthy individuals. However, the lack of biomarkers for this disease still constitutes a bottleneck in the clinical diagnosis. Here, ultra-high performance liquid chromatography coupled with Q-TOF mass spectrometry was applied to study plasma metabolite profiling from 57 HAPE and 57 control subjects. 14 differential plasma metabolites responsible for the discrimination between the two groups from discovery set (35 HAPE subjects and 35 healthy controls) were identified. Furthermore, 3 of the 14 metabolites (C8-ceramide, sphingosine and glutamine) were selected as candidate diagnostic biomarkers for HAPE using metabolic pathway impact analysis. The feasibility of using the combination of these three biomarkers for HAPE was evaluated, where the area under the receiver operating characteristic curve (AUC) was 0.981 and 0.942 in the discovery set and the validation set (22 HAPE subjects and 22 healthy controls), respectively. Taken together, these results suggested that this composite plasma metabolite signature may be used in HAPE diagnosis, especially after further investigation and verification with larger samples.

  7. Genomic signatures of germline gene expression.

    PubMed

    McVicker, Graham; Green, Phil

    2010-11-01

    Transcribed regions in the human genome differ from adjacent intergenic regions in transposable element density, crossover rates, and asymmetric substitution and sequence composition patterns. We tested whether these differences reflect selection or are instead a byproduct of germline transcription, using publicly available gene expression data from a variety of germline and somatic tissues. Crossover rate shows a strong negative correlation with gene expression in meiotic tissues, suggesting that crossover is inhibited by transcription. Strand-biased composition (G+T content) and A → G versus T → C substitution asymmetry are both positively correlated with germline gene expression. We find no evidence for a strand bias in allele frequency data, implying that the substitution asymmetry reflects a mutation rather than a fixation bias. The density of transposable elements is positively correlated with germline expression, suggesting that such elements preferentially insert into regions that are actively transcribed. For each of the features examined, our analyses favor a nonselective explanation for the observed trends and point to the role of germline gene expression in shaping the mammalian genome.

  8. Gene expression signatures in lymphoid tumours.

    PubMed

    Kees, Ursula R

    2004-04-01

    Lymphoid tumours comprise the acute and chronic leukaemias, the broad spectrum of lymphomas, including Hodgkin's disease, and multiple myeloma. The subdivision of the acute leukaemias according to the proliferating type of white blood cells has had a major impact on the care of these patients. More recently, specific chromosomal translocations have been used to identify patients who may benefit from more intensive therapies. The novel high-throughput genomic technologies, such as microarrays, provide new avenues for the molecular diagnosis of the haematological malignancies. Rapid advances in genome sequencing and gene expression profiling provide unprecedented opportunities to identify specific genes involved in complex biological processes, including tumorigenesis. The features of microarray technology and the variety of experimental approaches to elucidate lymphoid malignancies are discussed. Microarray technology has the potential to lead to more accurate prognostic assessment for patients and is expected to ultimately allow the clinician to select therapies optimally suited to each patient.

  9. Gene-expression signatures of Atlantic salmon's plastic life cycle

    USGS Publications Warehouse

    Aubin-Horth, N.; Letcher, B.H.; Hofmann, H.A.

    2009-01-01

    How genomic expression differs as a function of life history variation is largely unknown. Atlantic salmon exhibits extreme alternative life histories. We defined the gene-expression signatures of wild-caught salmon at two different life stages by comparing the brain expression profiles of mature sneaker males and immature males, and early migrants and late migrants. In addition to life-stage-specific signatures, we discovered a surprisingly large gene set that was differentially regulated-at similar magnitudes, yet in opposite direction-in both life history transitions. We suggest that this co-variation is not a consequence of many independent cellular and molecular switches in the same direction but rather represents the molecular equivalent of a physiological shift orchestrated by one or very few master regulators. ?? 2009 Elsevier Inc. All rights reserved.

  10. Motor current signature analysis method for diagnosing motor-operated devices

    SciTech Connect

    Haynes, H D; Eissenberg, D M

    1986-09-30

    A motor current noise signature analysis method for remotely monitoring the operating characteristics of an electric motor-operated device such as a motor-operated valve. Frequency domain signal analysis techniques are applied to a conditioned motor current signal to distinctly identify various operating parameters of the motor driven device from the motor current signature. The signature may be recorded and compared with subsequent signatures to detect operating abnormalities and degradation of the device. This diagnostic method does not require special equipment to be installed on the motor-operated device, and the current sensing may be performed at remote control locations, e.g., where the motor-operated devices are used in inaccessible or hostile environments. 6 figs.

  11. Diagnose

    NASA Astrophysics Data System (ADS)

    Schauer, Wolfgang

    Die Zunahme der Elektronik im Kraftfahrzeug, die Nutzung von Software zur Steuerung des Fahrzeugs und die erhöhte Komplexität moderner Einspritzsysteme stellen hohe Anforderungen an das Diagnosekonzept, die Überwachung im Fahrbetrieb (On-Board-Diagnose) und die Werkstattdiagnose (Bild 1). Basis der Werkstattdiagnose ist die geführte Fehlersuche, die verschiedene Möglichkeiten von Onboard- und Offboard-Prüfmethoden und Prüfgeräten verknüpft. Im Zuge der Verschärfung der Abgasgesetzgebung und der Forderung nach laufender Überwachung hat auch der Gesetzgeber die On-Board-Diagnose als Hilfsmittel zur Abgasüberwachung erkannt und eine herstellerunabhängige Standardisierung geschaffen. Dieses zusätzlich installierte System wird OBD-System (On Board Diagnostic System) genannt.

  12. A prognostic gene expression signature in infratentorial ependymoma.

    PubMed

    Wani, Khalida; Armstrong, Terri S; Vera-Bolanos, Elizabeth; Raghunathan, Aditya; Ellison, David; Gilbertson, Richard; Vaillant, Brian; Goldman, Stewart; Packer, Roger J; Fouladi, Maryam; Pollack, Ian; Mikkelsen, Tom; Prados, Michael; Omuro, Antonio; Soffietti, Riccardo; Ledoux, Alicia; Wilson, Charmaine; Long, Lihong; Gilbert, Mark R; Aldape, Ken

    2012-05-01

    Patients with ependymoma exhibit a wide range of clinical outcomes that are currently unexplained by clinical or histological factors. Little is known regarding molecular biomarkers that could predict clinical behavior. Since recent data suggest that these tumors display biological characteristics according to their location (cerebral vs. infratentorial vs. spinal cord), rather than explore a broad spectrum of ependymoma, we focused on molecular alterations in ependymomas arising in the infratentorial compartment. Unsupervised clustering of available gene expression microarray data revealed two major subgroups of infratentorial ependymoma. Group 1 tumors over expressed genes that were associated with mesenchyme, Group 2 tumors showed no distinct gene ontologies. To assess the prognostic significance of these gene expression subgroups, real-time reverse transcriptase polymerase chain reaction assays were performed on genes defining the subgroups in a training set. This resulted in a 10-gene prognostic signature. Multivariate analysis showed that the 10-gene signature was an independent predictor of recurrence-free survival after adjusting for clinical factors. Evaluation of an external dataset describing subgroups of infratentorial ependymomas showed concordance of subgroup definition, including validation of the mesenchymal subclass. Importantly, the 10-gene signature was validated as a predictor of recurrence-free survival in this dataset. Taken together, the results indicate a link between clinical outcome and biologically identified subsets of infratentorial ependymoma and offer the potential for prognostic testing to estimate clinical aggressiveness in these tumors.

  13. Conserved Expression Signatures between Medaka and Human Pigment Cell Tumors

    PubMed Central

    Schartl, Manfred; Kneitz, Susanne; Wilde, Brigitta; Wagner, Toni; Henkel, Christiaan V.; Spaink, Herman P.; Meierjohann, Svenja

    2012-01-01

    Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules. PMID:22693581

  14. GESearch: An Interactive GUI Tool for Identifying Gene Expression Signature.

    PubMed

    Ye, Ning; Yin, Hengfu; Liu, Jingjing; Dai, Xiaogang; Yin, Tongming

    2015-01-01

    The huge amount of gene expression data generated by microarray and next-generation sequencing technologies present challenges to exploit their biological meanings. When searching for the coexpression genes, the data mining process is largely affected by selection of algorithms. Thus, it is highly desirable to provide multiple options of algorithms in the user-friendly analytical toolkit to explore the gene expression signatures. For this purpose, we developed GESearch, an interactive graphical user interface (GUI) toolkit, which is written in MATLAB and supports a variety of gene expression data files. This analytical toolkit provides four models, including the mean, the regression, the delegate, and the ensemble models, to identify the coexpression genes, and enables the users to filter data and to select gene expression patterns by browsing the display window or by importing knowledge-based genes. Subsequently, the utility of this analytical toolkit is demonstrated by analyzing two sets of real-life microarray datasets from cell-cycle experiments. Overall, we have developed an interactive GUI toolkit that allows for choosing multiple algorithms for analyzing the gene expression signatures.

  15. Differentially Expressed Genes and Signature Pathways of Human Prostate Cancer

    PubMed Central

    Myers, Jennifer S.; von Lersner, Ariana K.; Robbins, Charles J.; Sang, Qing-Xiang Amy

    2015-01-01

    Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The “transforming growth factor-beta signaling” and “Ran regulation of mitotic spindle formation” pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran) for investigation in prostate cancer pathogenesis. PMID:26683658

  16. A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells

    PubMed Central

    Olsen, N; Sokka, T; Seehorn, C; Kraft, B; Maas, K; Moore, J; Aune, T

    2004-01-01

    Background: In previous studies the presence of a distinct gene expression pattern has been shown in peripheral blood cells from patients with autoimmune disease. Objective: To determine whether other specific signatures might be used to identify subsets of these autoimmune diseases and whether gene expression patterns in early disease might identify pathogenetic factors. Methods: Peripheral blood mononuclear cells were acquired from patients with rheumatoid arthritis (RA) and analysed by microarrays containing over 4300 named human genes. Patients with RA for <2 years were compared with subjects with longstanding RA (average duration 10 years) and with patients with other immune or autoimmune diagnoses. Results: Cluster analyses permitted separation of the patients with early RA (ERA) from those with longstanding disease. Comparison with other patient groups suggested that the ERA signature showed some overlap with that seen in the normal immune response to viral antigen as well as with a subset of patients with systemic lupus erythematosus. Conclusions: The ERA signature may reflect, in part, a response to an unknown infectious agent. Furthermore, shared features with some lupus patients suggest that common aetiological factors and pathogenetic pathways may be involved in these two autoimmune disorders. PMID:15479887

  17. Molecular classification of prostate cancer using curated expression signatures.

    PubMed

    Markert, Elke K; Mizuno, Hideaki; Vazquez, Alexei; Levine, Arnold J

    2011-12-27

    High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a significant number of patients with low Gleason scores develop aggressive disease as well. In an effort to understand molecular signatures associated with poor outcome in prostate cancer, we analyzed a microarray dataset characterizing 281 prostate cancers from a Swedish watchful-waiting cohort. Patients were classified on the basis of their mRNA microarray signature profiles indicating embryonic stem cell expression patterns (stemness), inactivation of the tumor suppressors p53 and PTEN, activation of several oncogenic pathways, and the TMPRSS2-ERG fusion. Unsupervised clustering identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome, a second group with intermediate survival outcome, characterized by the TMPRSS2-ERG fusion, and three groups with benign outcome. The stratification was validated on a second independent dataset of 150 tumor and metastatic samples from a clinical cohort at Memorial Sloan-Kettering Cancer Center. This classification is independent of Gleason score and therefore provides useful unique molecular profiles for prostate cancer prognosis, helping to predict poor outcome in patients with low or average Gleason scores.

  18. Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd

    NASA Astrophysics Data System (ADS)

    Wang, Zichen; Monteiro, Caroline D.; Jagodnik, Kathleen M.; Fernandez, Nicolas F.; Gundersen, Gregory W.; Rouillard, Andrew D.; Jenkins, Sherry L.; Feldmann, Axel S.; Hu, Kevin S.; McDermott, Michael G.; Duan, Qiaonan; Clark, Neil R.; Jones, Matthew R.; Kou, Yan; Goff, Troy; Woodland, Holly; Amaral, Fabio M. R.; Szeto, Gregory L.; Fuchs, Oliver; Schüssler-Fiorenza Rose, Sophia M.; Sharma, Shvetank; Schwartz, Uwe; Bausela, Xabier Bengoetxea; Szymkiewicz, Maciej; Maroulis, Vasileios; Salykin, Anton; Barra, Carolina M.; Kruth, Candice D.; Bongio, Nicholas J.; Mathur, Vaibhav; Todoric, Radmila D.; Rubin, Udi E.; Malatras, Apostolos; Fulp, Carl T.; Galindo, John A.; Motiejunaite, Ruta; Jüschke, Christoph; Dishuck, Philip C.; Lahl, Katharina; Jafari, Mohieddin; Aibar, Sara; Zaravinos, Apostolos; Steenhuizen, Linda H.; Allison, Lindsey R.; Gamallo, Pablo; de Andres Segura, Fernando; Dae Devlin, Tyler; Pérez-García, Vicente; Ma'Ayan, Avi

    2016-09-01

    Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization.

  19. Extraction and analysis of signatures from the Gene Expression Omnibus by the crowd

    PubMed Central

    Wang, Zichen; Monteiro, Caroline D.; Jagodnik, Kathleen M.; Fernandez, Nicolas F.; Gundersen, Gregory W.; Rouillard, Andrew D.; Jenkins, Sherry L.; Feldmann, Axel S.; Hu, Kevin S.; McDermott, Michael G.; Duan, Qiaonan; Clark, Neil R.; Jones, Matthew R.; Kou, Yan; Goff, Troy; Woodland, Holly; Amaral, Fabio M R.; Szeto, Gregory L.; Fuchs, Oliver; Schüssler-Fiorenza Rose, Sophia M.; Sharma, Shvetank; Schwartz, Uwe; Bausela, Xabier Bengoetxea; Szymkiewicz, Maciej; Maroulis, Vasileios; Salykin, Anton; Barra, Carolina M.; Kruth, Candice D.; Bongio, Nicholas J.; Mathur, Vaibhav; Todoric, Radmila D; Rubin, Udi E.; Malatras, Apostolos; Fulp, Carl T.; Galindo, John A.; Motiejunaite, Ruta; Jüschke, Christoph; Dishuck, Philip C.; Lahl, Katharina; Jafari, Mohieddin; Aibar, Sara; Zaravinos, Apostolos; Steenhuizen, Linda H.; Allison, Lindsey R.; Gamallo, Pablo; de Andres Segura, Fernando; Dae Devlin, Tyler; Pérez-García, Vicente; Ma'ayan, Avi

    2016-01-01

    Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization. PMID:27667448

  20. MicroRNA Expression Signature in Degenerative Aortic Stenosis

    PubMed Central

    2016-01-01

    Degenerative aortic stenosis, characterized by narrowing of the exit of the left ventricle of the heart, has become the most common valvular heart disease in the elderly. The aim of this study was to investigate the microRNA (miRNA) signature in degenerative AS. Through microarray analysis, we identified the miRNA expression signature in the tissue samples from healthy individuals (n = 4) and patients with degenerative AS (n = 4). Six miRNAs (hsa-miR-193a-3p, hsa-miR-29b-1-5p, hsa-miR-505-5p, hsa-miR-194-5p, hsa-miR-99b-3p, and hsa-miR-200b-3p) were overexpressed and 14 (hsa-miR-3663-3p, hsa-miR-513a-5p, hsa-miR-146b-5p, hsa-miR-1972, hsa-miR-718, hsa-miR-3138, hsa-miR-21-5p, hsa-miR-630, hsa-miR-575, hsa-miR-301a-3p, hsa-miR-636, hsa-miR-34a-3p, hsa-miR-21-3p, and hsa-miR-516a-5p) were downregulated in aortic tissue from AS patients. GeneSpring 13.1 was used to identify potential human miRNA target genes by comparing a 3-way comparison of predictions from TargetScan, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify potential pathways and functional annotations associated with AS. Twenty miRNAs were significantly differentially expressed between patients with AS samples and normal controls and identified potential miRNA targets and molecular pathways associated with this morbidity. This study describes the miRNA expression signature in degenerative AS and provides an improved understanding of the molecular pathobiology of this disease. PMID:27579316

  1. MicroRNA Expression Signature in Degenerative Aortic Stenosis.

    PubMed

    Shi, Jing; Liu, Hui; Wang, Hui; Kong, Xiangqing

    2016-01-01

    Degenerative aortic stenosis, characterized by narrowing of the exit of the left ventricle of the heart, has become the most common valvular heart disease in the elderly. The aim of this study was to investigate the microRNA (miRNA) signature in degenerative AS. Through microarray analysis, we identified the miRNA expression signature in the tissue samples from healthy individuals (n = 4) and patients with degenerative AS (n = 4). Six miRNAs (hsa-miR-193a-3p, hsa-miR-29b-1-5p, hsa-miR-505-5p, hsa-miR-194-5p, hsa-miR-99b-3p, and hsa-miR-200b-3p) were overexpressed and 14 (hsa-miR-3663-3p, hsa-miR-513a-5p, hsa-miR-146b-5p, hsa-miR-1972, hsa-miR-718, hsa-miR-3138, hsa-miR-21-5p, hsa-miR-630, hsa-miR-575, hsa-miR-301a-3p, hsa-miR-636, hsa-miR-34a-3p, hsa-miR-21-3p, and hsa-miR-516a-5p) were downregulated in aortic tissue from AS patients. GeneSpring 13.1 was used to identify potential human miRNA target genes by comparing a 3-way comparison of predictions from TargetScan, PITA, and microRNAorg databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to identify potential pathways and functional annotations associated with AS. Twenty miRNAs were significantly differentially expressed between patients with AS samples and normal controls and identified potential miRNA targets and molecular pathways associated with this morbidity. This study describes the miRNA expression signature in degenerative AS and provides an improved understanding of the molecular pathobiology of this disease.

  2. Gene Expression Signature in Adipose Tissue of Acromegaly Patients

    PubMed Central

    Hochberg, Irit; Tran, Quynh T.; Barkan, Ariel L.; Saltiel, Alan R.; Chandler, William F.; Bridges, Dave

    2015-01-01

    To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly. PMID:26087292

  3. Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

    PubMed

    Hochberg, Irit; Tran, Quynh T; Barkan, Ariel L; Saltiel, Alan R; Chandler, William F; Bridges, Dave

    2015-01-01

    To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly.

  4. Three serum metabolite signatures for diagnosing low-grade and high-grade bladder cancer

    PubMed Central

    Tan, Guangguo; Wang, Haibo; Yuan, Jianlin; Qin, Weijun; Dong, Xin; Wu, Hong; Meng, Ping

    2017-01-01

    To address the shortcomings of cystoscopy and urine cytology for detecting and grading bladder cancer (BC), ultrahigh performance liquid chromatography (UHPLC) coupled with Q-TOF mass spectrometry in conjunction with univariate and multivariate statistical analyses was employed as an alternative method for the diagnosis of BC. A series of differential serum metabolites were further identified for low-grade(LG) and high-grade(HG) BC patients, suggesting metabolic dysfunction in malignant proliferation, immune escape, differentiation, apoptosis and invasion of cancer cells in BC patients. In total, three serum metabolites including inosine, acetyl-N-formyl-5-methoxykynurenamine and PS(O-18:0/0:0) were selected by binary logistic regression analysis, and receiver operating characteristic (ROC) test based on their combined use for HG BC showed that the area under the curve (AUC) was 0.961 in the discovery set and 0.950 in the validation set when compared to LG BC. Likewise, this composite biomarker panel can also differentiate LG BC from healthy controls with the AUC of 0.993 and 0.991 in the discovery and validation set, respectively. This finding suggested that this composite serum metabolite signature was a promising and less invasive classifier for probing and grading BC, which deserved to be further investigated in larger samples. PMID:28382976

  5. Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

    EPA Science Inventory

    Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

  6. Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases.

    PubMed

    Tuller, T; Atar, S; Ruppin, E; Gurevich, M; Achiron, A

    2013-03-01

    different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.

  7. Multiclass cancer diagnosis using tumor gene expression signatures

    DOE PAGES

    Ramaswamy, S.; Tamayo, P.; Rifkin, R.; ...

    2001-12-11

    The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a supportmore » vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.« less

  8. Multiclass cancer diagnosis using tumor gene expression signatures

    SciTech Connect

    Ramaswamy, S.; Tamayo, P.; Rifkin, R.; Mukherjee, S.; Yeang, C. -H.; Angelo, M.; Ladd, C.; Reich, M.; Latulippe, E.; Mesirov, J. P.; Poggio, T.; Gerald, W.; Loda, M.; Lander, E. S.; Golub, T. R.

    2001-12-11

    The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

  9. A Gene Expression Signature for Chemoradiosensitivity of Colorectal Cancer Cells

    SciTech Connect

    Spitzner, Melanie; Emons, Georg; Kramer, Frank; Gaedcke, Jochen; Rave-Fraenk, Margret; Scharf, Jens-Gerd; Burfeind, Peter; Becker, Heinz; Beissbarth, Tim; Ghadimi, B. Michael; Ried, Thomas; Grade, Marian

    2010-11-15

    Purpose: The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, tumor response to multimodal treatment has varied greatly, ranging from complete resistance to complete pathologic regression. The prediction of the response is, therefore, an important clinical need. Methods and Materials: To establish in vitro models for studying the molecular basis of this heterogeneous tumor response, we exposed 12 colorectal cancer cell lines to 3 {mu}M of 5-fluorouracil and 2 Gy of radiation. The differences in treatment sensitivity were then correlated with the pretherapeutic gene expression profiles of these cell lines. Results: We observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q <.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. Conclusion: We are the first to report a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells. We anticipate that this analysis will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors.

  10. Brain Gene Expression Signatures From Cerebrospinal Fluid Exosome RNA Profiling

    NASA Technical Reports Server (NTRS)

    Zanello, S. B.; Stevens, B.; Calvillo, E.; Tang, R.; Gutierrez Flores, B.; Hu, L.; Skog, J.; Bershad, E.

    2016-01-01

    While the Visual Impairment and Intracranial Pressure (VIIP) syndrome observations have focused on ocular symptoms, spaceflight has been also associated with a number of other performance and neurologic signs, such as headaches, cognitive changes, vertigo, nausea, sleep/circadian disruption and mood alterations, which, albeit likely multifactorial, can also result from elevation of intracranial pressure (ICP). We therefore hypothesize that these various symptoms are caused by disturbances in the neurophysiology of the brain structures and are correlated with molecular markers in the cerebrospinal fluid (CSF) as indicators of neurophysiological changes. Exosomes are 30-200 nm microvesicles shed into all biofluids, including blood, urine, and CSF, carrying a highly rich source of intact protein and RNA cargo. Exosomes have been identified in human CSF, and their proteome and RNA pool is a potential new reservoir for biomarker discovery in neurological disorders. The purpose of this study is to investigate changes in brain gene expression via exosome analysis in patients suffering from ICP elevation of varied severity (idiopathic intracranial hypertension -IIH), a condition which shares some of the neuroophthalmological features of VIIP, as a first step toward obtaining evidence suggesting that cognitive function and ICP levels can be correlated with biomarkers in the CSF. Our preliminary work, reported last year, validated the exosomal technology applicable to CSF analysis and demonstrated that it was possible to obtain gene expression evidence of inflammation processes in traumatic brain injury patients. We are now recruiting patients with suspected IIH requiring lumbar puncture at Baylor College of Medicine. Both CSF (5 ml) and human plasma (10 ml) are being collected in order to compare the pattern of differentially expressed genes observed in CSF and in blood. Since blood is much more accessible than CSF, we would like to determine whether plasma biomarkers for

  11. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF

    PubMed Central

    Koot, Yvonne E. M.; van Hooff, Sander R.; Boomsma, Carolien M.; van Leenen, Dik; Groot Koerkamp, Marian J. A.; Goddijn, Mariëtte; Eijkemans, Marinus J. C.; Fauser, Bart C. J. M.; Holstege, Frank C. P.; Macklon, Nick S.

    2016-01-01

    The primary limiting factor for effective IVF treatment is successful embryo implantation. Recurrent implantation failure (RIF) is a condition whereby couples fail to achieve pregnancy despite consecutive embryo transfers. Here we describe the collection of gene expression profiles from mid-luteal phase endometrial biopsies (n = 115) from women experiencing RIF and healthy controls. Using a signature discovery set (n = 81) we identify a signature containing 303 genes predictive of RIF. Independent validation in 34 samples shows that the gene signature predicts RIF with 100% positive predictive value (PPV). The strength of the RIF associated expression signature also stratifies RIF patients into distinct groups with different subsequent implantation success rates. Exploration of the expression changes suggests that RIF is primarily associated with reduced cellular proliferation. The gene signature will be of value in counselling and guiding further treatment of women who fail to conceive upon IVF and suggests new avenues for developing intervention. PMID:26797113

  12. A host-based RT-PCR gene expression signature to identify acute respiratory viral infection.

    PubMed

    Zaas, Aimee K; Burke, Thomas; Chen, Minhua; McClain, Micah; Nicholson, Bradly; Veldman, Timothy; Tsalik, Ephraim L; Fowler, Vance; Rivers, Emanuel P; Otero, Ronny; Kingsmore, Stephen F; Voora, Deepak; Lucas, Joseph; Hero, Alfred O; Carin, Lawrence; Woods, Christopher W; Ginsburg, Geoffrey S

    2013-09-18

    Improved ways to diagnose acute respiratory viral infections could decrease inappropriate antibacterial use and serve as a vital triage mechanism in the event of a potential viral pandemic. Measurement of the host response to infection is an alternative to pathogen-based diagnostic testing and may improve diagnostic accuracy. We have developed a host-based assay with a reverse transcription polymerase chain reaction (RT-PCR) TaqMan low-density array (TLDA) platform for classifying respiratory viral infection. We developed the assay using two cohorts experimentally infected with influenza A H3N2/Wisconsin or influenza A H1N1/Brisbane, and validated the assay in a sample of adults presenting to the emergency department with fever (n = 102) and in healthy volunteers (n = 41). Peripheral blood RNA samples were obtained from individuals who underwent experimental viral challenge or who presented to the emergency department and had microbiologically proven viral respiratory infection or systemic bacterial infection. The selected gene set on the RT-PCR TLDA assay classified participants with experimentally induced influenza H3N2 and H1N1 infection with 100 and 87% accuracy, respectively. We validated this host gene expression signature in a cohort of 102 individuals arriving at the emergency department. The sensitivity of the RT-PCR test was 89% [95% confidence interval (CI), 72 to 98%], and the specificity was 94% (95% CI, 86 to 99%). These results show that RT-PCR-based detection of a host gene expression signature can classify individuals with respiratory viral infection and sets the stage for prospective evaluation of this diagnostic approach in a clinical setting.

  13. Characteristics and Validation Techniques for PCA-Based Gene-Expression Signatures

    PubMed Central

    Welsh, Eric A.

    2017-01-01

    Background. Many gene-expression signatures exist for describing the biological state of profiled tumors. Principal Component Analysis (PCA) can be used to summarize a gene signature into a single score. Our hypothesis is that gene signatures can be validated when applied to new datasets, using inherent properties of PCA. Results. This validation is based on four key concepts. Coherence: elements of a gene signature should be correlated beyond chance. Uniqueness: the general direction of the data being examined can drive most of the observed signal. Robustness: if a gene signature is designed to measure a single biological effect, then this signal should be sufficiently strong and distinct compared to other signals within the signature. Transferability: the derived PCA gene signature score should describe the same biology in the target dataset as it does in the training dataset. Conclusions. The proposed validation procedure ensures that PCA-based gene signatures perform as expected when applied to datasets other than those that the signatures were trained upon. Complex signatures, describing multiple independent biological components, are also easily identified. PMID:28265563

  14. Gene expression-based prognostic signatures in lung cancer: ready for clinical use?

    PubMed

    Subramanian, Jyothi; Simon, Richard

    2010-04-07

    A substantial number of studies have reported the development of gene expression-based prognostic signatures for lung cancer. The ultimate aim of such studies should be the development of well-validated clinically useful prognostic signatures that improve therapeutic decision making beyond current practice standards. We critically reviewed published studies reporting the development of gene expression-based prognostic signatures for non-small cell lung cancer to assess the progress made toward this objective. Studies published between January 1, 2002, and February 28, 2009, were identified through a PubMed search. Following hand-screening of abstracts of the identified articles, 16 were selected as relevant. Those publications were evaluated in detail for appropriateness of the study design, statistical validation of the prognostic signature on independent datasets, presentation of results in an unbiased manner, and demonstration of medical utility for the new signature beyond that obtained using existing treatment guidelines. Based on this review, we found little evidence that any of the reported gene expression signatures are ready for clinical application. We also found serious problems in the design and analysis of many of the studies. We suggest a set of guidelines to aid the design, analysis, and evaluation of prognostic signature studies. These guidelines emphasize the importance of focused study planning to address specific medically important questions and the use of unbiased analysis methods to evaluate whether the resulting signatures provide evidence of medical utility beyond standard of care-based prognostic factors.

  15. Building predictive gene signatures through simultaneous assessment of transcription factor activation and gene expression.

    EPA Science Inventory

    Building predictive gene signatures through simultaneous assessment of transcription factor activation and gene expression Exposure to many drugs and environmentally-relevant chemicals can cause adverse outcomes. These adverse outcomes, such as cancer, have been linked to mol...

  16. A gene expression signature for RSV: clinical implications and limitations.

    PubMed

    Openshaw, Peter J M

    2013-11-01

    Peter Openshaw discusses the challenges in advancing respiratory syncytial virus (RSV) treatments and the implications of a study by Mejias and colleagues using a newly identified gene signature for diagnosis and prediction of RSV severity. Please see later in the article for the Editors' Summary.

  17. Host gene expression classifiers diagnose acute respiratory illness etiology

    PubMed Central

    Nichols, Marshall; Burke, Thomas; Ko, Emily R.; McClain, Micah T.; Hudson, Lori L.; Mazur, Anna; Freeman, Debra H.; Veldman, Tim; Langley, Raymond J.; Quackenbush, Eugenia B.; Glickman, Seth W.; Cairns, Charles B.; Jaehne, Anja K.; Rivers, Emanuel P.; Otero, Ronny M.; Zaas, Aimee K.; Kingsmore, Stephen F.; Lucas, Joseph; Fowler, Vance G.; Carin, Lawrence; Ginsburg, Geoffrey S.; Woods, Christopher W.

    2016-01-01

    Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational, cohort study determined whether host gene expression patterns discriminate non-infectious from infectious illness, and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or non-infectious illness as well as 44 healthy controls was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a non-infectious cause of illness (26 probes). Overall accuracy was 87% (238/273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, p<0.03) and three published classifiers of bacterial vs. viral infection (78-83%). The classifiers developed here externally validated in five publicly available datasets (AUC 0.90-0.99). A sixth publically available dataset included twenty-five patients with co-identification of bacterial and viral pathogens. Applying the ARI classifiers defined four distinct groups: a host response to bacterial ARI; viral ARI; co-infection; and neither a bacterial nor viral response. These findings create an opportunity to develop and utilize host gene expression classifiers as diagnostic platforms to combat inappropriate antibiotic use and emerging antibiotic resistance. PMID:26791949

  18. Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

    PubMed Central

    Kurian, Sunil M.; Novais, Marta; Whisenant, Thomas; Gelbart, Terri; Buxbaum, Joel N.; Kelly, Jeffery W.; Coelho, Teresa; Salomon, Daniel R.

    2016-01-01

    Background: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. Methods and Findings: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. Conclusions: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation

  19. Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants

    SciTech Connect

    Leone, Angelique; Nie, Alex; Brandon Parker, J.; Sawant, Sharmilee; Piechta, Leigh-Anne; Kelley, Michael F. Mark Kao, L.; Jim Proctor, S.; Verheyen, Geert; Johnson, Mark D.; Lord, Peter G.; McMillian, Michael K.

    2014-03-15

    Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds—chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates. - Highlights: • 28 of 97 drugs gave a positive OS/RM gene expression signature in rat liver. • The specificity of the signature for human idiosyncratic hepatotoxicants was 98%. • The sensitivity of the signature for human idiosyncratic hepatotoxicants was 75%. • The signature can help eliminate hepatotoxicants from drug development.

  20. Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis

    PubMed Central

    Rosenberg, Alan M.; Yeung, Rae S. M.; Morris, Quaid

    2016-01-01

    Gene expression-based signatures help identify pathways relevant to diseases and treatments, but are challenging to construct when there is a diversity of disease mechanisms and treatments in patients with complex diseases. To overcome this challenge, we present a new application of an in silico gene expression deconvolution method, ISOpure-S1, and apply it to identify a common gene expression signature corresponding to response to treatment in 33 juvenile idiopathic arthritis (JIA) patients. Using pre- and post-treatment gene expression profiles only, we found a gene expression signature that significantly correlated with a reduction in the number of joints with active arthritis, a measure of clinical outcome (Spearman rho = 0.44, p = 0.040, Bonferroni correction). This signature may be associated with a decrease in T-cells, monocytes, neutrophils and platelets. The products of most differentially expressed genes include known biomarkers for JIA such as major histocompatibility complexes and interleukins, as well as novel biomarkers including α-defensins. This method is readily applicable to expression datasets of other complex diseases to uncover shared mechanistic patterns in heterogeneous samples. PMID:27244050

  1. Characterising Cytokine Gene Expression Signatures in Patients with Severe Sepsis

    PubMed Central

    Grealy, Robert; White, Mary; Stordeur, Patrick; Kelleher, Dermot; Doherty, Derek G.; McManus, Ross; Ryan, Thomas

    2013-01-01

    Introduction. Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. Methods. A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction. Results. Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFNγ, and TNFα gene expression. An algorithm utilising mRNA copy number for TNFα, IFNγ, IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive and gram-negative infection and was similar following medical and surgical severe sepsis. Severity of organ failure was associated with serum IL6 protein levels but not with any index of cytokine gene expression in PBMCs. Conclusions. Immune regulatory cytokine gene expression in PBMC provides a robust method of modelling patients' response to infection. PMID:23935244

  2. Expression Signatures of Long Noncoding RNAs in Adolescent Idiopathic Scoliosis

    PubMed Central

    Liu, Xiao-Yang; Wang, Liang; Yu, Bin; Zhuang, Qian-yu; Wang, Yi-Peng

    2015-01-01

    Purpose. Adolescent idiopathic scoliosis (AIS), the most common pediatric spinal deformity, is considered a complex genetic disease. Causing genes and pathogenesis of AIS are still unclear. This study was designed to identify differentially expressed long noncoding RNAs (lncRNAs) involving the pathogenesis of AIS. Methods. We first performed comprehensive screening of lncRNA and mRNA in AIS patients and healthy children using Agilent human lncRNA + mRNA Array V3.0 microarray. LncRNAs expression in different AIS patients was further evaluated using quantitative PCR. Results. A total of 139 lncRNAs and 546 mRNAs were differentially expressed between AIS patients and healthy control. GO and Pathway analysis showed that these mRNAs might be involved in bone mineralization, neuromuscular junction, skeletal system morphogenesis, nucleotide and nucleic acid metabolism, and regulation of signal pathway. Four lncRNAs (ENST00000440778.1, ENST00000602322.1, ENST00000414894.1, and TCONS_00028768) were differentially expressed between different patients when grouped according to age, height, classification, severity of scoliosis, and Risser grade. Conclusions. This study demonstrates the abnormal expression of lncRNAs and mRNAs in AIS, and the expression of some lncRNAs was related to clinical features. This study is helpful for further understanding of lncRNAs in pathogenesis, treatment, and prognosis of AIS. PMID:26421281

  3. Identifying a gene expression signature of cluster headache in blood

    PubMed Central

    Eising, Else; Pelzer, Nadine; Vijfhuizen, Lisanne S.; Vries, Boukje de; Ferrari, Michel D.; ‘t Hoen, Peter A. C.; Terwindt, Gisela M.; van den Maagdenberg, Arn M. J. M.

    2017-01-01

    Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache. PMID:28074859

  4. mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate Cancer

    PubMed Central

    Penney, Kathryn L.; Sinnott, Jennifer A.; Fall, Katja; Pawitan, Yudi; Hoshida, Yujin; Kraft, Peter; Stark, Jennifer R.; Fiorentino, Michelangelo; Perner, Sven; Finn, Stephen; Calza, Stefano; Flavin, Richard; Freedman, Matthew L.; Setlur, Sunita; Sesso, Howard D.; Andersson, Swen-Olof; Martin, Neil; Kantoff, Philip W.; Johansson, Jan-Erik; Adami, Hans-Olov; Rubin, Mark A.; Loda, Massimo; Golub, Todd R.; Andrén, Ove; Stampfer, Meir J.; Mucci, Lorelei A.

    2011-01-01

    Purpose Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. PMID:21537050

  5. An Epigenetic Signature for Monoallelic Olfactory Receptor Expression

    PubMed Central

    Magklara, Angeliki; Yen, Angela; Colquitt, Bradley M.; Clowney, E. Josephine; Allen, William; Markenscoff-Papadimitriou, Eirene; Evans, Zoe A.; Kheradpour, Pouya; Mountoufaris, George; Carey, Catriona; Barnea, Gilad; Kellis, Manolis; Lomvardas, Stavros

    2011-01-01

    SUMMARY Constitutive heterochromatin is traditionally viewed as the static form of heterochromatin that silences pericentromeric and telomeric repeats in a cell cycle and differentiation independent manner. Here, we show that in the mouse olfactory epithelium, olfactory receptor (OR) genes are marked, in a highly dynamic fashion, with the molecular hallmarks of constitutive heterochromatin, H3K9me3 and H4K20me3. The cell-type and developmentally dependent deposition of these marks along the OR clusters is, most likely, reversed during the process of OR choice to allow for monogenic and monoallelic OR expression. In contrast to the current view of OR choice, our data suggest that OR silencing takes place before OR expression, indicating that it is not the product of an OR-elicited feedback signal. This suggests a new role for chromatin-mediated silencing as the molecular foundation upon which singular and stochastic selection can be applied. PMID:21529909

  6. Integrative analysis of lung development-cancer expression associations reveals the roles of signatures with inverse expression patterns.

    PubMed

    Zhang, Chunlong; Li, Chunquan; Xu, Yanjun; Feng, Li; Shang, Desi; Yang, Xinmiao; Han, Junwei; Sun, Zeguo; Li, Yixue; Li, Xia

    2015-05-01

    Recent studies have focused on exploring the associations between organ development and malignant tumors; however, the clinical relevance of the development signatures was inadequately addressed in lung cancer. In this study, we explored the associations between lung development and lung cancer progression by analyzing a total of two development and seven cancer datasets. We identified representative expression patterns (continuously up- and down-regulated) from development and cancer profiles, and inverse pattern associations were observed at both the gene and functional levels. Furthermore, we dissected the biological processes dominating the associations, and found that proliferation and immunity were respectively involved in the two inverse development-cancer expression patterns. Through sub-pathway analysis of the signatures with inverse expression patterns, we finally identified a 13-gene risk signature from the cell cycle sub-pathway, and evaluated its predictive performance for lung cancer patient clinical outcome using independent cohorts. Our findings indicated that the integrative analysis of development and cancer expression patterns provided a framework for identifying effective molecular signatures for clinical utility.

  7. Gene Expression Signature-Based Screening Identifies New Broadly Effective Influenza A Antivirals

    PubMed Central

    Josset, Laurence; Textoris, Julien; Loriod, Béatrice; Ferraris, Olivier; Moules, Vincent; Lina, Bruno; N'Guyen, Catherine; Diaz, Jean-Jacques; Rosa-Calatrava, Manuel

    2010-01-01

    Classical antiviral therapies target viral proteins and are consequently subject to resistance. To counteract this limitation, alternative strategies have been developed that target cellular factors. We hypothesized that such an approach could also be useful to identify broad-spectrum antivirals. The influenza A virus was used as a model for its viral diversity and because of the need to develop therapies against unpredictable viruses as recently underlined by the H1N1 pandemic. We proposed to identify a gene-expression signature associated with infection by different influenza A virus subtypes which would allow the identification of potential antiviral drugs with a broad anti-influenza spectrum of activity. We analyzed the cellular gene expression response to infection with five different human and avian influenza A virus strains and identified 300 genes as differentially expressed between infected and non-infected samples. The most 20 dysregulated genes were used to screen the connectivity map, a database of drug-associated gene expression profiles. Candidate antivirals were then identified by their inverse correlation to the query signature. We hypothesized that such molecules would induce an unfavorable cellular environment for influenza virus replication. Eight potential antivirals including ribavirin were identified and their effects were tested in vitro on five influenza A strains. Six of the molecules inhibited influenza viral growth. The new pandemic H1N1 virus, which was not used to define the gene expression signature of infection, was inhibited by five out of the eight identified molecules, demonstrating that this strategy could contribute to identifying new broad anti-influenza agents acting on cellular gene expression. The identified infection signature genes, the expression of which are modified upon infection, could encode cellular proteins involved in the viral life cycle. This is the first study showing that gene expression-based screening can be

  8. A novel gene expression signature for bone metastasis in breast carcinomas.

    PubMed

    Savci-Heijink, C Dilara; Halfwerk, Hans; Koster, Jan; van de Vijver, Marc J

    2016-04-01

    Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up-regulated genes (NAT1, BBS1 and PH-4) were

  9. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.

    PubMed

    Baechler, Emily C; Batliwalla, Franak M; Karypis, George; Gaffney, Patrick M; Ortmann, Ward A; Espe, Karl J; Shark, Katherine B; Grande, William J; Hughes, Karis M; Kapur, Vivek; Gregersen, Peter K; Behrens, Timothy W

    2003-03-04

    Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.

  10. Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis.

    PubMed

    Zheng, C; Li, L; Haak, M; Brors, B; Frank, O; Giehl, M; Fabarius, A; Schatz, M; Weisser, A; Lorentz, C; Gretz, N; Hehlmann, R; Hochhaus, A; Seifarth, W

    2006-06-01

    Despite recent success in the treatment of early-stage disease, blastic phase (BP) of chronic myeloid leukemia (CML) that is characterized by rapid expansion of therapy-refractory and differentiation-arrested blasts, remains a therapeutic challenge. The development of resistance upon continuous administration of imatinib mesylate is associated with poor prognosis pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. To identify transcriptional signatures that may explain pathological characteristics and aggressive behavior of BP blasts, we performed comparative gene expression profiling on CD34+ Ph+ cells purified from patients with untreated newly diagnosed chronic phase CML (CP, n=11) and from patients in BP (n=9) using Affymetrix oligonucleotide arrays. Supervised microarray data analysis revealed 114 differentially expressed genes (P<10(-4)), 34 genes displaying more than two-fold transcriptional changes when comparing CP and BP groups. While 24 of these genes were downregulated, 10 genes, especially suppressor of cytokine signalling 2 (SOCS2), CAMPATH-1 antigen (CD52), and four human leukocyte antigen-related genes were strongly overexpressed in BP. Expression of selected genes was validated by real-time-polymerase chain reaction and flow cytometry. Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy.

  11. Expression profiling elucidates a molecular gene signature for pulmonary hypertension in sarcoidosis

    PubMed Central

    Singla, Sunit; Zhou, Tong; Javaid, Kamran; Abbasi, Taimur; Casanova, Nancy; Zhang, Wei; Ma, Shwu-Fan; Wade, Michael S.; Noth, Imre; Sweiss, Nadera J.; Garcia, Joe G. N.

    2016-01-01

    Abstract Pulmonary hypertension (PH), when it complicates sarcoidosis, carries a poor prognosis, in part because it is difficult to detect early in patients with worsening respiratory symptoms. Pathogenesis of sarcoidosis occurs via incompletely characterized mechanisms that are distinct from the mechanisms of pulmonary vascular remodeling well known to occur in conjunction with other chronic lung diseases. To address the need for a biomarker to aid in early detection as well as the gap in knowledge regarding the mechanisms of PH in sarcoidosis, we used genome-wide peripheral blood gene expression analysis and identified an 18-gene signature capable of distinguishing sarcoidosis patients with PH (n = 8), sarcoidosis patients without PH (n = 17), and healthy controls (n = 45). The discriminative accuracy of this 18-gene signature was 100% in separating sarcoidosis patients with PH from those without it. If validated in a large replicate cohort, this signature could potentially be used as a diagnostic molecular biomarker for sarcoidosis-associated PH. PMID:28090288

  12. A composite gene expression signature optimizes prediction of colorectal cancer metastasis and outcome

    PubMed Central

    Schell, Michael J.; Yang, Mingli; Missiaglia, Edoardo; Delorenzi, Mauro; Soneson, Charlotte; Yue, Binglin; Nebozhyn, Michael V.; Loboda, Andrey; Bloom, Gregory; Yeatman, Timothy J

    2015-01-01

    Purpose We previously found that an epithelial-to-mesenchymal transition (EMT)-based gene expression signature was highly correlated to the first principal component (PC1) of 326 colorectal cancer (CRC) tumors and was prognostic. This study was designed to improve these signatures for better prediction of metastasis and outcome. Experimental Design 468 CRC tumors including all stages (I–IV) and metastatic lesions were used to develop a new prognostic score (ΔPC1.EMT) by subtracting the EMT signature score from its correlated PC1 signature score. The score was validated on six other independent datasets with total 3697 tumors. Results ΔPC1.EMT was found to be far more predictive of metastasis and outcome than its parent scores. It performed well in Stages I–III, amongst MSI subtypes, and across multiple mutation-based subclasses, demonstrating a refined capacity to predict distant metastatic potential in tumors even with a “good” prognosis. For example, in the PETACC-3 clinical trial dataset it predicted worse overall survival in an adjusted multivariable model for Stage III patients (HR by IQR=1.50, 95%CI=1.25–1.81, P=0.000016, N=644). The improved performance of ΔPC1.EMT was related to its propensity of identifying epithelial-like subpopulations as well as mesenchymal-like subpopulations. Biologically, the signature was correlated positively with RAS signaling but negatively with mitochondrial metabolism. ΔPC1.EMT was a “best of assessed” prognostic score when compared to ten other known prognostic signatures. Conclusion The study developed a prognostic signature score with a propensity of detecting non-EMT features, including epithelial cancer stem cell-related properties, thereby improving its potential to predict metastasis and poorer outcome in Stages I-III patients. PMID:26446941

  13. A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients

    PubMed Central

    Afroz, Sumbul; Giddaluru, Jeevan; Vishwakarma, Sandeep; Naz, Saima; Khan, Aleem Ahmed; Khan, Nooruddin

    2017-01-01

    Rheumatoid arthritis (RA), a symmetric polyarticular arthritis, has long been feared as one of the most disabling forms of arthritis. Identification of gene signatures associated with RA onset and progression would lead toward development of novel diagnostics and therapeutic interventions. This study was undertaken to identify unique gene signatures of RA patients through large-scale meta-profiling of a diverse collection of gene expression data sets. We carried out a meta-analysis of 8 publicly available RA patients’ (107 RA patients and 76 healthy controls) gene expression data sets and further validated a few meta-signatures in RA patients through quantitative real-time PCR (RT-qPCR). We identified a robust meta-profile comprising 33 differentially expressed genes, which were consistently and significantly expressed across all the data sets. Our meta-analysis unearthed upregulation of a few novel gene signatures including PLCG2, HLA-DOB, HLA-F, EIF4E2, and CYFIP2, which were validated in peripheral blood mononuclear cell samples of RA patients. Further, functional and pathway enrichment analysis reveals perturbation of several meta-genes involved in signaling pathways pertaining to inflammation, antigen presentation, hypoxia, and apoptosis during RA. Additionally, PLCG2 (phospholipase Cγ2) popped out as a novel meta-gene involved in most of the pathways relevant to RA including inflammasome activation, platelet aggregation, and activation, thereby suggesting PLCG2 as a potential therapeutic target for controlling excessive inflammation during RA. In conclusion, these findings highlight the utility of meta-analysis approach in identifying novel gene signatures that might provide mechanistic insights into disease onset, progression and possibly lead toward the development of better diagnostic and therapeutic interventions against RA. PMID:28210261

  14. A Comprehensive Gene Expression Meta-analysis Identifies Novel Immune Signatures in Rheumatoid Arthritis Patients.

    PubMed

    Afroz, Sumbul; Giddaluru, Jeevan; Vishwakarma, Sandeep; Naz, Saima; Khan, Aleem Ahmed; Khan, Nooruddin

    2017-01-01

    Rheumatoid arthritis (RA), a symmetric polyarticular arthritis, has long been feared as one of the most disabling forms of arthritis. Identification of gene signatures associated with RA onset and progression would lead toward development of novel diagnostics and therapeutic interventions. This study was undertaken to identify unique gene signatures of RA patients through large-scale meta-profiling of a diverse collection of gene expression data sets. We carried out a meta-analysis of 8 publicly available RA patients' (107 RA patients and 76 healthy controls) gene expression data sets and further validated a few meta-signatures in RA patients through quantitative real-time PCR (RT-qPCR). We identified a robust meta-profile comprising 33 differentially expressed genes, which were consistently and significantly expressed across all the data sets. Our meta-analysis unearthed upregulation of a few novel gene signatures including PLCG2, HLA-DOB, HLA-F, EIF4E2, and CYFIP2, which were validated in peripheral blood mononuclear cell samples of RA patients. Further, functional and pathway enrichment analysis reveals perturbation of several meta-genes involved in signaling pathways pertaining to inflammation, antigen presentation, hypoxia, and apoptosis during RA. Additionally, PLCG2 (phospholipase Cγ2) popped out as a novel meta-gene involved in most of the pathways relevant to RA including inflammasome activation, platelet aggregation, and activation, thereby suggesting PLCG2 as a potential therapeutic target for controlling excessive inflammation during RA. In conclusion, these findings highlight the utility of meta-analysis approach in identifying novel gene signatures that might provide mechanistic insights into disease onset, progression and possibly lead toward the development of better diagnostic and therapeutic interventions against RA.

  15. Gene-expression signatures of Atlantic salmon’s plastic life cycle

    PubMed Central

    Aubin-Horth, Nadia; Letcher, Benjamin H.; Hofmann, Hans A.

    2009-01-01

    How genomic expression differs as a function of life history variation is largely unknown. Atlantic salmon exhibits extreme alternative life histories. We defined the gene-expression signatures of wild-caught salmon at two different life stages by comparing the brain expression profiles of mature sneaker males and immature males, and early migrants and late migrants. In addition to life-stage-specific signatures, we discovered a surprisingly large gene set that was differentially regulated - at similar magnitudes, yet in opposite direction - in both life history transitions. We suggest that this co-variation is not a consequence of many independent cellular and molecular switches in the same direction but rather represents the molecular equivalent of a physiological shift orchestrated by one or very few master regulators. PMID:19401203

  16. Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients.

    PubMed

    Liu, Rong; Zeng, Ying; Zhou, Cheng-Fang; Wang, Ying; Li, Xi; Liu, Zhao-Qian; Chen, Xiao-Ping; Zhang, Wei; Zhou, Hong-Hao

    2017-12-01

    Dysregulated long noncoding RNAs (lncRNAs) are potential markers of several tumor prognoses. This study aimed to develop a lncRNA expression signature that can predict chemotherapeutic sensitivity for patients with advanced stage and high-grade serous ovarian cancer (HGS-OvCa) treated with platinum-based chemotherapy. The lncRNA expression profiles of 258 HGS-OvCa patients from The Cancer Genome Atlas were analyzed. Results revealed that an eight-lncRNA signature was significantly associated with chemosensitivity in the multivariate logistic regression model, which can accurately predict the chemosensitivity of patients [Area under curve (AUC) = 0.83]. The association of a chemosensitivity predictor with molecular subtypes indicated the excellent prognosis performance of this marker in differentiated, mesenchymal, and immunoreactive subtypes (AUC > 0.8). The significant correlation between ZFAS1 expression and chemosensitivity was confirmed in 233 HGS-OvCa patients from the Gene Expression Omnibus datasets (GSE9891, GSE63885, and GSE51373). In vitro experiments demonstrated that the ZFAS1 expression was upregulated by cisplatin in A2008, HeyA8, and HeyC2 cell lines. This finding suggested that ZFAS1 may participate in platinum resistance. Therefore, the evaluation of the eight-lncRNA signature may be clinically implicated in the selection of platinum-resistant HGS-OvCa patients. The role of ZFAS1 in platinum resistance should be further investigated.

  17. Protein Expression Signatures for Inhibition of Epidermal Growth Factor Receptor-mediated Signaling*

    PubMed Central

    Myers, Matthew V.; Manning, H. Charles; Coffey, Robert J.; Liebler, Daniel C.

    2012-01-01

    Analysis of cellular signaling networks typically involves targeted measurements of phosphorylated protein intermediates. However, phosphoproteomic analyses usually require affinity enrichment of phosphopeptides and can be complicated by artifactual changes in phosphorylation caused by uncontrolled preanalytical variables, particularly in the analysis of tissue specimens. We asked whether changes in protein expression, which are more stable and easily analyzed, could reflect network stimulation and inhibition. We employed this approach to analyze stimulation and inhibition of the epidermal growth factor receptor (EGFR) by EGF and selective EGFR inhibitors. Shotgun analysis of proteomes from proliferating A431 cells, EGF-stimulated cells, and cells co-treated with the EGFR inhibitors cetuximab or gefitinib identified groups of differentially expressed proteins. Comparisons of these protein groups identified 13 proteins whose EGF-induced expression changes were reversed by both EGFR inhibitors. Targeted multiple reaction monitoring analysis verified differential expression of 12 of these proteins, which comprise a candidate EGFR inhibition signature. We then tested these 12 proteins by multiple reaction monitoring analysis in three other models: 1) a comparison of DiFi (EGFR inhibitor-sensitive) and HCT116 (EGFR-insensitive) cell lines, 2) in formalin-fixed, paraffin-embedded mouse xenograft DiFi and HCT116 tumors, and 3) in tissue biopsies from a patient with the gastric hyperproliferative disorder Ménétrier's disease who was treated with cetuximab. Of the proteins in the candidate signature, a core group, including c-Jun, Jagged-1, and Claudin 4, were decreased by EGFR inhibitors in all three models. Although the goal of these studies was not to validate a clinically useful EGFR inhibition signature, the results confirm the hypothesis that clinically used EGFR inhibitors generate characteristic protein expression changes. This work further outlines a prototypical

  18. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

    PubMed Central

    Flake, Darl D.; Busam, Klaus; Cockerell, Clay; Helm, Klaus; McNiff, Jennifer; Reed, Jon; Tschen, Jaime; Kim, Jinah; Barnhill, Raymond; Elenitsas, Rosalie; Prieto, Victor G.; Nelson, Jonathan; Kimbrell, Hillary; Kolquist, Kathryn A.; Brown, Krystal L.; Warf, M. Bryan; Roa, Benjamin B.; Wenstrup, Richard J.

    2016-01-01

    BACKGROUND Recently, a 23‐gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions. METHODS A set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis. RESULTS The gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%. CONCLUSIONS These results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617–628. © 2016 American Cancer Society. PMID:27768230

  19. Identification of Gene-Expression Signatures and Protein Markers for Breast Cancer Grading and Staging

    PubMed Central

    Yao, Fang; Zhang, Chi; Du, Wei; Liu, Chao; Xu, Ying

    2015-01-01

    The grade of a cancer is a measure of the cancer's malignancy level, and the stage of a cancer refers to the size and the extent that the cancer has spread. Here we present a computational method for prediction of gene signatures and blood/urine protein markers for breast cancer grades and stages based on RNA-seq data, which are retrieved from the TCGA breast cancer dataset and cover 111 pairs of disease and matching adjacent noncancerous tissues with pathologists-assigned stages and grades. By applying a differential expression and an SVM-based classification approach, we found that 324 and 227 genes in cancer have their expression levels consistently up-regulated vs. their matching controls in a grade- and stage-dependent manner, respectively. By using these genes, we predicted a 9-gene panel as a gene signature for distinguishing poorly differentiated from moderately and well differentiated breast cancers, and a 19-gene panel as a gene signature for discriminating between the moderately and well differentiated breast cancers. Similarly, a 30-gene panel and a 21-gene panel are predicted as gene signatures for distinguishing advanced stage (stages III-IV) from early stage (stages I-II) cancer samples and for distinguishing stage II from stage I samples, respectively. We expect these gene panels can be used as gene-expression signatures for cancer grade and stage classification. In addition, of the 324 grade-dependent genes, 188 and 66 encode proteins that are predicted to be blood-secretory and urine-excretory, respectively; and of the 227 stage-dependent genes, 123 and 51 encode proteins predicted to be blood-secretory and urine-excretory, respectively. We anticipate that some combinations of these blood and urine proteins could serve as markers for monitoring breast cancer at specific grades and stages through blood and urine tests. PMID:26375396

  20. A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer.

    PubMed

    Lai, Xianyin; Wang, Mu; McElyea, Samantha Deitz; Sherman, Stuart; House, Michael; Korc, Murray

    2017-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that often presents clinically at an advanced stage and that may be confused with chronic pancreatitis (CP). Conversely, CP may be misdiagnosed as PDAC leading to unwarranted pancreas resection. Therefore, early PDAC diagnosis and clear differentiation between PDAC and CP are crucial for improved care. Exosomes are circulating microvesicles whose components can serve as cancer biomarkers. We compared exosomal glypican-1 (GPC1) and microRNA levels in normal control subjects and in patients with PDAC and CP. We report that exosomal GPC1 is not diagnostic for PDAC, whereas high exosomal levels of microRNA-10b, (miR-10b), miR-21, miR-30c, and miR-181a and low miR-let7a readily differentiate PDAC from normal control and CP samples. By contrast with GPC1, elevated exosomal miR levels decreased to normal values within 24 h following PDAC resection. All 29 PDAC cases exhibited significantly elevated exosomal miR-10b and miR-30c levels, whereas 8 cases had normal or slightly increased CA 19-9 levels. Thus, our exosomal miR signature is superior to exosomal GPC1 or plasma CA 19-9 levels in establishing a diagnosis of PDAC and differentiating between PDAC and CP.

  1. Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.

    PubMed

    Quaranta, Maria; Knapp, Bettina; Garzorz, Natalie; Mattii, Martina; Pullabhatla, Venu; Pennino, Davide; Andres, Christian; Traidl-Hoffmann, Claudia; Cavani, Andrea; Theis, Fabian J; Ring, Johannes; Schmidt-Weber, Carsten B; Eyerich, Stefanie; Eyerich, Kilian

    2014-07-09

    Previous attempts to gain insight into the pathogenesis of psoriasis and eczema by comparing their molecular signatures were hampered by the high interindividual variability of those complex diseases. In patients affected by both psoriasis and nonatopic or atopic eczema simultaneously (n = 24), an intraindividual comparison of the molecular signatures of psoriasis and eczema identified genes and signaling pathways regulated in common and exclusive for each disease across all patients. Psoriasis-specific genes were important regulators of glucose and lipid metabolism, epidermal differentiation, as well as immune mediators of T helper 17 (TH17) responses, interleukin-10 (IL-10) family cytokines, and IL-36. Genes in eczema related to epidermal barrier, reduced innate immunity, increased IL-6, and a TH2 signature. Within eczema subtypes, a mutually exclusive regulation of epidermal differentiation genes was observed. Furthermore, only contact eczema was driven by inflammasome activation, apoptosis, and cellular adhesion. On the basis of this comprehensive picture of the pathogenesis of psoriasis and eczema, a disease classifier consisting of NOS2 and CCL27 was created. In an independent cohort of eczema (n = 28) and psoriasis patients (n = 25), respectively, this classifier diagnosed all patients correctly and also identified initially misdiagnosed or clinically undifferentiated patients.

  2. Expression of Von Hippel – Lindau (VHL) gene mutation in diagnosed cases of renal cell carcinoma

    PubMed Central

    Shahzad, Humera; Kehar, Shahnaz Imdad; Ali, Shahzad; Tariq, Naila

    2014-01-01

    Objective: To evaluate the expression of Von Hippel Lindau (VHL) gene in diagnosed cases of renal cell carcinoma. Methods: This cross sectional study was conducted in department of Pathology, Basic Medical Sciences Institute, JPMC, Karachi, from January 2007 to December 2012. Paraffin embedded blocks of 30 cases of radical nephrectomy specimens diagnosed as renal cell carcinoma including CCRCC 21 (70%) CCPRCC, 3 (10%), PRCC 2 (6.79%), hybrid tumor 4 (13.3%), chromophobe tumor (0%) processed for VHL gene expression on Polymerase Chain Reaction. Results: All the 30 cases previously diagnosed as renal cell carcinoma were processed on PCR, VHL gene mutations were seen in 20 (95.23%) of CCRCC while a single case was negative for VHL mutations. All CCPRCC were negative for VHL mutation. Among the hybrid tumor 03 cases with foci of clear cells show VHL mutation while a single case showing combination of clear cells and chromophobe cells was negative for mutation. Both the cases of PRCC were positive for mutation. Exon 3 mutation at base pair 194 seen in 8 (32%) cases and Exon 2 mutation at base pair 150-159 seen in 17 (68%) cases. None of the cases showed Exon 1 mutation. Conclusion: The present study shows that majority of CCRCC showed VHL mutation including the hybrid tumor with clear cell component in our population. PMID:25097537

  3. Distinct microRNA expression signatures in human right atrial and ventricular myocardium.

    PubMed

    Zhang, Yangyang; Wang, Xiaowei; Xu, Xiaohan; Wang, Jun; Liu, Xiang; Chen, Yijiang

    2012-12-01

    Human atrial and ventricular myocardium has distinct structure and physiology. MicroRNAs (miRNAs) are the central players in the regulation of gene expression, participating in many physiological processes. A comprehensive knowledge of miRNA expression in the human heart is essential for the understanding of myocardial function. The aim of this study was to compare the miRNA signature in human right atrial and ventricular myocardium. Agilent human miRNA arrays were used to indicate the miRNA expression signatures of the right atrial (n = 8) and ventricular (n = 9) myocardium of healthy individuals. Quantitative reverse transcription-polymerase chain reactions (qRT-PCRs) were used to validate the array results. DIANA-mirPath was used to incorporate the miRNAs into pathways. MiRNA arrays showed that 169 miRNAs were expressed at different levels in human right atrial and ventricular myocardium. The unsupervised hierarchical clustering analysis based on the 169 dysregulated miRNAs showed that miRNA expression categorized two well-defined clusters that corresponded to human right atrial and ventricular myocardium. The qRT-PCR results correlated well with the microarray data. Bioinformatic analysis indicated the potential miRNA targets and molecular pathways. This study indicates that distinct miRNA expression signatures in human right atrial and ventricular myocardium. The findings provide a novel understanding of the molecular differences between human atrial and ventricular myocardium and may establish a framework for an anatomically detailed evaluation of cardiac function regulation.

  4. Predicting Autism Spectrum Disorder Using Blood-based Gene Expression Signatures and Machine Learning

    PubMed Central

    Oh, Dong Hoon; Kim, Il Bin; Kim, Seok Hyeon; Ahn, Dong Hyun

    2017-01-01

    Objective The aim of this study was to identify a transcriptomic signature that could be used to classify subjects with autism spectrum disorder (ASD) compared to controls on the basis of blood gene expression profiles. The gene expression profiles could ultimately be used as diagnostic biomarkers for ASD. Methods We used the published microarray data (GSE26415) from the Gene Expression Omnibus database, which included 21 young adults with ASD and 21 age- and sex-matched unaffected controls. Nineteen differentially expressed probes were identified from a training dataset (n=26, 13 ASD cases and 13 controls) using the limma package in R language (adjusted p value <0.05) and were further analyzed in a test dataset (n=16, 8 ASD cases and 8 controls) using machine learning algorithms. Results Hierarchical cluster analysis showed that subjects with ASD were relatively well-discriminated from controls. Based on the support vector machine and K-nearest neighbors analysis, validation of 19-DE probes with a test dataset resulted in an overall class prediction accuracy of 93.8% as well as a sensitivity and specificity of 100% and 87.5%, respectively. Conclusion The results of our exploratory study suggest that the gene expression profiles identified from the peripheral blood samples of young adults with ASD can be used to identify a biological signature for ASD. Further study using a larger cohort and more homogeneous datasets is required to improve the diagnostic accuracy. PMID:28138110

  5. Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis

    PubMed Central

    de Jong, Simone; Newhouse, Stephen J.; Patel, Hamel; Lee, Sanghyuck; Dempster, David; Curtis, Charles; Paya-Cano, Jose; Murphy, Declan; Wilson, C. Ellie; Horder, Jamie; Mendez, M. Andreina; Asherson, Philip; Rivera, Margarita; Costello, Helen; Maltezos, Stefanos; Whitwell, Susannah; Pitts, Mark; Tye, Charlotte; Ashwood, Karen L.; Bolton, Patrick; Curran, Sarah; McGuffin, Peter; Dobson, Richard; Breen, Gerome

    2016-01-01

    Background Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. Aims To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). Method Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD–ASD (n = 16) and healthy controls (n = 78). Results Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures. Conclusions Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors. PMID:27151072

  6. Computational analysis of expression of human embryonic stem cell-associated signatures in tumors

    PubMed Central

    2011-01-01

    Background The cancer stem cell model has been proposed based on the linkage between human embryonic stem cells and human cancer cells. However, the evidences supporting the cancer stem cell model remain to be collected. In this study, we extensively examined the expression of human embryonic stem cell-associated signatures including core genes, transcription factors, pathways and microRNAs in various cancers using the computational biology approach. Results We used the class comparison analysis and survival analysis algorithms to identify differentially expressed genes and their associated transcription factors, pathways and microRNAs among normal vs. tumor or good prognosis vs. poor prognosis phenotypes classes based on numerous human cancer gene expression data. We found that most of the human embryonic stem cell- associated signatures were frequently identified in the analysis, suggesting a strong linkage between human embryonic stem cells and cancer cells. Conclusions The present study revealed the close linkage between the human embryonic stem cell associated gene expression profiles and cancer-associated gene expression profiles, and therefore offered an indirect support for the cancer stem cell theory. However, many interest issues remain to be addressed further. PMID:22041030

  7. A Cell Type-Specific Expression Signature Predicts Haploinsufficient Autism-Susceptibility Genes.

    PubMed

    Zhang, Chaolin; Shen, Yufeng

    2017-02-01

    Recent studies have identified many genes with rare de novo mutations in autism, but a limited number of these have been conclusively established as disease-susceptibility genes due to the lack of recurrence and confounding background mutations. Such extreme genetic heterogeneity severely limits recurrence-based statistical power even in studies with a large sample size. Here, we use cell-type specific expression profiles to differentiate mutations in autism patients from those in unaffected siblings. We report a gene expression signature in different neuronal cell types shared by genes with likely gene-disrupting (LGD) mutations in autism cases. This signature reflects haploinsufficiency of risk genes enriched in transcriptional and post-transcriptional regulators, with the strongest positive associations with specific types of neurons in different brain regions, including cortical neurons, cerebellar granule cells, and striatal medium spiny neurons. When used to prioritize genes with a single LGD mutation in cases, a D-score derived from the signature achieved a precision of 40% as compared with the 15% baseline with a minimal loss in sensitivity. An ensemble model combining D-score with mutation intolerance metrics from Exome Aggregation Consortium further improved the precision to 60%, resulting in 117 high-priority candidates. These prioritized lists can facilitate identification of additional autism-susceptibility genes.

  8. Next-generation sequencing of microRNAs uncovers expression signatures in polarized macrophages.

    PubMed

    Cobos Jiménez, Viviana; Bradley, Edward J; Willemsen, Antonius M; van Kampen, Antoine H C; Baas, Frank; Kootstra, Neeltje A

    2014-02-01

    microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at a posttranscriptional level and play a crucial role in the development of cells of the immune system. Macrophages are essential for generating inflammatory reactions upon tissue damage and encountering of invading pathogens, yet modulation of their immune responses is critical for maintaining tissue homeostasis. Macrophages can present different phenotypes, depending on the cytokine environment they encounter in the affected tissues. In this study, we have identified expression signatures of miRNAs that are differentially regulated during maturation of monocytes and polarization of macrophages by cytokines. We present a comprehensive characterization of miRNA expression in human monocytes and M1, M2a, and M2c polarized macrophages, using next-generation sequencing. Furthermore, we show that miRNA expression signatures are closely related to the various immune functions of polarized macrophages and therefore are involved in shaping the diverse phenotypes of these cells. The miRNAs identified here serve as markers for identification of inflammatory macrophages involved in the development of immune responses. Our findings contribute to understanding the role of miRNAs in determining the macrophage function in healthy and diseased tissues.

  9. Semantic Signature: Comparative Interpretation of Gene Expression on a Semantic Space.

    PubMed

    Kim, Jihun; Kim, Keewon; Kim, Ju Han

    2016-01-01

    Background. Interpretation of microarray data remains challenging because biological meaning should be extracted from enormous numeric matrices and be presented explicitly. Moreover, huge public repositories of microarray dataset are ready to be exploited for comparative analysis. This study aimed to provide a platform where essential implication of a microarray experiment could be visually expressed and various microarray datasets could be intuitively compared. Results. On the semantic space, gene sets from Molecular Signature Database (MSigDB) were plotted as landmarks and their relative distances were calculated by Lin's semantic similarity measure. By formal concept analysis, a microarray dataset was transformed into a concept lattice with gene clusters as objects and Gene Ontology terms as attributes. Concepts of a lattice were located on the semantic space reflecting semantic distance from landmarks and edges between concepts were drawn; consequently, a specific geographic pattern could be observed from a microarray dataset. We termed a distinctive geography shared by microarray datasets of the same category as "semantic signature." Conclusions. "Semantic space," a map of biological entities, could serve as a universal platform for comparative microarray analysis. When microarray data were displayed on the semantic space as concept lattices, "semantic signature," characteristic geography for a microarray experiment, could be discovered.

  10. A common molecular signature in ASD gene expression: following Root 66 to autism.

    PubMed

    Diaz-Beltran, L; Esteban, F J; Wall, D P

    2016-01-05

    Several gene expression experiments on autism spectrum disorders have been conducted using both blood and brain tissue. Individually, these studies have advanced our understanding of the molecular systems involved in the molecular pathology of autism and have formed the bases of ongoing work to build autism biomarkers. In this study, we conducted an integrated systems biology analysis of 9 independent gene expression experiments covering 657 autism, 9 mental retardation and developmental delay and 566 control samples to determine if a common signature exists and to test whether regulatory patterns in the brain relevant to autism can also be detected in blood. We constructed a matrix of differentially expressed genes from these experiments and used a Jaccard coefficient to create a gene-based phylogeny, validated by bootstrap. As expected, experiments and tissue types clustered together with high statistical confidence. However, we discovered a statistically significant subgrouping of 3 blood and 2 brain data sets from 3 different experiments rooted by a highly correlated regulatory pattern of 66 genes. This Root 66 appeared to be non-random and of potential etiologic relevance to autism, given their enriched roles in neurological processes key for normal brain growth and function, learning and memory, neurodegeneration, social behavior and cognition. Our results suggest that there is a detectable autism signature in the blood that may be a molecular echo of autism-related dysregulation in the brain.

  11. An immune-inflammation gene expression signature in prostate tumors of smokers

    PubMed Central

    Yi, Ming; Tang, Wei; Luo, Jun; Dorsey, Tiffany H.; Stagliano, Katherine E.; Gillespie, John W.; Hudson, Robert S.; Terunuma, Atsushi; Shoe, Jennifer L.; Haines, Diana C.; Yfantis, Harris G.; Han, Misop; Martin, Damali N.; Jordan, Symone V.; Borin, James F.; Naslund, Michael J.; Alexander, Richard B.; Stephens, Robert M.; Loffredo, Christopher A.; Lee, Dong H.; Putluri, Nagireddy; Sreekumar, Arun; Hurwitz, Arthur A.; Ambs, Stefan

    2016-01-01

    Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggested that nicotine was sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers. PMID:26719530

  12. An Orthologous Epigenetic Gene Expression Signature Derived from Differentiating Embryonic Stem Cells Identifies Regulators of Cardiogenesis.

    PubMed

    Busser, Brian W; Lin, Yongshun; Yang, Yanqin; Zhu, Jun; Chen, Guokai; Michelson, Alan M

    2015-01-01

    Here we used predictive gene expression signatures within a multi-species framework to identify the genes that underlie cardiac cell fate decisions in differentiating embryonic stem cells. We show that the overlapping orthologous mouse and human genes are the most accurate candidate cardiogenic genes as these genes identified the most conserved developmental pathways that characterize the cardiac lineage. An RNAi-based screen of the candidate genes in Drosophila uncovered numerous novel cardiogenic genes. shRNA knockdown combined with transcriptome profiling of the newly-identified transcription factors zinc finger protein 503 and zinc finger E-box binding homeobox 2 and the well-known cardiac regulatory factor NK2 homeobox 5 revealed that zinc finger E-box binding homeobox 2 activates terminal differentiation genes required for cardiomyocyte structure and function whereas zinc finger protein 503 and NK2 homeobox 5 are required for specification of the cardiac lineage. We further demonstrated that an essential role of NK2 homeobox 5 and zinc finger protein 503 in specification of the cardiac lineage is the repression of gene expression programs characteristic of alternative cell fates. Collectively, these results show that orthologous gene expression signatures can be used to identify conserved cardiogenic pathways.

  13. Gene Expression Profiling Identifies IRF4-Associated Molecular Signatures in Hematological Malignancies

    PubMed Central

    Wang, Ling; Yao, Zhi Q.; Moorman, Jonathan P.; Xu, Yanji; Ning, Shunbin

    2014-01-01

    The lymphocyte-specific transcription factor Interferon (IFN) Regulatory Factor 4 (IRF4) is implicated in certain types of lymphoid and myeloid malignancies. However, the molecular mechanisms underlying its interactions with these malignancies are largely unknown. In this study, we have first profiled molecular signatures associated with IRF4 expression in associated cancers, by analyzing existing gene expression profiling datasets. Our results show that IRF4 is overexpressed in melanoma, in addition to previously reported contexts including leukemia, myeloma, and lymphoma, and that IRF4 is associated with a unique gene expression pattern in each context. A pool of important genes involved in B-cell development, oncogenesis, cell cycle regulation, and cell death including BATF, LIMD1, CFLAR, PIM2, and CCND2 are common signatures associated with IRF4 in non-Hodgkin B cell lymphomas. We confirmed the correlation of IRF4 with LIMD1 and CFLAR in a panel of cell lines derived from lymphomas. Moreover, we profiled the IRF4 transcriptome in the context of EBV latent infection, and confirmed several genes including IFI27, IFI44, GBP1, and ARHGAP18, as well as CFLAR as novel targets for IRF4. These results provide valuable information for understanding the IRF4 regulatory network, and improve our knowledge of the unique roles of IRF4 in different hematological malignancies. PMID:25207815

  14. Identification of Aging-Associated Gene Expression Signatures That Precede Intestinal Tumorigenesis

    PubMed Central

    Okuchi, Yoshihisa; Imajo, Masamichi; Mizuno, Rei; Kamioka, Yuji; Miyoshi, Hiroyuki; Taketo, Makoto Mark; Nagayama, Satoshi; Sakai, Yoshiharu; Matsuda, Michiyuki

    2016-01-01

    Aging-associated alterations of cellular functions have been implicated in various disorders including cancers. Due to difficulties in identifying aging cells in living tissues, most studies have focused on aging-associated changes in whole tissues or certain cell pools. Thus, it remains unclear what kinds of alterations accumulate in each cell during aging. While analyzing several mouse lines expressing fluorescent proteins (FPs), we found that expression of FPs is gradually silenced in the intestinal epithelium during aging in units of single crypt composed of clonal stem cell progeny. The cells with low FP expression retained the wild-type Apc allele and the tissues composed of them did not exhibit any histological abnormality. Notably, the silencing of FPs was also observed in intestinal adenomas and the surrounding normal mucosae of Apc-mutant mice, and mediated by DNA methylation of the upstream promoter. Our genome-wide analysis then showed that the silencing of FPs reflects specific gene expression alterations during aging, and that these alterations occur in not only mouse adenomas but also human sporadic and hereditary (familial adenomatous polyposis) adenomas. Importantly, pharmacological inhibition of DNA methylation, which suppresses adenoma development in Apc-mutant mice, reverted the aging-associated silencing of FPs and gene expression alterations. These results identify aging-associated gene expression signatures that are heterogeneously induced by DNA methylation and precede intestinal tumorigenesis triggered by Apc inactivation, and suggest that pharmacological inhibition of the signature genes could be a novel strategy for the prevention and treatment of intestinal tumors. PMID:27589228

  15. PYGM expression analysis in white blood cells: a complementary tool for diagnosing McArdle disease?

    PubMed

    de Luna, Noemí; Brull, Astrid; Lucia, Alejandro; Santalla, Alfredo; Garatachea, Nuria; Martí, Ramon; Andreu, Antoni L; Pinós, Tomàs

    2014-12-01

    McArdle disease is caused by an inherited deficiency of the enzyme myophosphorylase, resulting in exercise intolerance from childhood and acute crises of early fatigue and contractures. In severe cases, these manifestations can be accompanied by rhabdomyolysis, myoglobinuria, and fatal renal failure. Diagnosis of McArdle disease is based on clinical diagnostic tests, together with an absence of myophosphorylase activity in skeletal muscle biopsies and genetic analysis of the myophosphorylase-encoding gene, PYGM. The recently reported association between myophosphorylase and Rac1 GTPase in a T lymphocyte cell line prompted us to study myophosphorylase expression in white blood cells (WBCs) from 20 healthy donors and 30 McArdle patients by flow cytometry using a fluorescent-labeled PYGM antibody. We found that T lymphocytes expressed myophosphorylase in healthy donors, but expression was significantly lower in McArdle patients (p<0.001). PYGM mRNA levels were also lower in white blood cells from McArdle patients. Nevertheless, in 13% of patients (who were either heterozygotes or homozygotes for the most common PYGM pathogenic mutation among Caucasians (p.R50X)), the percentage of myophosphorylase-positive white blood cells was not different compared with the control group. Our findings suggest that analysis of myophosphorylase expression in white blood cells might be a useful, less-invasive, complementary test for diagnosing McArdle disease.

  16. MARQ: an online tool to mine GEO for experiments with similar or opposite gene expression signatures.

    PubMed

    Vazquez, Miguel; Nogales-Cadenas, Ruben; Arroyo, Javier; Botías, Pedro; García, Raul; Carazo, Jose M; Tirado, Francisco; Pascual-Montano, Alberto; Carmona-Saez, Pedro

    2010-07-01

    The enormous amount of data available in public gene expression repositories such as Gene Expression Omnibus (GEO) offers an inestimable resource to explore gene expression programs across several organisms and conditions. This information can be used to discover experiments that induce similar or opposite gene expression patterns to a given query, which in turn may lead to the discovery of new relationships among diseases, drugs or pathways, as well as the generation of new hypotheses. In this work, we present MARQ, a web-based application that allows researchers to compare a query set of genes, e.g. a set of over- and under-expressed genes, against a signature database built from GEO datasets for different organisms and platforms. MARQ offers an easy-to-use and integrated environment to mine GEO, in order to identify conditions that induce similar or opposite gene expression patterns to a given experimental condition. MARQ also includes additional functionalities for the exploration of the results, including a meta-analysis pipeline to find genes that are differentially expressed across different experiments. The application is freely available at http://marq.dacya.ucm.es.

  17. A hemocyte gene expression signature correlated with predictive capacity of oysters to survive Vibrio infections

    PubMed Central

    2012-01-01

    Background The complex balance between environmental and host factors is an important determinant of susceptibility to infection. Disturbances of this equilibrium may result in multifactorial diseases as illustrated by the summer mortality syndrome, a worldwide and complex phenomenon that affects the oysters, Crassostrea gigas. The summer mortality syndrome reveals a physiological intolerance making this oyster species susceptible to diseases. Exploration of genetic basis governing the oyster resistance or susceptibility to infections is thus a major goal for understanding field mortality events. In this context, we used high-throughput genomic approaches to identify genetic traits that may characterize inherent survival capacities in C. gigas. Results Using digital gene expression (DGE), we analyzed the transcriptomes of hemocytes (immunocompetent cells) of oysters able or not able to survive infections by Vibrio species shown to be involved in summer mortalities. Hemocytes were nonlethally collected from oysters before Vibrio experimental infection, and two DGE libraries were generated from individuals that survived or did not survive. Exploration of DGE data and microfluidic qPCR analyses at individual level showed an extraordinary polymorphism in gene expressions, but also a set of hemocyte-expressed genes whose basal mRNA levels discriminate oyster capacity to survive infections by the pathogenic V. splendidus LGP32. Finally, we identified a signature of 14 genes that predicted oyster survival capacity. Their expressions are likely driven by distinct transcriptional regulation processes associated or not associated to gene copy number variation (CNV). Conclusions We provide here for the first time in oyster a gene expression survival signature that represents a useful tool for understanding mortality events and for assessing genetic traits of interest for disease resistance selection programs. PMID:22708697

  18. MicroRNA Expression Signature Is Altered in the Cardiac Remodeling Induced by High Fat Diets.

    PubMed

    Guedes, Elaine Castilho; França, Gustavo Starvaggi; Lino, Caroline Antunes; Koyama, Fernanda Christtanini; Moreira, Luana do Nascimento; Alexandre, Juliana Gomes; Barreto-Chaves, Maria Luiza M; Galante, Pedro Alexandre Favoretto; Diniz, Gabriela Placoná

    2016-08-01

    Recent studies have revealed the involvement of microRNAs (miRNAs) in the control of cardiac hypertrophy and myocardial function. In addition, several reports have demonstrated that high fat (HF) diet induces cardiac hypertrophy and remodeling. In the current study, we investigated the effect of diets containing different percentages of fat on the cardiac miRNA expression signature. To address this question, male C57Bl/6 mice were fed with a low fat (LF) diet or two HF diets, containing 45 kcal% fat (HF45%) and 60 kcal% fat (HF60%) for 10 and 20 weeks. HF60% diet promoted an increase on body weight, fasting glycemia, insulin, leptin, total cholesterol, triglycerides, and induced glucose intolerance. HF feeding promoted cardiac remodeling, as evidenced by increased cardiomyocyte transverse diameter and interstitial fibrosis. RNA sequencing analysis demonstrated that HF feeding induced distinct miRNA expression patterns in the heart. HF45% diet for 10 and 20 weeks changed the abundance of 64 and 26 miRNAs in the heart, respectively. On the other hand, HF60% diet for 10 and 20 weeks altered the abundance of 27 and 88 miRNAs in the heart, respectively. Bioinformatics analysis indicated that insulin signaling pathway was overrepresented in response to HF diet. An inverse correlation was observed between cardiac levels of GLUT4 and miRNA-29c. Similarly, we found an inverse correlation between expression of GSK3β and the expression of miRNA-21a-3p, miRNA-29c-3p, miRNA-144-3p, and miRNA-195a-3p. In addition, miRNA-1 overexpression prevented cardiomyocyte hypertrophy. Taken together, our results revealed differentially expressed miRNA signatures in the heart in response to different HF diets. J. Cell. Physiol. 231: 1771-1783, 2016. © 2015 Wiley Periodicals, Inc.

  19. Embryonic stem cell gene expression signatures in the canine mammary tumor: a bioinformatics approach.

    PubMed

    Zamani-Ahmadmahmudi, Mohamad

    2016-08-01

    Canine breast cancer was considered as an ideal model of comparative oncology for the human breast cancer, as there is significant overlap between biological and clinical characteristics of the human and canine breast cancer. We attempt to clarify expression profile of the embryonic stem cell (ES) gene signatures in canine breast cancer. Using microarray datasets (GSE22516 and GSE20718), expression of the three major ES gene signatures (modules or gene-sets), including Myc, ESC-like, and PRC modules, was primarily analyzed through Gene-Set Enrichment Analysis (GSEA) method in tumor and healthy datasets. For confirmation of the primary results, an additional 13 ES gene-sets which were categorized into four groups including ES expressed (ES exp1 and ES exp2), NOS targets (Nanog targets, Oct4 targets, Sox2 targets, NOS targets, and NOS TFs), Polycomb targets (Suz12 targets, Eed targets, H3K27 bound, and PRC2 targets), and Myc targets (Myc targets1, and Myc targets2) were tested in the tumor and healthy datasets. Our results revealed that there is a valuable overlap between canine and human breast cancer ES gene-sets expression profile, where Myc and ESC-like modules were up-regulated and PRC module was down-regulated in metastatic canine mammary gland tumors. Further analysis of the secondary gene-sets indicated overexpression of the ES expressed, NOS targets (Nanog targets, Oct4 targets, Sox2 targets, and NOS targets), and Myc targets and underexpression of the Polycomb targets in metastatic canine breast cancer.

  20. Genome-wide analysis of microRNA and mRNA expression signatures in cancer

    PubMed Central

    Li, Ming-hui; Fu, Sheng-bo; Xiao, Hua-sheng

    2015-01-01

    Cancer is an extremely diverse and complex disease that results from various genetic and epigenetic changes such as DNA copy-number variations, mutations, and aberrant mRNA and/or protein expression caused by abnormal transcriptional regulation. The expression profiles of certain microRNAs (miRNAs) and messenger RNAs (mRNAs) are closely related to cancer progression stages. In the past few decades, DNA microarray and next-generation sequencing techniques have been widely applied to identify miRNA and mRNA signatures for cancers on a genome-wide scale and have provided meaningful insights into cancer diagnosis, prognosis and personalized medicine. In this review, we summarize the progress in genome-wide analysis of miRNAs and mRNAs as cancer biomarkers, highlighting their diagnostic and prognostic roles. PMID:26299954

  1. An atlas of human gene expression from massively parallel signature sequencing (MPSS)

    PubMed Central

    Jongeneel, C. Victor; Delorenzi, Mauro; Iseli, Christian; Zhou, Daixing; Haudenschild, Christian D.; Khrebtukova, Irina; Kuznetsov, Dmitry; Stevenson, Brian J.; Strausberg, Robert L.; Simpson, Andrew J.G.; Vasicek, Thomas J.

    2005-01-01

    We have used massively parallel signature sequencing (MPSS) to sample the transcriptomes of 32 normal human tissues to an unprecedented depth, thus documenting the patterns of expression of almost 20,000 genes with high sensitivity and specificity. The data confirm the widely held belief that differences in gene expression between cell and tissue types are largely determined by transcripts derived from a limited number of tissue-specific genes, rather than by combinations of more promiscuously expressed genes. Expression of a little more than half of all known human genes seems to account for both the common requirements and the specific functions of the tissues sampled. A classification of tissues based on patterns of gene expression largely reproduces classifications based on anatomical and biochemical properties. The unbiased sampling of the human transcriptome achieved by MPSS supports the idea that most human genes have been mapped, if not functionally characterized. This data set should prove useful for the identification of tissue-specific genes, for the study of global changes induced by pathological conditions, and for the definition of a minimal set of genes necessary for basic cell maintenance. The data are available on the Web at http://mpss.licr.org and http://sgb.lynxgen.com. PMID:15998913

  2. Visualization and analysis for multidimensional gene expressions signature of cigarette smoking

    NASA Astrophysics Data System (ADS)

    Wang, Changbo; Xiao, Zhao; Zhang, Tianlun; Cui, Jin; Pang, Chenming

    2011-11-01

    Biologists often use gene chip to get massive experimental data in the field of bioscience and chemical sciences. Facing a large amount of experimental data, researchers often need to find out a few interesting data or simple regulations. This paper presents a set of methods to visualize and analyze the data for gene expression signatures of people who smoke. We use the latest research data from National Center for Biotechnology Information. Totally, there are more than 400 thousand expressions data. Using these data, we can use parallel coordinates method to visualize the different gene expressions between smokers and nonsmokers and we can distinguish non-smokers, former smokers and current smokers by using the different colors. It can be easy to find out which gene is more important during the lung cancer angiogenesis in the smoking people. In another way, we can use a hierarchical model to visualize the inner relation of different genes. The location of the nodes shows different expression moment and the distance to the root shows the sequence of the expression. We can use the ring layout to represent all the nodes, and connect the different nodes which are related with color lines. Combined with the parallel coordinates method, the visualization result show the important genes and some inner relation obviously, which is useful for examination and prevention of lung cancer.

  3. Effector CD4+ T cell expression signatures and immune-mediated disease associated genes.

    PubMed

    Zhang, Wei; Ferguson, John; Ng, Sok Meng; Hui, Ken; Goh, Gerald; Lin, Aiping; Esplugues, Enric; Flavell, Richard A; Abraham, Clara; Zhao, Hongyu; Cho, Judy H

    2012-01-01

    Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune-mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis.

  4. Genetic and epigenetic regulation and expression signatures of glutathione S-transferases in developing mouse liver.

    PubMed

    Cui, Julia Yue; Choudhuri, Supratim; Knight, Tamara R; Klaassen, Curtis D

    2010-07-01

    The hepatic glutathione S-transferases (Gsts) are critical phase II enzymes in protecting cellular macromolecules against electrophiles and oxidative stress. Little is known about the ontogeny of Gsts and the underlying regulatory mechanisms during liver development. Therefore, in this study, the ontogeny and the regulatory mechanisms of 19 known Gst isoforms were investigated in mouse liver from 2 days before birth to postnatal day 45. With the exception of Gstm5 and MGst2 that showed a progressive decline in postnatal messenger RNA (mRNA) expression, most other Gst isoforms showed a progressive increase in postnatal mRNA expression. Two-way hierarchical clustering revealed three distinct expression patterns of these Gsts isoforms: perinatal, adolescent, and adult enriched. The expression signatures of certain Gst isoforms showed positive association with the ontogeny of critical xenobiotic-sensing transcription factors, including aryl hydrocarbon receptor, pregnane X receptor (PXR), constitutive androstane receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor-2. Specifically, genome-wide chromatin immunoprecipitation coupled with the next generation sequencing technology (ChIP-Seq) revealed direct PXR-binding sites to the Gsta, Gstm, Gstt, and Gstp polycistron clusters as well as to the Mgst1 gene locus. Chromatin immunoprecipitation-on-chip analysis demonstrated that DNA methylation and histone H3K27-trimethylation (H3K27me3), two-gene expression-suppressing epigenetic marks, were consistently low around the Gstz1 gene locus. In contrast, enrichment of histone H3K4-dimethylation (H3K4me2), a hallmark for gene activation, increased 60% around the Gstz1 gene locus from prenatal to the young adult period. Regression analysis revealed a strong correlation between the enrichment of H3K4me2 and Gstz1 mRNA expression (r = 0.76). In conclusion, this study characterized three distinct ontogenic expression signatures of the 19 Gst isoforms

  5. Gene Expression Profiling Specifies Chemokine, Mitochondrial and Lipid Metabolism Signatures in Leprosy

    PubMed Central

    Guerreiro, Luana Tatiana Albuquerque; Robottom-Ferreira, Anna Beatriz; Ribeiro-Alves, Marcelo; Toledo-Pinto, Thiago Gomes; Rosa Brito, Tiana; Rosa, Patrícia Sammarco; Sandoval, Felipe Galvan; Jardim, Márcia Rodrigues; Antunes, Sérgio Gomes; Shannon, Edward J.; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal; Williams, Diana Lynn; Moraes, Milton Ozório

    2013-01-01

    Herein, we performed microarray experiments in Schwann cells infected with live M. leprae and identified novel differentially expressed genes (DEG) in M. leprae infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an in vitro model using THP-1 cells was infected with live Mycobacterium leprae and M. bovis bacillus Calmette-Guérin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate M. bovis BCG from M. leprae infection. Specific signatures of susceptible responses after M. leprae infection when compared to BCG lead to repression of genes, including CCL2, CCL3, IL8 and SOD2. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of CCL2 and CCL3 in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up-regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only LDLR and CCL4. A general immune and mitochondrial hypo-responsive state occurs in response to M. leprae infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy. PMID:23798993

  6. Airway basal cells of healthy smokers express an embryonic stem cell signature relevant to lung cancer.

    PubMed

    Shaykhiev, Renat; Wang, Rui; Zwick, Rachel K; Hackett, Neil R; Leung, Roland; Moore, Malcolm A S; Sima, Camelia S; Chao, Ion Wa; Downey, Robert J; Strulovici-Barel, Yael; Salit, Jacqueline; Crystal, Ronald G

    2013-09-01

    Activation of the human embryonic stem cell (hESC) signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pattern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung adenocarcinoma (AdCa) was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival, and higher frequency of TP53 mutations. BC-S shared with hESC and a considerable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evidence that smoking-induced reprogramming of airway BC toward the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carcinomas in humans.

  7. Gene Expression Music Algorithm-Based Characterization of the Ewing Sarcoma Stem Cell Signature

    PubMed Central

    2016-01-01

    Gene Expression Music Algorithm (GEMusicA) is a method for the transformation of DNA microarray data into melodies that can be used for the characterization of differentially expressed genes. Using this method we compared gene expression profiles from endothelial cells (EC), hematopoietic stem cells, neuronal stem cells, embryonic stem cells (ESC), and mesenchymal stem cells (MSC) and defined a set of genes that can discriminate between the different stem cell types. We analyzed the behavior of public microarray data sets from Ewing sarcoma (“Ewing family tumors,” EFT) cell lines and biopsies in GEMusicA after prefiltering DNA microarray data for the probe sets from the stem cell signature. Our results demonstrate that individual Ewing sarcoma cell lines have a high similarity to ESC or EC. Ewing sarcoma cell lines with inhibited Ewing sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWSR1-FLI1) oncogene retained the similarity to ESC and EC. However, correlation coefficients between GEMusicA-processed expression data between EFT and ESC decreased whereas correlation coefficients between EFT and EC as well as between EFT and MSC increased after knockdown of EWSR1-FLI1. Our data support the concept of EFT being derived from cells with features of embryonic and endothelial cells. PMID:27446218

  8. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature

    PubMed Central

    Viollet, Coralie; Davis, David A.; Tekeste, Shewit S.; Reczko, Martin; Pezzella, Francesco; Ragoussis, Jiannis

    2017-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases. PMID:28046107

  9. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature.

    PubMed

    Viollet, Coralie; Davis, David A; Tekeste, Shewit S; Reczko, Martin; Ziegelbauer, Joseph M; Pezzella, Francesco; Ragoussis, Jiannis; Yarchoan, Robert

    2017-01-01

    Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.

  10. Transcriptome-Level Signatures in Gene Expression and Gene Expression Variability during Bacterial Adaptive Evolution

    PubMed Central

    Erickson, Keesha E.; Otoupal, Peter B.

    2017-01-01

    ABSTRACT Antibiotic-resistant bacteria are an increasingly serious public health concern, as strains emerge that demonstrate resistance to almost all available treatments. One factor that contributes to the crisis is the adaptive ability of bacteria, which exhibit remarkable phenotypic and gene expression heterogeneity in order to gain a survival advantage in damaging environments. This high degree of variability in gene expression across biological populations makes it a challenging task to identify key regulators of bacterial adaptation. Here, we research the regulation of adaptive resistance by investigating transcriptome profiles of Escherichia coli upon adaptation to disparate toxins, including antibiotics and biofuels. We locate potential target genes via conventional gene expression analysis as well as using a new analysis technique examining differential gene expression variability. By investigating trends across the diverse adaptation conditions, we identify a focused set of genes with conserved behavior, including those involved in cell motility, metabolism, membrane structure, and transport, and several genes of unknown function. To validate the biological relevance of the observed changes, we synthetically perturb gene expression using clustered regularly interspaced short palindromic repeat (CRISPR)-dCas9. Manipulation of select genes in combination with antibiotic treatment promotes adaptive resistance as demonstrated by an increased degree of antibiotic tolerance and heterogeneity in MICs. We study the mechanisms by which identified genes influence adaptation and find that select differentially variable genes have the potential to impact metabolic rates, mutation rates, and motility. Overall, this work provides evidence for a complex nongenetic response, encompassing shifts in gene expression and gene expression variability, which underlies adaptive resistance. IMPORTANCE Even initially sensitive bacteria can rapidly thwart antibiotic treatment

  11. Transcriptome-Level Signatures in Gene Expression and Gene Expression Variability during Bacterial Adaptive Evolution.

    PubMed

    Erickson, Keesha E; Otoupal, Peter B; Chatterjee, Anushree

    2017-01-01

    Antibiotic-resistant bacteria are an increasingly serious public health concern, as strains emerge that demonstrate resistance to almost all available treatments. One factor that contributes to the crisis is the adaptive ability of bacteria, which exhibit remarkable phenotypic and gene expression heterogeneity in order to gain a survival advantage in damaging environments. This high degree of variability in gene expression across biological populations makes it a challenging task to identify key regulators of bacterial adaptation. Here, we research the regulation of adaptive resistance by investigating transcriptome profiles of Escherichia coli upon adaptation to disparate toxins, including antibiotics and biofuels. We locate potential target genes via conventional gene expression analysis as well as using a new analysis technique examining differential gene expression variability. By investigating trends across the diverse adaptation conditions, we identify a focused set of genes with conserved behavior, including those involved in cell motility, metabolism, membrane structure, and transport, and several genes of unknown function. To validate the biological relevance of the observed changes, we synthetically perturb gene expression using clustered regularly interspaced short palindromic repeat (CRISPR)-dCas9. Manipulation of select genes in combination with antibiotic treatment promotes adaptive resistance as demonstrated by an increased degree of antibiotic tolerance and heterogeneity in MICs. We study the mechanisms by which identified genes influence adaptation and find that select differentially variable genes have the potential to impact metabolic rates, mutation rates, and motility. Overall, this work provides evidence for a complex nongenetic response, encompassing shifts in gene expression and gene expression variability, which underlies adaptive resistance. IMPORTANCE Even initially sensitive bacteria can rapidly thwart antibiotic treatment through stress

  12. A Meta-analysis of Gene Expression Signatures of Blood Pressure and Hypertension

    PubMed Central

    Chen, Brian H.; Liu, Chunyu; Joehanes, Roby; Johnson, Andrew D.; Yao, Chen; Ying, Sai-xia; Courchesne, Paul; Milani, Lili; Raghavachari, Nalini; Wang, Richard; Liu, Poching; Reinmaa, Eva; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G.; Hernandez, Dena G.; Bandinelli, Stefania; Singleton, Andrew; Melzer, David; Metspalu, Andres; Carstensen, Maren; Grallert, Harald; Herder, Christian; Meitinger, Thomas; Peters, Annette; Roden, Michael; Waldenberger, Melanie; Dörr, Marcus; Felix, Stephan B.; Zeller, Tanja; Vasan, Ramachandran; O'Donnell, Christopher J.; Munson, Peter J.; Yang, Xia; Prokisch, Holger; Völker, Uwe; van Meurs, Joyce B. J.; Ferrucci, Luigi; Levy, Daniel

    2015-01-01

    Genome-wide association studies (GWAS) have uncovered numerous genetic variants (SNPs) that are associated with blood pressure (BP). Genetic variants may lead to BP changes by acting on intermediate molecular phenotypes such as coded protein sequence or gene expression, which in turn affect BP variability. Therefore, characterizing genes whose expression is associated with BP may reveal cellular processes involved in BP regulation and uncover how transcripts mediate genetic and environmental effects on BP variability. A meta-analysis of results from six studies of global gene expression profiles of BP and hypertension in whole blood was performed in 7017 individuals who were not receiving antihypertensive drug treatment. We identified 34 genes that were differentially expressed in relation to BP (Bonferroni-corrected p<0.05). Among these genes, FOS and PTGS2 have been previously reported to be involved in BP-related processes; the others are novel. The top BP signature genes in aggregate explain 5%–9% of inter-individual variance in BP. Of note, rs3184504 in SH2B3, which was also reported in GWAS to be associated with BP, was found to be a trans regulator of the expression of 6 of the transcripts we found to be associated with BP (FOS, MYADM, PP1R15A, TAGAP, S100A10, and FGBP2). Gene set enrichment analysis suggested that the BP-related global gene expression changes include genes involved in inflammatory response and apoptosis pathways. Our study provides new insights into molecular mechanisms underlying BP regulation, and suggests novel transcriptomic markers for the treatment and prevention of hypertension. PMID:25785607

  13. Glycan-related gene expression signatures in breast cancer subtypes; relation to survival.

    PubMed

    Potapenko, Ivan O; Lüders, Torben; Russnes, Hege G; Helland, Åslaug; Sørlie, Therese; Kristensen, Vessela N; Nord, Silje; Lingjærde, Ole C; Børresen-Dale, Anne-Lise; Haakensen, Vilde D

    2015-04-01

    Alterations in glycan structures are early signs of malignancy and have recently been proposed to be in part a driving force behind malignant transformation. Here, we explore whether differences in expression of genes related to the process of glycosylation exist between breast carcinoma subtypes - and look for their association to clinical parameters. Five expression datasets of 454 invasive breast carcinomas, 31 ductal carcinomas in situ (DCIS), and 79 non-malignant breast tissue samples were analysed. Results were validated in 1960 breast carcinomas. 419 genes encoding glycosylation-related proteins were selected. The DCIS samples appeared expression-wise similar to carcinomas, showing altered gene expression related to glycosaminoglycans (GAGs) and N-glycans when compared to non-malignant samples. In-situ lesions with different aggressiveness potentials demonstrated changes in glycosaminoglycan sulfation and adhesion proteins. Subtype-specific expression patterns revealed down-regulation of genes encoding glycan-binding proteins in the luminal A and B subtypes. Clustering basal-like samples using a consensus list of genes differentially expressed across discovery datasets produced two clusters with significantly differing prognosis in the validation dataset. Finally, our analyses suggest that glycolipids may play an important role in carcinogenesis of breast tumors - as demonstrated by association of B3GNT5 and UGCG genes to patient survival. In conclusion, most glycan-specific changes occur early in the carcinogenic process. We have identified glycan-related alterations specific to breast cancer subtypes including a prognostic signature for two basal-like subgroups. Future research in this area may potentially lead to markers for better prognostication and treatment stratification of breast cancer patients.

  14. Meta-Analysis of Gene Expression Signatures Defining the Epithelial to Mesenchymal Transition during Cancer Progression

    PubMed Central

    Gröger, Christian J.; Grubinger, Markus; Waldhör, Thomas; Vierlinger, Klemens; Mikulits, Wolfgang

    2012-01-01

    The epithelial to mesenchymal transition (EMT) represents a crucial event during cancer progression and dissemination. EMT is the conversion of carcinoma cells from an epithelial to a mesenchymal phenotype that associates with a higher cell motility as well as enhanced chemoresistance and cancer stemness. Notably, EMT has been increasingly recognized as an early event of metastasis. Numerous gene expression studies (GES) have been conducted to obtain transcriptome signatures and marker genes to understand the regulatory mechanisms underlying EMT. Yet, no meta-analysis considering the multitude of GES of EMT has been performed to comprehensively elaborate the core genes in this process. Here we report the meta-analysis of 18 independent and published GES of EMT which focused on different cell types and treatment modalities. Computational analysis revealed clustering of GES according to the type of treatment rather than to cell type. GES of EMT induced via transforming growth factor-β and tumor necrosis factor-α treatment yielded uniformly defined clusters while GES of models with alternative EMT induction clustered in a more complex fashion. In addition, we identified those up- and downregulated genes which were shared between the multitude of GES. This core gene list includes well known EMT markers as well as novel genes so far not described in this process. Furthermore, several genes of the EMT-core gene list significantly correlated with impaired pathological complete response in breast cancer patients. In conclusion, this meta-analysis provides a comprehensive survey of available EMT expression signatures and shows fundamental insights into the mechanisms that are governing carcinoma progression. PMID:23251436

  15. A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival

    PubMed Central

    Botta, C; Di Martino, M T; Ciliberto, D; Cucè, M; Correale, P; Rossi, M; Tagliaferri, P; Tassone, P

    2016-01-01

    Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment. PMID:27983725

  16. Aging-dependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination.

    PubMed

    Thakar, Juilee; Mohanty, Subhasis; West, A Phillip; Joshi, Samit R; Ueda, Ikuyo; Wilson, Jean; Meng, Hailong; Blevins, Tamara P; Tsang, Sui; Trentalange, Mark; Siconolfi, Barbara; Park, Koonam; Gill, Thomas M; Belshe, Robert B; Kaech, Susan M; Shadel, Gerald S; Kleinstein, Steven H; Shaw, Albert C

    2015-01-01

    To elucidate gene expression pathways underlying age-associated impairment in influenza vaccine response, we screened young (age 21-30) and older (age≥65) adults receiving influenza vaccine in two consecutive seasons and identified those with strong or absent response to vaccine, including a subset of older adults meeting criteria for frailty. PBMCs obtained prior to vaccination (Day 0) and at day 2 or 4, day 7 and day 28 post-vaccine were subjected to gene expression microarray analysis. We defined a response signature and also detected induction of a type I interferon response at day 2 and a plasma cell signature at day 7 post-vaccine in young responders. The response signature was dysregulated in older adults, with the plasma cell signature induced at day 2, and was never induced in frail subjects (who were all non-responders). We also identified a mitochondrial signature in young vaccine responders containing genes mediating mitochondrial biogenesis and oxidative phosphorylation that was consistent in two different vaccine seasons and verified by analyses of mitochondrial content and protein expression. These results represent the first genome-wide transcriptional profiling analysis of age-associated dynamics following influenza vaccination, and implicate changes in mitochondrial biogenesis and function as a critical factor in human vaccine responsiveness.

  17. Gene Expression Signature Analysis Identifies Vorinostat as a Candidate Therapy for Gastric Cancer

    PubMed Central

    Choi, Woonyoung; Park, Yun-Yong; Kim, KyoungHyun; Kim, Sang-Bae; Lee, Ju-Seog; Mills, Gordon B.; Cho, Jae Yong

    2011-01-01

    Background Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. Methodology/Principal Findings Using microarray technology, we generated a gene expression profile of human gastric cancer–specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. Conclusions/Significance We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment. PMID:21931799

  18. Gene expression signatures in tree shrew choroid in response to three myopiagenic conditions

    PubMed Central

    He, Li; Frost, Michael R.; Siegwart, John T.; Norton, Thomas T.

    2014-01-01

    We examined gene expression in tree shrew choroid in response to three different myopiagenic conditions: minus lens (ML) wear, form deprivation (FD), and continuous darkness (DK). Four groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye opening (days of visual experience [DVE]), the ML group wore a monocular −5 D lens for 2 days. The FD group wore a monocular translucent diffuser for 2 days. The DK group experienced continuous darkness binocularly for 11 days, starting at 17 DVE. An age-matched normal group was examined at 26 DVE. Quantitative PCR was used to measure the relative (treated eye vs. control eye) differences in mRNA levels in the choroid for 77 candidate genes. Small myopic changes were observed in the treated eyes (relative to the control eyes) of the ML group (−1.0 ± 0.2 D; mean ± SEM) and FD group (−1.9 ± 0.2 D). A larger myopia developed in the DK group (−4.4 ± 1.0 D) relative to Normal eyes (both groups, mean of right and left eyes). In the ML group, 28 genes showed significant differential mRNA expression; eighteen were down-regulated. A very similar pattern occurred in the FD group; twenty-seven of the same genes were similarly regulated, along with five additional genes. Fewer expression differences in the DK group were significant compared to normal or the control eyes of the ML and FD groups, but the pattern was similar to that of the ML and FD differential expression patterns. These data suggest that, at the level of the choroid, the gene expression signatures produced by “GO” emmetropization signals are highly similar despite the different visual conditions. PMID:25072854

  19. A gene expression signature that can predict green tea exposure and chemopreventive efficacy of lung cancer in mice.

    PubMed

    Lu, Yan; Yao, Ruisheng; Yan, Ying; Wang, Yian; Hara, Yukihiko; Lubet, Ronald A; You, Ming

    2006-02-15

    Green tea has been shown to be a potent chemopreventive agent against lung tumorigenesis in animal models. Previously, we found that treatment of A/J mice with either green tea (0.6% in water) or a defined green tea catechin extract (polyphenon E; 2.0 g/kg in diet) inhibited lung tumor tumorigenesis. Here, we described expression profiling of lung tissues derived from these studies to determine the gene expression signature that can predict the exposure and efficacy of green tea in mice. We first profiled global gene expressions in normal lungs versus lung tumors to determine genes which might be associated with the tumorigenic process (TUM genes). Gene expression in control tumors and green tea-treated tumors (either green tea or polyphenon E) were compared to determine those TUM genes whose expression levels in green tea-treated tumors returned to levels seen in normal lungs. We established a 17-gene expression profile specific for exposure to effective doses of either green tea or polyphenon E. This gene expression signature was altered both in normal lungs and lung adenomas when mice were exposed to green tea or polyphenon E. These experiments identified patterns of gene expressions that both offer clues for green tea's potential mechanisms of action and provide a molecular signature specific for green tea exposure.

  20. Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5'fluoruracil-based adjuvant chemotherapy.

    PubMed

    Giráldez, María Dolores; Lozano, Juan José; Cuatrecasas, Míriam; Alonso-Espinaco, Virginia; Maurel, Joan; Mármol, Maribel; Hörndler, Carlos; Ortego, Javier; Alonso, Vicente; Escudero, Pilar; Ramírez, Gina; Petry, Christoph; Lasalvia, Luis; Bohmann, Kerstin; Wirtz, Ralph; Mira, Aurea; Castells, Antoni

    2013-03-01

    Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high-risk patients. This study was aimed to identify a gene-expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5'fluoruracil (5FU)-based adjuvant chemotherapy. Two-hundred and twenty-eight patients diagnosed with Stages II-III colon cancer and treated with surgical resection and 5FU-based adjuvant chemotherapy were included. RNA was extracted from formalin-fixed, paraffin-embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT-qPCR. A tumor recurrence predicting model, including clinico-pathological variables and gene-expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71-4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12-6.42; p = 0.03). Identification of a new gene-expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU-based chemotherapy, and its combination in a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies.

  1. Lupus anti-ribosomal P autoantibody proteomes express convergent biclonal signatures.

    PubMed

    Al Kindi, M A; Colella, A D; Beroukas, D; Chataway, T K; Gordon, T P

    2016-04-01

    Lupus-specific anti-ribosomal P (anti-Rib-P) autoantibodies have been implicated in the pathogenesis of neurological complications in systemic lupus erythematosus (SLE). The aim of the present study was to determine variable (V)-region signatures of secreted autoantibody proteomes specific for the Rib-P heterocomplex and investigate the molecular basis of the reported cross-reactivity with Sm autoantigen. Anti-Rib-P immunoglobulins (IgGs) were purified from six anti-Rib-P-positive sera by elution from enzyme-linked immunosorbent assay (ELISA) plates coated with either native Rib-P proteins or an 11-amino acid peptide (11-C peptide) representing the conserved COOH-terminal P epitope. Rib-P- and 11-C peptide-specific IgGs were analysed for heavy (H) and light (L) chain clonality and V-region expression using an electrophoretic and de-novo and database-driven mass spectrometric sequencing workflow. Purified anti-Rib-P and anti-SmD IgGs were tested for cross-reactivity on ELISA and their proteome data sets analysed for shared clonotypes. Anti-Rib-P autoantibody proteomes were IgG1 kappa-restricted and comprised two public clonotypes defined by unique H/L chain pairings. The major clonotypic population was specific for the common COOH-terminal epitope, while the second shared the same pairing signature as a recently reported anti-SmD clonotype, accounting for two-way immunoassay cross-reactivity between these lupus autoantibodies. Sequence convergence of anti-Rib-P proteomes suggests common molecular pathways of autoantibody production and identifies stereotyped clonal populations that are thought to play a pathogenic role in neuropsychiatric lupus. Shared clonotypic structures for anti-Rib-P and anti-Sm responses suggest a common B cell clonal origin for subsets of these lupus-specific autoantibodies.

  2. MicroRNA Expression Signatures During Malignant Progression From Barrett's Esophagus.

    PubMed

    Bansal, Ajay; Gupta, Vijayalaxmi; Wang, Kenneth

    2016-06-01

    The rapid increase and poor survival of esophageal adenocarcinoma (EAC) have led to significant efforts to promote early detection. Given that the premalignant lesion of Barrett's esophagus (BE) is the major known risk factor for EAC, multiple investigators have studied biomarker signatures that can predict malignant progression of BE to EAC. MicroRNAs, a novel class of gene regulators, are small non-coding RNAs and have been associated with carcinogenesis. MicroRNAs are ideal biomarkers because of their remarkable stability in fixed tissues, a common method for collection of clinical specimens, and in blood either within exosomes or as microRNA-protein complexes. Multiple studies show potential of microRNAs as tissue and blood biomarkers for diagnosis and prognosis of EAC but the results need confirmation in prospective studies. Although head-to-head comparisons are lacking, microRNA panels require less genes than messenger RNA panels for diagnosis of EAC in BE. MicroRNA diagnostic panels will need to be compared for accuracy against global measures of genome instability that were recently shown to be good predictors of progression but require sophisticated analytic techniques. Early studies on blood microRNA panels are promising but have found microRNA markers to be inconsistent among studies. MicroRNA expression in blood is different between various microRNA sub-compartments such as exosomes and microRNA-protein complexes and could affect blood microRNA measurements. Further standardization is needed to yield consistent results. We have summarized the current understanding of the tissue and blood microRNA signatures that may predict the development and progression of EAC.

  3. Colon Cancer Cells Gene Expression Signature As Response to 5- Fluorouracil, Oxaliplatin, and Folinic Acid Treatment

    PubMed Central

    Negrei, Carolina; Hudita, Ariana; Ginghina, Octav; Galateanu, Bianca; Voicu, Sorina Nicoleta; Stan, Miriana; Costache, Marieta; Fenga, Concettina; Drakoulis, Nikolaos; Tsatsakis, Aristidis M.

    2016-01-01

    5-FU cytotoxicity mechanism has been assigned both to the miss-incorporation of fluoronucleotides into RNA and DNA and to the inhibition of thymidylate synthase. 5-FU is one of the most widely used chemotherapeutic drugs, although it has severe side effects that may vary between patients. Pharmacogenetic studies related to 5-FU have been traditionally focused on the rate-limiting catabolic enzyme, dihydropyrimidine dehydrogenase that breaks 80–85% of 5-FU into its inactive metabolite. Choosing the right dosing scheme and chemotherapy strategy for each individual patient remains challenging for personalized chemotherapy management. In the general effort toward reduction of colorectal cancer mortality, in vitro screening studies play a very important role. To accelerate translation research, increasing interest has been focused on using in vivo-like models such as three-dimensional spheroids. The development of higher throughput assays to quantify phenotypic changes in spheroids is an active research area. Consequently, in this study we used the microarray technology to reveal the HT-29 colorectal adenocarcinoma cells gene expression signature as response to 5-FU/OXP/FA treatment in a state of the art 3D culture system. We report here an increased reactive oxygen species production under treatment, correlated with a decrease in cell viability and proliferation potential. With respect to the HT-29 cells gene expression under the treatment with 5-FU/OXP/FA, we found 15.247 genes that were significantly differentially expressed (p < 0.05) with a fold change higher that two-fold. Among these, 7136 genes were upregulated and 8111 genes were downregulated under experimental conditions as compared to untreated cells. The most relevant and statistic significant (p < 0.01) pathways in the experiment are associated with the genes that displayed significant differential expression and are related to intracellular signaling, oxidative stress, apoptosis, and cancer. PMID

  4. A signature microRNA expression profile for the cellular response to thermal stress

    NASA Astrophysics Data System (ADS)

    Wilmink, Gerald J.; Roth, Caleb C.; Ketchum, Norma; Ibey, Bennett L.; Waterworth, Angela; Suarez, Maria; Roach, William P.

    2009-02-01

    Recently, an extensive layer of intra-cellular signals was discovered that was previously undetected by genetic radar. It is now known that this layer consists primarily of a class of short noncoding RNA species that are referred to as microRNAs (miRNAs). MiRNAs regulate protein synthesis at the post-transcriptional level, and studies have shown that they are involved in many fundamental cellular processes. In this study, we hypothesized that miRNAs may be involved in cellular stress response mechanisms, and that cells exposed to thermal stress may exhibit a signature miRNA expression profile indicative of their functional involvement in such mechanisms. To test our hypothesis, human dermal fibroblasts were exposed to an established hyperthermic protocol, and the ensuing miRNA expression levels were evaluated 4 hr post-exposure using microRNA microarray gene chips. The microarray data shows that 123 miRNAs were differentially expressed in cells exposed to thermal stress. We collectively refer to these miRNAs as thermalregulated microRNAs (TRMs). Since miRNA research is in its infancy, it is interesting to note that only 27 of the 123 TRMs are currently annotated in the Sanger miRNA registry. Prior to publication, we plan to submit the remaining novel 96 miRNA gene sequences for proper naming. Computational and thermodynamic modeling algorithms were employed to identify putative mRNA targets for the TRMs, and these studies predict that TRMs regulate the mRNA expression of various proteins that are involved in the cellular stress response. Future empirical studies will be conducted to validate these theoretical predictions, and to further examine the specific role that TRMs play in the cellular stress response.

  5. Gene expression signature of DMBA-induced hamster buccal pouch carcinomas: modulation by chlorophyllin and ellagic acid.

    PubMed

    Vidya Priyadarsini, Ramamurthi; Kumar, Neeraj; Khan, Imran; Thiyagarajan, Paranthaman; Kondaiah, Paturu; Nagini, Siddavaram

    2012-01-01

    Chlorophyllin (CHL), a water-soluble, semi-synthetic derivative of chlorophyll and ellagic acid (EA), a naturally occurring polyphenolic compound in berries, grapes, and nuts have been reported to exert anticancer effects in various human cancer cell lines and in animal tumour models. The present study was undertaken to examine the mechanism underlying chemoprevention and changes in gene expression pattern induced by dietary supplementation of chlorophyllin and ellagic acid in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by whole genome profiling using pangenomic microarrays. In hamsters painted with DMBA, the expression of 1,700 genes was found to be altered significantly relative to control. Dietary supplementation of chlorophyllin and ellagic acid modulated the expression profiles of 104 and 37 genes respectively. Microarray analysis also revealed changes in the expression of TGFβ receptors, NF-κB, cyclin D1, and matrix metalloproteinases (MMPs) that may play a crucial role in the transformation of the normal buccal pouch to a malignant phenotype. This gene expression signature was altered on treatment with chlorophyllin and ellagic acid. Our study has also revealed patterns of gene expression signature specific for chlorophyllin and ellagic acid exposure. Thus dietary chlorophyllin and ellagic acid that can reverse gene expression signature associated with carcinogenesis are novel candidates for cancer prevention and therapy.

  6. A Five-Gene Expression Signature Predicts Clinical Outcome of Ovarian Serous Cystadenocarcinoma

    PubMed Central

    Guo, Wenna

    2016-01-01

    Ovarian serous cystadenocarcinoma is a common malignant tumor of female genital organs. Treatment is generally less effective as patients are usually diagnosed in the late stage. Therefore, a well-designed prognostic marker provides valuable data for optimizing therapy. In this study, we analyzed 303 samples of ovarian serous cystadenocarcinoma and the corresponding RNA-seq data. We observed the correlation between gene expression and patients' survival and eventually established a risk assessment model of five factors using Cox proportional hazards regression analysis. We found that the survival time in high-risk patients was significantly shorter than in low-risk patients in both training and testing sets after Kaplan-Meier analysis. The AUROC value was 0.67 when predicting the survival time in testing set, which indicates a relatively high specificity and sensitivity. The results suggest diagnostic and therapeutic applications of our five-gene model for ovarian serous cystadenocarcinoma. PMID:27478834

  7. Blood-Based Gene Expression Signatures of Autistic Infants and Toddlers

    PubMed Central

    Glatt, Stephen J.; Tsuang, Ming T.; Winn, Mary; Chandler, Sharon D.; Collins, Melanie; Lopez, Linda; Weinfeld, Melanie; Carter, Cindy; Schork, Nicholas

    2013-01-01

    Objective Autism spectrum disorders (ASDs) are highly heritable neurodevelopmental disorders that onset clinically during the first years of life. ASD-risk biomarkers expressed early in life could significantly impact diagnosis and treatment, but no transcriptome-wide biomarker classifiers derived from fresh blood samples from children with autism have yet emerged. Method Using a community-based, prospective, longitudinal method, we identified 60 infants and toddlers at-risk for ASDs (autistic disorder and pervasive developmental disorder), 34 at-risk for language delay (LD), 17 at-risk for global developmental delay (DD), and 68 typically developing (TD) comparison children. Diagnoses were confirmed via longitudinal follow-up. Each child's mRNA expression profile in peripheral blood mononuclear cells (PBMCs) was determined by microarray. Results Potential ASD biomarkers were discovered in one half of the sample and used to build a classifier with high diagnostic accuracy in the remaining half of the sample. Conclusions The mRNA expression abnormalities reliably observed in PBMCs, which are safely and easily assayed in babies, offer the first potential peripheral blood-based early biomarker panel of risk for autism in infants and toddlers. Future work should verify these biomarkers and evaluate if they may also serve as indirect indices of deviant molecular neural mechanisms in autism. PMID:22917206

  8. Baseline Gene Expression Signatures in Monocytes from Multiple Sclerosis Patients Treated with Interferon-beta

    PubMed Central

    Bustamante, Marta F.; Nurtdinov, Ramil N.; Río, Jordi; Montalban, Xavier; Comabella, Manuel

    2013-01-01

    Background A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment. Methods Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays. Results and discussion Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb. PMID:23637780

  9. MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.

    PubMed

    Sandoval, Juan; Díaz-Lagares, Angel; Salgado, Rocío; Servitje, Octavio; Climent, Fina; Ortiz-Romero, Pablo L; Pérez-Ferriols, Amparo; Garcia-Muret, Maria P; Estrach, Teresa; Garcia, Mar; Nonell, Lara; Esteller, Manel; Pujol, Ramon M; Espinet, Blanca; Gallardo, Fernando

    2015-04-01

    MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.

  10. Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance

    PubMed Central

    Shi, Ke-Qing; Lin, Zhuo; Chen, Xiang-Jian; Song, Mei; Wang, Yu-Qun; Cai, Yi-Jing; Yang, Nai-Bing; Zheng, Ming-Hua; Dong, Jin-Zhong; Zhang, Lei; Chen, Yong-Ping

    2015-01-01

    microRNA (miRNA) expression profiles varied greatly among current studies due to different technological platforms and small sample size. Systematic and integrative analysis of published datesets that compared the miRNA expression profiles between hepatocellular carcinoma (HCC) tissue and paired adjacent noncancerous liver tissue was performed to determine candidate HCC associated miRNAs. Moreover, we further validated the confirmed miRNAs in a clinical setting using qRT-PCR and Tumor Cancer Genome Atlas (TCGA) dataset. A miRNA integrated-signature of 5 upregulated and 8 downregulated miRNAs was identified from 26 published datesets in HCC using robust rank aggregation method. qRT-PCR demonstrated that miR-93-5p, miR-224-5p, miR-221-3p and miR-21-5p was increased, whereas the expression of miR-214-3p, miR-199a-3p, miR-195-5p, miR-150-5p and miR-145-5p was decreased in the HCC tissues, which was also validated on TCGA dataset. A miRNA based score using LASSO regression model provided a high accuracy for identifying HCC tissue (AUC = 0.982): HCC risk score = 0.180E_miR-221 + 0.0262E_miR-21 - 0.007E_miR-223 - 0.185E_miR-130a. E_miR-n = Log 2 (expression of microRNA n). Furthermore, expression of 5 miRNAs (miR-222, miR-221, miR-21 miR-214 and miR-130a) correlated with pathological tumor grade. Cox regression analysis showed that miR-21 was related with 3-year survival (hazard ratio [HR]: 1.509, 95%CI: 1.079–2.112, P = 0.016) and 5-year survival (HR: 1.416, 95%CI: 1.057–1.897, P = 0.020). However, none of the deregulated miRNAs was related with microscopic vascular invasion. This study provides a basis for further clinical application of miRNAs in HCC. PMID:26231037

  11. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    PubMed Central

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-01-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity. PMID:26472689

  12. Long non-coding RNAs as novel expression signatures modulate DNA damage and repair in cadmium toxicology

    NASA Astrophysics Data System (ADS)

    Zhou, Zhiheng; Liu, Haibai; Wang, Caixia; Lu, Qian; Huang, Qinhai; Zheng, Chanjiao; Lei, Yixiong

    2015-10-01

    Increasing evidence suggests that long non-coding RNAs (lncRNAs) are involved in a variety of physiological and pathophysiological processes. Our study was to investigate whether lncRNAs as novel expression signatures are able to modulate DNA damage and repair in cadmium(Cd) toxicity. There were aberrant expression profiles of lncRNAs in 35th Cd-induced cells as compared to untreated 16HBE cells. siRNA-mediated knockdown of ENST00000414355 inhibited the growth of DNA-damaged cells and decreased the expressions of DNA-damage related genes (ATM, ATR and ATRIP), while increased the expressions of DNA-repair related genes (DDB1, DDB2, OGG1, ERCC1, MSH2, RAD50, XRCC1 and BARD1). Cadmium increased ENST00000414355 expression in the lung of Cd-exposed rats in a dose-dependent manner. A significant positive correlation was observed between blood ENST00000414355 expression and urinary/blood Cd concentrations, and there were significant correlations of lncRNA-ENST00000414355 expression with the expressions of target genes in the lung of Cd-exposed rats and the blood of Cd exposed workers. These results indicate that some lncRNAs are aberrantly expressed in Cd-treated 16HBE cells. lncRNA-ENST00000414355 may serve as a signature for DNA damage and repair related to the epigenetic mechanisms underlying the cadmium toxicity and become a novel biomarker of cadmium toxicity.

  13. Quantitative analysis of competition in posttranscriptional regulation reveals a novel signature in target expression variation.

    PubMed

    Klironomos, Filippos D; Berg, Johannes

    2013-02-19

    When small RNAs are loaded onto Argonaute proteins they can form the RNA-induced silencing complexes (RISCs), which mediate RNA interference (RNAi). RISC-formation is dependent on a shared pool of Argonaute proteins and RISC-loading factors, and is susceptible to competition among small RNAs. We present a mathematical model that aims to understand how small RNA competition for RISC-formation affects target gene repression. We discuss that small RNA activity is limited by RISC-formation, RISC-degradation, and the availability of Argonautes. We show that different competition conditions for RISC-loading result in different signatures of RNAi determined also by the amount of RISC-recycling taking place. In particular, we find that the small RNAs, although less efficient at RISC-formation, can perform in the low RISC-recycling range as well as their more effective counterparts. Additionally, we predict that under conditions of low RISC-loading efficiency and high RISC-recycling, the variation in target levels increases linearly with the target transcription rate. Furthermore, we show that RISC-recycling determines the effect that Argonaute scarcity conditions have on target expression variation. Our observations, taken together, offer a framework of predictions that can be used to infer from data the particular characteristics of underlying RNAi activity.

  14. A gene expression signature of confinement in peripheral blood of red wolves (Canis rufus).

    PubMed

    Kennerly, Erin; Ballmann, Anne; Martin, Stanton; Wolfinger, Russ; Gregory, Simon; Stoskopf, Michael; Gibson, Greg

    2008-06-01

    The stresses that animals experience as a result of modification of their ecological circumstances induce physiological changes that leave a signature in profiles of gene expression. We illustrate this concept in a comparison of free range and confined North American red wolves (Canis rufus). Transcription profiling of peripheral blood samples from 13 red wolf individuals in the Alligator River region of North Carolina revealed a strong signal of differentiation. Four hundred eighty-two out of 2980 transcripts detected on Illumina HumanRef8 oligonucleotide bead arrays were found to differentiate free range and confined wolves at a false discovery rate of 12.8% and P < 0.05. Over-representation of genes in focal adhesion, insulin signalling, proteasomal, and tryptophan metabolism pathways suggests the activation of pro-inflammatory and stress responses in confined animals. Consequently, characterization of differential transcript abundance in an accessible tissue such as peripheral blood identifies biomarkers that could be useful in animal management practices and for evaluating the impact of habitat changes on population health, particularly as attention turns to the impact of climate change on physiology and in turn species distributions.

  15. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

    PubMed Central

    Varshney, Arushi; Scott, Laura J.; Welch, Ryan P.; Erdos, Michael R.; Chines, Peter S.; Narisu, Narisu; Albanus, Ricardo D’O.; Orchard, Peter; Wolford, Brooke N.; Kursawe, Romy; Vadlamudi, Swarooparani; Cannon, Maren E.; Didion, John P.; Hensley, John; Kirilusha, Anthony; Bonnycastle, Lori L.; Taylor, D. Leland; Watanabe, Richard; Mohlke, Karen L.; Boehnke, Michael; Collins, Francis S.; Parker, Stephen C. J.; Stitzel, Michael L.

    2017-01-01

    Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition. PMID:28193859

  16. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes.

    PubMed

    Varshney, Arushi; Scott, Laura J; Welch, Ryan P; Erdos, Michael R; Chines, Peter S; Narisu, Narisu; Albanus, Ricardo D'O; Orchard, Peter; Wolford, Brooke N; Kursawe, Romy; Vadlamudi, Swarooparani; Cannon, Maren E; Didion, John P; Hensley, John; Kirilusha, Anthony; Bonnycastle, Lori L; Taylor, D Leland; Watanabe, Richard; Mohlke, Karen L; Boehnke, Michael; Collins, Francis S; Parker, Stephen C J; Stitzel, Michael L

    2017-02-28

    Genome-wide association studies (GWAS) have identified >100 independent SNPs that modulate the risk of type 2 diabetes (T2D) and related traits. However, the pathogenic mechanisms of most of these SNPs remain elusive. Here, we examined genomic, epigenomic, and transcriptomic profiles in human pancreatic islets to understand the links between genetic variation, chromatin landscape, and gene expression in the context of T2D. We first integrated genome and transcriptome variation across 112 islet samples to produce dense cis-expression quantitative trait loci (cis-eQTL) maps. Additional integration with chromatin-state maps for islets and other diverse tissue types revealed that cis-eQTLs for islet-specific genes are specifically and significantly enriched in islet stretch enhancers. High-resolution chromatin accessibility profiling using assay for transposase-accessible chromatin sequencing (ATAC-seq) in two islet samples enabled us to identify specific transcription factor (TF) footprints embedded in active regulatory elements, which are highly enriched for islet cis-eQTL. Aggregate allelic bias signatures in TF footprints enabled us de novo to reconstruct TF binding affinities genetically, which support the high-quality nature of the TF footprint predictions. Interestingly, we found that T2D GWAS loci were strikingly and specifically enriched in islet Regulatory Factor X (RFX) footprints. Remarkably, within and across independent loci, T2D risk alleles that overlap with RFX footprints uniformly disrupt the RFX motifs at high-information content positions. Together, these results suggest that common regulatory variations have shaped islet TF footprints and the transcriptome and that a confluent RFX regulatory grammar plays a significant role in the genetic component of T2D predisposition.

  17. Combining modelling and experimental approaches to explain how calcium signatures are decoded by calmodulin-binding transcription activators (CAMTAs) to produce specific gene expression responses.

    PubMed

    Liu, Junli; Whalley, Helen J; Knight, Marc R

    2015-10-01

    Experimental data show that Arabidopsis thaliana is able to decode different calcium signatures to produce specific gene expression responses. It is also known that calmodulin-binding transcription activators (CAMTAs) have calmodulin (CaM)-binding domains. Therefore, the gene expression responses regulated by CAMTAs respond to calcium signals. However, little is known about how different calcium signatures are decoded by CAMTAs to produce specific gene expression responses. A dynamic model of Ca(2+) -CaM-CAMTA binding and gene expression responses is developed following thermodynamic and kinetic principles. The model is parameterized using experimental data. Then it is used to analyse how different calcium signatures are decoded by CAMTAs to produce specific gene expression responses. Modelling analysis reveals that: calcium signals in the form of cytosolic calcium concentration elevations are nonlinearly amplified by binding of Ca(2+) , CaM and CAMTAs; amplification of Ca(2+) signals enables calcium signatures to be decoded to give specific CAMTA-regulated gene expression responses; gene expression responses to a calcium signature depend upon its history and accumulate all the information during the lifetime of the calcium signature. Information flow from calcium signatures to CAMTA-regulated gene expression responses has been established by combining experimental data with mathematical modelling.

  18. KRAS driven expression signature has prognostic power superior to mutation status in non‐small cell lung cancer

    PubMed Central

    Nagy, Ádám; Pongor, Lőrinc Sándor; Szabó, András; Santarpia, Mariacarmela

    2016-01-01

    KRAS is the most frequently mutated oncogene in non‐small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA‐seq data into KRAS mutated and wild type groups. Mann‐Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a “transcriptomic fingerprint” of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis. Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage. We generated a “surrogate signature” of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself. PMID:27859136

  19. From big data to diagnosis and prognosis: gene expression signatures in liver hepatocellular carcinoma

    PubMed Central

    Cai, Xiao-yong; Wen, Dong-yue; Ye, Zhi-hua; Liang, Liang; Zhang, Lu; Wang, Han-lin

    2017-01-01

    Background Liver hepatocellular carcinoma accounts for the overwhelming majority of primary liver cancers and its belated diagnosis and poor prognosis call for novel biomarkers to be discovered, which, in the era of big data, innovative bioinformatics and computational techniques can prove to be highly helpful in. Methods Big data aggregated from The Cancer Genome Atlas and Natural Language Processing were integrated to generate differentially expressed genes. Relevant signaling pathways of differentially expressed genes went through Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes and Panther pathway enrichment analysis and protein-protein interaction network. The pathway ranked high in the enrichment analysis was further investigated, and selected genes with top priority were evaluated and assessed in terms of their diagnostic and prognostic values. Results A list of 389 genes was generated by overlapping genes from The Cancer Genome Atlas and Natural Language Processing. Three pathways demonstrated top priorities, and the one with specific associations with cancers, ‘pathways in cancer,’ was analyzed with its four highlighted genes, namely, BIRC5, E2F1, CCNE1, and CDKN2A, which were validated using Oncomine. The detection pool composed of the four genes presented satisfactory diagnostic power with an outstanding integrated AUC of 0.990 (95% CI [0.982–0.998], P < 0.001, sensitivity: 96.0%, specificity: 96.5%). BIRC5 (P = 0.021) and CCNE1 (P = 0.027) were associated with poor prognosis, while CDKN2A (P = 0.066) and E2F1 (P = 0.088) demonstrated no statistically significant differences. Discussion The study illustrates liver hepatocellular carcinoma gene signatures, related pathways and networks from the perspective of big data, featuring the cancer-specific pathway with priority, ‘pathways in cancer.’ The detection pool of the four highlighted genes, namely BIRC5, E2F1, CCNE1 and CDKN2A, should be further investigated

  20. Validation study of existing gene expression signatures for anti-TNF treatment in patients with rheumatoid arthritis.

    PubMed

    Toonen, Erik J M; Gilissen, Christian; Franke, Barbara; Kievit, Wietske; Eijsbouts, Agnes M; den Broeder, Alfons A; van Reijmersdal, Simon V; Veltman, Joris A; Scheffer, Hans; Radstake, Timothy R D J; van Riel, Piet L C M; Barrera, Pilar; Coenen, Marieke J H

    2012-01-01

    So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response.

  1. Validation Study of Existing Gene Expression Signatures for Anti-TNF Treatment in Patients with Rheumatoid Arthritis

    PubMed Central

    Toonen, Erik J. M.; Gilissen, Christian; Franke, Barbara; Kievit, Wietske; Eijsbouts, Agnes M.; den Broeder, Alfons A.; van Reijmersdal, Simon V.; Veltman, Joris A.; Scheffer, Hans; Radstake, Timothy R. D. J.; van Riel, Piet L. C. M.; Barrera, Pilar; Coenen, Marieke J. H.

    2012-01-01

    So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response. PMID:22457743

  2. No Specific Gene Expression Signature in Human Granulosa and Cumulus Cells for Prediction of Oocyte Fertilisation and Embryo Implantation

    PubMed Central

    Burnik Papler, Tanja; Vrtacnik Bokal, Eda; Lovrecic, Luca; Kopitar, Andreja Natasa; Maver, Ales

    2015-01-01

    In human IVF procedures objective and reliable biomarkers of oocyte and embryo quality are needed in order to increase the use of single embryo transfer (SET) and thus prevent multiple pregnancies. During folliculogenesis there is an intense bi-directional communication between oocyte and follicular cells. For this reason gene expression profile of follicular cells could be an important indicator and biomarker of oocyte and embryo quality. The objective of this study was to identify gene expression signature(s) in human granulosa (GC) and cumulus (CC) cells predictive of successful embryo implantation and oocyte fertilization. Forty-one patients were included in the study and individual GC and CC samples were collected; oocytes were cultivated separately, allowing a correlation with IVF outcome and elective SET was performed. Gene expression analysis was performed using microarrays, followed by a quantitative real-time PCR validation. After statistical analysis of microarray data, there were no significantly differentially expressed genes (FDR<0,05) between non-fertilized and fertilized oocytes and non-implanted and implanted embryos in either of the cell type. Furthermore, the results of quantitative real-time PCR were in consent with microarray data as there were no significant differences in gene expression of genes selected for validation. In conclusion, we did not find biomarkers for prediction of oocyte fertilization and embryo implantation in IVF procedures in the present study. PMID:25769026

  3. Identifying protective host gene expression signatures within the spleen during West Nile virus infection in the collaborative cross model.

    PubMed

    Green, Richard; Wilkins, Courtney; Thomas, Sunil; Sekine, Aimee; Ireton, Renee C; Ferris, Martin T; Hendrick, Duncan M; Voss, Kathleen; de Villena, Fernando Pardo-Manuel; Baric, Ralph; Heise, Mark; Gale, Michael

    2016-12-01

    Flaviviruses are hematophagous arthropod-viruses that pose global challenges to human health. Like Zika virus, West Nile Virus (WNV) is a flavivirus for which no approved vaccine exists [1]. The role host genetics play in early detection and response to WNV still remains largely unexplained. In order to capture the impact of genetic variation on innate immune responses, we studied gene expression following WNV infection using the collaborative cross (CC). The CC is a mouse genetics resource composed of hundreds of independently bred, octo-parental recombinant inbred mouse lines [2]. To accurately capture the host immune gene expression signatures of West Nile infection, we used the nanostring platform to evaluate expression in spleen tissue isolated from CC mice infected with WNV over a time course of 4, 7, and 12 days' post-infection [3]. Nanostring is a non-amplification based digital method to quantitate gene expression that uses color-coded molecular barcodes to detect hundreds of transcripts in a sample. Using this approach, we identified unique gene signatures in spleen tissue at days 4, 7, and 12 following WNV infection, which delineated distinct differences between asymptomatic and symptomatic CC lines. We also identified novel immune genes. Data was deposited into the Gene Expression Omnibus under accession GSE86000.

  4. Pharmacologic inhibition of RORγt regulates Th17 signature gene expression and suppresses cutaneous inflammation in vivo.

    PubMed

    Skepner, Jill; Ramesh, Radha; Trocha, Mark; Schmidt, Darby; Baloglu, Erkan; Lobera, Mercedes; Carlson, Thaddeus; Hill, Jonathan; Orband-Miller, Lisa A; Barnes, Ashley; Boudjelal, Mohamed; Sundrud, Mark; Ghosh, Shomir; Yang, Jianfei

    2014-03-15

    IL-17-producing CD4(+)Th17 cells, CD8(+)Tc17 cells, and γδ T cells play critical roles in the pathogenesis of autoimmune psoriasis. RORγt is required for the differentiation of Th17 cells and expression of IL-17. In this article, we describe a novel, potent, and selective RORγt inverse agonist (TMP778), and its inactive diastereomer (TMP776). This chemistry, for the first time to our knowledge, provides a unique and powerful set of tools to probe RORγt-dependent functions. TMP778, but not TMP776, blocked human Th17 and Tc17 cell differentiation and also acutely modulated IL-17A production and inflammatory Th17-signature gene expression (Il17a, Il17f, Il22, Il26, Ccr6, and Il23) in mature human Th17 effector/memory T cells. In addition, TMP778, but not TMP776, inhibited IL-17A production in both human and mouse γδ T cells. IL-23-induced IL-17A production was also blocked by TMP778 treatment. In vivo targeting of RORγt in mice via TMP778 administration reduced imiquimod-induced psoriasis-like cutaneous inflammation. Further, TMP778 selectively regulated Th17-signature gene expression in mononuclear cells isolated from both the blood and affected skin of psoriasis patients. In summary, to our knowledge, we are the first to demonstrate that RORγt inverse agonists: 1) inhibit Tc17 cell differentiation, as well as IL-17 production by γδ T cells and CD8(+) Tc17 cells; 2) block imiquimod-induced cutaneous inflammation; 3) inhibit Th17 signature gene expression by cells isolated from psoriatic patient samples; and 4) block IL-23-induced IL-17A expression. Thus, RORγt is a tractable drug target for the treatment of cutaneous inflammatory disorders, which may afford additional therapeutic benefit over existing modalities that target only IL-17A.

  5. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis

    PubMed Central

    Zhan, Fenghuang; Barlogie, Bart; Arzoumanian, Varant; Huang, Yongsheng; Williams, David R.; Hollmig, Klaus; Pineda-Roman, Mauricio; Tricot, Guido; van Rhee, Frits; Zangari, Maurizio; Dhodapkar, Madhav; Shaughnessy, John D.

    2007-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n = 22) and patients with stringently defined MGUS/smoldering MM (n = 24) and symptomatic MM (n = 351) (P < .001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24 + 20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P = .006), was associated with low-risk clinical and molecular features and superior survival (P < .01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias. PMID:17023574

  6. Comparative proteomic analysis of four Bacillus clausii strains: proteomic expression signature distinguishes protein profile of the strains.

    PubMed

    Lippolis, Rosa; Gnoni, Antonio; Abbrescia, Anna; Panelli, Damiano; Maiorano, Stefania; Paternoster, Maria Stefania; Sardanelli, Anna Maria; Papa, Sergio; Gaballo, Antonio

    2011-11-18

    A comparative proteomic approach, using two dimensional gel electrophoresis and mass spectrometry, has been developed to compare and elucidate the differences among the cellular proteomes of four closely related isogenic O/C, SIN, N/R and T, B. clausii strains during both exponential and stationary phases of growth. Image analysis of the electropherograms reveals a high degree of concordance among the four proteomes, some proteins result, however, differently expressed. The proteins spots exhibiting high different expression level were identified, by mass-spectrometry analysis, as alcohol dehydrogenase (ADHA, EC1.2.1.3; ABC0046 isoform) aldehyde dehydrogenase (DHAS, EC 1.2.1.3; ABC0047 isoform) and flagellin-protein of B. clausii KSM-k16. The different expression levels of the two dehydrogenases were confirmed by quantitative RT-PCR and dehydrogenases enzymatic activity. The different patterns of protein expression can be considered as cell proteome signatures of the different strains.

  7. A differentially expressed set of microRNAs in cerebro-spinal fluid (CSF) can diagnose CNS malignancies.

    PubMed

    Drusco, Alessandra; Bottoni, Arianna; Laganà, Alessandro; Acunzo, Mario; Fassan, Matteo; Cascione, Luciano; Antenucci, Anna; Kumchala, Prasanthi; Vicentini, Caterina; Gardiman, Marina P; Alder, Hansjuerg; Carosi, Mariantonia A; Ammirati, Mario; Gherardi, Stefano; Luscrì, Marilena; Carapella, Carmine; Zanesi, Nicola; Croce, Carlo M

    2015-08-28

    Central Nervous System malignancies often require stereotactic biopsy or biopsy for differential diagnosis, and for tumor staging and grading. Furthermore, stereotactic biopsy can be non-diagnostic or underestimate grading. Hence, there is a compelling need of new diagnostic biomarkers to avoid such invasive procedures. Several biological markers have been proposed, but they can only identify specific prognostic subtype of Central Nervous System tumors, and none of them has found a standardized clinical application.The aim of the study was to identify a Cerebro-Spinal Fluid microRNA signature that could differentiate among Central Nervous System malignancies.CSF total RNA of 34 neoplastic and of 14 non-diseased patients was processed by NanoString. Comparison among groups (Normal, Benign, Glioblastoma, Medulloblastoma, Metastasis and Lymphoma) lead to the identification of a microRNA profile that was further confirmed by RT-PCR and in situ hybridization.Hsa-miR-451, -711, 935, -223 and -125b were significantly differentially expressed among the above mentioned groups, allowing us to draw an hypothetical diagnostic chart for Central Nervous System malignancies.This is the first study to employ the NanoString technique for Cerebro-Spinal Fluid microRNA profiling. In this article, we demonstrated that Cerebro-Spinal Fluid microRNA profiling mirrors Central Nervous System physiologic or pathologic conditions. Although more cases need to be tested, we identified a diagnostic Cerebro-Spinal Fluid microRNA signature with good perspectives for future diagnostic clinical applications.

  8. Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease

    PubMed Central

    Bouquet, Jerome; Soloski, Mark J.; Swei, Andrea; Cheadle, Chris; Federman, Scot; Billaud, Jean-Noel; Rebman, Alison W.; Kabre, Beniwende; Halpert, Richard; Boorgula, Meher

    2016-01-01

    ABSTRACT Lyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the “window period” of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets. PMID:26873097

  9. LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures

    PubMed Central

    Duan, Qiaonan; Flynn, Corey; Niepel, Mario; Hafner, Marc; Muhlich, Jeremy L.; Fernandez, Nicolas F.; Rouillard, Andrew D.; Tan, Christopher M.; Chen, Edward Y.; Golub, Todd R.; Sorger, Peter K.; Subramanian, Aravind; Ma'ayan, Avi

    2014-01-01

    For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using the L1000 technology have been produced. The L1000 technology is a cost-effective method to profile gene expression in large scale. LINCS Canvas Browser (LCB) is an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating many of the currently available LINCS L1000 data. LCB implements two compacted layered canvases, one to visualize clustered L1000 expression data, and the other to display enrichment analysis results using 30 different gene set libraries. Clicking on an experimental condition highlights gene-sets enriched for the differentially expressed genes from the selected experiment. A search interface allows users to input gene lists and query them against over 100 000 conditions to find the top matching experiments. The tool integrates many resources for an unprecedented potential for new discoveries in systems biology and systems pharmacology. The LCB application is available at http://www.maayanlab.net/LINCS/LCB. Customized versions will be made part of the http://lincscloud.org and http://lincs.hms.harvard.edu websites. PMID:24906883

  10. LINCS Canvas Browser: interactive web app to query, browse and interrogate LINCS L1000 gene expression signatures.

    PubMed

    Duan, Qiaonan; Flynn, Corey; Niepel, Mario; Hafner, Marc; Muhlich, Jeremy L; Fernandez, Nicolas F; Rouillard, Andrew D; Tan, Christopher M; Chen, Edward Y; Golub, Todd R; Sorger, Peter K; Subramanian, Aravind; Ma'ayan, Avi

    2014-07-01

    For the Library of Integrated Network-based Cellular Signatures (LINCS) project many gene expression signatures using the L1000 technology have been produced. The L1000 technology is a cost-effective method to profile gene expression in large scale. LINCS Canvas Browser (LCB) is an interactive HTML5 web-based software application that facilitates querying, browsing and interrogating many of the currently available LINCS L1000 data. LCB implements two compacted layered canvases, one to visualize clustered L1000 expression data, and the other to display enrichment analysis results using 30 different gene set libraries. Clicking on an experimental condition highlights gene-sets enriched for the differentially expressed genes from the selected experiment. A search interface allows users to input gene lists and query them against over 100 000 conditions to find the top matching experiments. The tool integrates many resources for an unprecedented potential for new discoveries in systems biology and systems pharmacology. The LCB application is available at http://www.maayanlab.net/LINCS/LCB. Customized versions will be made part of the http://lincscloud.org and http://lincs.hms.harvard.edu websites.

  11. High cereblon expression is associated with better survival in patients with newly diagnosed multiple myeloma treated with thalidomide maintenance.

    PubMed

    Broyl, Annemiek; Kuiper, Rowan; van Duin, Mark; van der Holt, Bronno; el Jarari, Laila; Bertsch, Uta; Zweegman, Sonja; Buijs, Arjan; Hose, Dirk; Lokhorst, Henk M; Goldschmidt, Hartmut; Sonneveld, Pieter

    2013-01-24

    Recently, cereblon (CRBN) expression was found to be essential for the activity of thalidomide and lenalidomide. In the present study, we investigated whether the clinical efficacy of thalidomide in multiple myeloma is associated with CRBN expression in myeloma cells. Patients with newly diagnosed multiple myeloma were included in the HOVON-65/GMMG-HD4 trial, in which postintensification treatment in 1 arm consisted of daily thalidomide (50 mg) for 2 years. Gene-expression profiling, determined at the start of the trial, was available for 96 patients who started thalidomide maintenance. In this patient set, increase of CRBN gene expression was significantly associated with longerprogression-free survival (P = .005). In contrast, no association between CRBN expression and survival was observed in the arm with bortezomib maintenance. We conclude that CRBN expression may be associated with the clinical efficacy of thalidomide. This trial has been registered at the Nederlands Trial Register (www.trialregister.nl) as NTR213; at the European Union Drug Regulating Authorities Clinical Trials (EudraCT) as 2004-000944-26; and at the International Standard Randomized Controlled Trial Number (ISRCTN) as 64455289.

  12. Identification of Single- and Multiple-Class Specific Signature Genes from Gene Expression Profiles by Group Marker Index

    PubMed Central

    Tsai, Yu-Shuen; Aguan, Kripamoy; Pal, Nikhil R.; Chung, I-Fang

    2011-01-01

    Informative genes from microarray data can be used to construct prediction model and investigate biological mechanisms. Differentially expressed genes, the main targets of most gene selection methods, can be classified as single- and multiple-class specific signature genes. Here, we present a novel gene selection algorithm based on a Group Marker Index (GMI), which is intuitive, of low-computational complexity, and efficient in identification of both types of genes. Most gene selection methods identify only single-class specific signature genes and cannot identify multiple-class specific signature genes easily. Our algorithm can detect de novo certain conditions of multiple-class specificity of a gene and makes use of a novel non-parametric indicator to assess the discrimination ability between classes. Our method is effective even when the sample size is small as well as when the class sizes are significantly different. To compare the effectiveness and robustness we formulate an intuitive template-based method and use four well-known datasets. We demonstrate that our algorithm outperforms the template-based method in difficult cases with unbalanced distribution. Moreover, the multiple-class specific genes are good biomarkers and play important roles in biological pathways. Our literature survey supports that the proposed method identifies unique multiple-class specific marker genes (not reported earlier to be related to cancer) in the Central Nervous System data. It also discovers unique biomarkers indicating the intrinsic difference between subtypes of lung cancer. We also associate the pathway information with the multiple-class specific signature genes and cross-reference to published studies. We find that the identified genes participate in the pathways directly involved in cancer development in leukemia data. Our method gives a promising way to find genes that can involve in pathways of multiple diseases and hence opens up the possibility of using an existing

  13. Identification of Gene Expression Signatures in the Chicken Intestinal Intraepithelial Lymphocytes in Response to Herb Additive Supplementations

    PubMed Central

    Won, Kyeong-Hye; Song, Ki-Duk; Park, Jong-Eun; Kim, Duk-Kyung; Na, Chong-Sam

    2016-01-01

    Anethole and garlic have an immune modulatory effects on avian coccidiosis, and these effects are correlated with gene expression changes in intestinal epithelial lymphocytes (IELs). In this study, we integrated gene expression datasets from two independent experiments and investigated gene expression profile changes by anethole and garlic respectively, and identified gene expression signatures, which are common targets of these herbs as they might be used for the evaluation of the effect of plant herbs on immunity toward avian coccidiosis. We identified 4,382 and 371 genes, which were differentially expressed in IELs of chickens supplemented with garlic and anethole respectively. The gene ontology (GO) term of differentially expressed genes (DEGs) from garlic treatment resulted in the biological processes (BPs) related to proteolysis, e.g., “modification-dependent protein catabolic process”, “proteolysis involved in cellular protein catabolic process”, “cellular protein catabolic process”, “protein catabolic process”, and “ubiquitin-dependent protein catabolic process”. In GO analysis, one BP term, “Proteolysis”, was obtained. Among DEGs, 300 genes were differentially regulated in response to both garlic and anethole, and 234 and 59 genes were either up- or down-regulated in supplementation with both herbs. Pathway analysis resulted in enrichment of the pathways related to digestion such as “Starch and sucrose metabolism” and “Insulin signaling pathway”. Taken together, the results obtained in the present study could contribute to the effective development of evaluation system of plant herbs based on molecular signatures related with their immunological functions in chicken IELs. PMID:26954117

  14. Gene expression profiling by high throughput sequencing to determine signatures for the bovine receptive uterus at early gestation.

    PubMed

    Van Hoeck, Veerle; Scolari, Saara C; Pugliesi, Guilherme; Gonella-Diaza, Angela M; Andrade, Sónia C S; Gasparin, Gustavo R; Coutinho, Luiz L; Binelli, Mario

    2015-09-01

    The uterus plays a central role among the reproductive tissues in the context of early embryo-maternal communication and a successful pregnancy depends on a complex series of endometrial molecular and cellular events. The factors responsible for the initial interaction between maternal and embryonic tissues, leading to the establishment of pregnancy, remain poorly understood. In this context, Illumina's next-generation sequencing technology has been used to discover the uterine transcriptome signature that is favourable for ongoing pregnancy. More specifically, the present report documents on a retrospective in vivo study in which data on pregnancy outcome were linked to uterine gene expression signatures on day 6 (bovine model). Using the RNA-Seq method, 14.654 reference genes were effectively analysed for differential expression between pregnant and non-pregnant uterine tissue. Transcriptome data revealed that 216 genes were differently expressed when comparing uterine tissue from pregnant and non-pregnant cows. All read sequences were deposited in the Sequence Read Archive (SRA) of the NCBI (http://www.ncbi.nlm.nih.gov/sra). An overview of the gene expression data has been deposited in NCBI's Gene Expression Omnibus (GEO) and is accessible through GEO Series accession number GSE65117. This allows the research community to enhance reproducibility and allows for new discoveries by comparing datasets of signatures linked to receptivity and/or pregnancy success. The resulting information can serve as tool to identify valuable and urgently needed biomarkers for scoring maternal receptivity and even for accurate detection of early pregnancy, which is a matter of cross-species interest. Beyond gene expression analysis as a marker tool, the RNA-Seq information on pregnant uterine tissue can be used to gain novel mechanistic insights, such as by identifying alternative splicing events, allele-specific expression, and rare and novel transcripts that might be involved in

  15. Gene expression profiling by high throughput sequencing to determine signatures for the bovine receptive uterus at early gestation

    PubMed Central

    Van Hoeck, Veerle; Scolari, Saara C.; Pugliesi, Guilherme; Gonella-Diaza, Angela M.; Andrade, Sónia C.S.; Gasparin, Gustavo R.; Coutinho, Luiz L.; Binelli, Mario

    2015-01-01

    The uterus plays a central role among the reproductive tissues in the context of early embryo-maternal communication and a successful pregnancy depends on a complex series of endometrial molecular and cellular events. The factors responsible for the initial interaction between maternal and embryonic tissues, leading to the establishment of pregnancy, remain poorly understood. In this context, Illumina's next-generation sequencing technology has been used to discover the uterine transcriptome signature that is favourable for ongoing pregnancy. More specifically, the present report documents on a retrospective in vivo study in which data on pregnancy outcome were linked to uterine gene expression signatures on day 6 (bovine model). Using the RNA-Seq method, 14.654 reference genes were effectively analysed for differential expression between pregnant and non-pregnant uterine tissue. Transcriptome data revealed that 216 genes were differently expressed when comparing uterine tissue from pregnant and non-pregnant cows. All read sequences were deposited in the Sequence Read Archive (SRA) of the NCBI (http://www.ncbi.nlm.nih.gov/sra). An overview of the gene expression data has been deposited in NCBI's Gene Expression Omnibus (GEO) and is accessible through GEO Series accession number GSE65117. This allows the research community to enhance reproducibility and allows for new discoveries by comparing datasets of signatures linked to receptivity and/or pregnancy success. The resulting information can serve as tool to identify valuable and urgently needed biomarkers for scoring maternal receptivity and even for accurate detection of early pregnancy, which is a matter of cross-species interest. Beyond gene expression analysis as a marker tool, the RNA-Seq information on pregnant uterine tissue can be used to gain novel mechanistic insights, such as by identifying alternative splicing events, allele-specific expression, and rare and novel transcripts that might be involved in

  16. Gene expression signature discriminates sporadic from post-radiotherapy-induced thyroid tumors

    PubMed Central

    Ory, Catherine; Ugolin, Nicolas; Levalois, Céline; Lacroix, Ludovic; Caillou, Bernard; Bidart, Jean-Michel; Schlumberger, Martin; Diallo, Ibrahima; de Vathaire, Florent; Hofman, Paul; Santini, José; Malfoy, Bernard; Chevillard, Sylvie

    2011-01-01

    Both external and internal exposure to ionizing radiation are strong risk factors for the development of thyroid tumors. Until now, the diagnosis of radiation-induced thyroid tumors has been deduced from a network of arguments taken together with the individual history of radiation exposure. Neither the histological features nor the genetic alterations observed in these tumors have been shown to be specific fingerprints of an exposure to radiation. The aim of our work is to define ionizing radiation-related molecular specificities in a series of secondary thyroid tumors developed in the radiation field of patients treated by radiotherapy. To identify molecular markers that could represent a radiation-induction signature, we compared 25K microarray transcriptome profiles of a learning set of 28 thyroid tumors, which comprised 14 follicular thyroid adenomas (FTA) and 14 papillary thyroid carcinomas (PTC), either sporadic or consecutive to external radiotherapy in childhood. We identified a signature composed of 322 genes which discriminates radiation-induced tumors (FTA and PTC) from their sporadic counterparts. The robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 29 tumors (16 FTA and 13 PTC). After the histology code break by the clinicians, 26/29 tumors were well classified regarding tumor etiology, 1 was undetermined, and 2 were misclassified. Our results help shed light on radiation-induced thyroid carcinogenesis, since specific molecular pathways are deregulated in radiation-induced tumors. PMID:21148326

  17. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome

    PubMed Central

    de la Morena, M. Teresa; Eitson, Jennifer L.; Dozmorov, Igor M.; Belkaya, Serkan; Hoover, Ashley R.; Anguiano, Esperanza; Pascual, M. Virginia; van Oers, Nicolai S.C.

    2013-01-01

    Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3 Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4× normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance. PMID:23454892

  18. Signature MicroRNA expression patterns identified in humans with 22q11.2 deletion/DiGeorge syndrome.

    PubMed

    de la Morena, M Teresa; Eitson, Jennifer L; Dozmorov, Igor M; Belkaya, Serkan; Hoover, Ashley R; Anguiano, Esperanza; Pascual, M Virginia; van Oers, Nicolai S C

    2013-04-01

    Patients with 22q11.2 deletion syndrome have heterogeneous clinical presentations including immunodeficiency, cardiac anomalies, and hypocalcemia. The syndrome arises from hemizygous deletions of up to 3Mb on chromosome 22q11.2, a region that contains 60 genes and 4 microRNAs. MicroRNAs are important post-transcriptional regulators of gene expression, with mutations in several microRNAs causal to specific human diseases. We characterized the microRNA expression patterns in the peripheral blood of patients with 22q11.2 deletion syndrome (n=31) compared to normal controls (n=22). Eighteen microRNAs had a statistically significant differential expression (p<0.05), with miR-185 expressed at 0.4× normal levels. The 22q11.2 deletion syndrome cohort exhibited microRNA expression hyper-variability and group dysregulation. Selected microRNAs distinguished patients with cardiac anomalies, hypocalcemia, and/or low circulating T cell counts. In summary, microRNA profiling of chromosome 22q11.2 deletion syndrome/DiGeorge patients revealed a signature microRNA expression pattern distinct from normal controls with clinical relevance.

  19. Dual RNA Sequencing Reveals the Expression of Unique Transcriptomic Signatures in Lipopolysaccharide-Induced BV-2 Microglial Cells

    PubMed Central

    Kim, Sun Hwa; Park, Kyoung Sun; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

    2015-01-01

    Microglial cells become rapidly activated through interactions with pathogens, and the persistent activation of these cells is associated with various neurodegenerative diseases. Previous studies have investigated the transcriptomic signatures in microglia or macrophages using microarray technologies. However, this method has numerous restrictions, such as spatial biases, uneven probe properties, low sensitivity, and dependency on the probes spotted. To overcome this limitation and identify novel transcribed genes in response to LPS, we used RNA Sequencing (RNA-Seq) to determine the novel transcriptomic signatures in BV-2 microglial cells. Sequencing assessment and quality evaluation showed that approximately 263 and 319 genes (≥ 1.5 log2-fold), such as cytokines and chemokines, were strongly induced after 2 and 4 h, respectively, and the induction of several genes with unknown immunological functions was also observed. Importantly, we observed that previously unidentified transcription factors (TFs) (irf1, irf7, and irf9), histone demethylases (kdm4a) and DNA methyltransferases (dnmt3l) were significantly and selectively expressed in BV-2 microglial cells. The gene expression levels, transcription start sites (TSS), isoforms, and differential promoter usage revealed a complex pattern of transcriptional and post-transcriptional gene regulation upon infection with LPS. In addition, gene ontology, molecular networks and pathway analyses identified the top significantly regulated functional classification, canonical pathways and network functions at each activation status. Moreover, we further analyzed differentially expressed genes to identify transcription factor (TF) motifs (−950 to +50 bp of the 5’ upstream promoters) and epigenetic mechanisms. Furthermore, we confirmed that the expressions of key inflammatory genes as well as pro-inflammatory mediators in the supernatants were significantly induced in LPS treated primary microglial cells. This

  20. The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

    PubMed Central

    Ning, Gang; Bijron, Jonathan G.; Yamamoto, Yusuke; Wang, Xia; Howitt, Brooke E.; Herfs, Michael; Yang, Eric; Hong, Yue; Cornille, Maxence; Wu, Lingyan; Hanamornroongruang, Suchanan; McKeon, Frank D.; Crum, Christopher P.; Xian, Wa

    2014-01-01

    The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynecologic tract and adult fallopian tube were Krt7p/PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1) and oncogenesis (stathmin). This shared expression signature between benign and

  1. Microarray analysis of Ewing's sarcoma family of tumours reveals characteristic gene expression signatures associated with metastasis and resistance to chemotherapy.

    PubMed

    Schaefer, Karl-Ludwig; Eisenacher, Martin; Braun, Yvonne; Brachwitz, Kristin; Wai, Daniel H; Dirksen, Uta; Lanvers-Kaminsky, Claudia; Juergens, Heribert; Herrero, David; Stegmaier, Sabine; Koscielniak, Ewa; Eggert, Angelika; Nathrath, Michaela; Gosheger, Georg; Schneider, Dominik T; Bury, Carsten; Diallo-Danebrock, Raihanatou; Ottaviano, Laura; Gabbert, Helmut E; Poremba, Christopher

    2008-03-01

    In Ewing's sarcoma family of tumours (ESFT), the clinically most adverse prognostic parameters are the presence of tumour metastasis at time of diagnosis and poor response to neoadjuvant chemotherapy. To identify genes differentially regulated between metastatic and localised tumours, we analysed 27 ESFT specimens using Affymetrix microarrays. Functional annotation of differentially regulated genes revealed 29 over-represented pathways including PDGF, TP53, NOTCH, and WNT1-signalling. Regression of primary tumours (n=20) induced by polychemotherapy was found to be correlated with the expression of genes involved in angiogenesis, apoptosis, ubiquitin proteasome pathway, and PI3 kinase and p53 pathways. These findings could be confirmed by in vitro cytotoxicity assays. A set of 46 marker genes correctly classifies these 20 tumours as responding versus non-responding. We conclude that expression signatures of initial tumour biopsies can help to identify ESFT patients at high risk to develop tumour metastasis or to suffer from a therapy refractory cancer.

  2. High IFIT1 expression predicts improved clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma.

    PubMed

    Zhang, Jin-Feng; Chen, Yao; Lin, Guo-Shi; Zhang, Jian-Dong; Tang, Wen-Long; Huang, Jian-Huang; Chen, Jin-Shou; Wang, Xing-Fu; Lin, Zhi-Xiong

    2016-06-01

    Interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) plays a key role in growth suppression and apoptosis promotion in cancer cells. Interferon was reported to induce the expression of IFIT1 and inhibit the expression of O-6-methylguanine-DNA methyltransferase (MGMT).This study aimed to investigate the expression of IFIT1, the correlation between IFIT1 and MGMT, and their impact on the clinical outcome in newly diagnosed glioblastoma. The expression of IFIT1 and MGMT and their correlation were investigated in the tumor tissues from 70 patients with newly diagnosed glioblastoma. The effects on progression-free survival and overall survival were evaluated. Of 70 cases, 57 (81.4%) tissue samples showed high expression of IFIT1 by immunostaining. The χ(2) test indicated that the expression of IFIT1 and MGMT was negatively correlated (r = -0.288, P = .016). Univariate and multivariate analyses confirmed high IFIT1 expression as a favorable prognostic indicator for progression-free survival (P = .005 and .017) and overall survival (P = .001 and .001), respectively. Patients with 2 favorable factors (high IFIT1 and low MGMT) had an improved prognosis as compared with others. The results demonstrated significantly increased expression of IFIT1 in newly diagnosed glioblastoma tissue. The negative correlation between IFIT1 and MGMT expression may be triggered by interferon. High IFIT1 can be a predictive biomarker of favorable clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma.

  3. Association of a cytarabine chemosensitivity related gene expression signature with survival in cytogenetically normal acute myeloid leukemia

    PubMed Central

    Yan, Han; Wen, Lu; Tan, Dan; Xie, Pan; Pang, Feng-mei; Zhou, Hong-hao; Zhang, Wei; Liu, Zhao-qian; Tang, Jie; Li, Xi; Chen, Xiao-ping

    2017-01-01

    The prognosis of cytogenetically normal acute myeloid leukemia (CN-AML) varies greatly among patients. Achievement of complete remission (CR) after chemotherapy is indispensable for a better prognosis. To develop a gene signature predicting overall survival (OS) in CN-AML, we performed data mining procedure based on whole genome expression data of both blood cancer cell lines and AML patients from open access database. A gene expression signature including 42 probes was derived. These probes were significantly associated with both cytarabine half maximal inhibitory concentration values in blood cancer cell lines and OS in CN-AML patients. By using cox regression analysis and linear regression analysis, a chemo-sensitive score calculated algorithm based on mRNA expression levels of the 42 probes was established. The scores were associated with OS in both the training sample (p=5.13 × 10−4, HR=2.040, 95% CI: 1.364-3.051) and the validation sample (p=0.002, HR=2.528, 95% CI: 1.393-4.591) of the GSE12417 dataset from Gene Expression Omnibus. In The Cancer Genome Atlas (TCGA) CN-AML patients, higher scores were found to be associated with both worse OS (p=0.013, HR=2.442, 95% CI: 1.205-4.950) and DFS (p=0.015, HR=2.376, 95% CI: 1.181-4.779). Results of gene ontology (GO) analysis showed that all the significant GO Terms were correlated with cellular component of mitochondrion. In summary, a novel gene set that could predict prognosis of CN-AML was identified presently, which provided a new way to identify genes impacting AML chemo-sensitivity and prognosis. PMID:27903973

  4. The Correlation-Base-Selection Algorithm for Diagnostic Schizophrenia Based on Blood-Based Gene Expression Signatures

    PubMed Central

    Zhang, Hang; Xie, Ziyang; Yang, Yuwen; Zhao, Yizhen

    2017-01-01

    Microarray analysis of gene expression is often used to diagnose different types of disease. Many studies report remarkable achievements in nervous system disease. Clinical diagnosis of schizophrenia (SCZ) still depends on doctors' experience, which is unreliable and needs to be more objective and quantified. To solve this problem, we collected whole blood gene expression data from four studies, including 152 individuals with schizophrenia (SCZ) and 138 normal controls in different regions. The correlation-based feature selection (CFS, one of the machine learning methods) algorithm was applied in this study, and 103 significantly differentially expressed genes between patients and controls, called “feature genes,” were selected; then, a model for SCZ diagnosis was built. The samples were subdivided into 10 groups, and cross-validation showed that the model we constructed achieved nearly 100% classification accuracy. Mathematical evaluation of the datasets before and after data processing proved the effectiveness of our algorithm. Feature genes were enriched in Parkinson's disease, oxidative phosphorylation, and TGF-beta signaling pathways, which were previously reported to be associated with SCZ. These results suggest that the analysis of gene expression in whole blood by our model could be a useful tool for diagnosing SCZ. PMID:28280741

  5. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression

    PubMed Central

    Brkic, Zana; Maria, Naomi I; van Helden-Meeuwsen, Cornelia G; van de Merwe, Joop P; van Daele, Paul L; Dalm, Virgil A; Wildenberg, Manon E; Beumer, Wouter; Drexhage, Hemmo A; Versnel, Marjan A

    2013-01-01

    Objective To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called ‘IFN type I signature’, in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF). Methods Expression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score≥10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS. Results An IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren's Syndrome Disease Activity Index scores; higher anti-Ro52, anti-Ro60 and anti-La autoantibodies; higher rheumatoid factor; higher serum IgG; lower C3, lower absolute lymphocyte and neutrophil counts; (b)higher BAFF gene expression in monocytes. In addition, serum of signature-positive patients induced BAFF gene expression in monocytes. Conclusions The monocyte IFN type I signature identifies a subgroup of patients with pSS with a higher clinical disease activity together with higher BAFF mRNA expression. Such patients might benefit from treatment blocking IFN type I production or activity. PMID:22736090

  6. Long non-coding RNA SOX2OT: expression signature, splicing patterns, and emerging roles in pluripotency and tumorigenesis

    PubMed Central

    Shahryari, Alireza; Jazi, Marie Saghaeian; Samaei, Nader M.; Mowla, Seyed J.

    2015-01-01

    SOX2 overlapping transcript (SOX2OT) is a long non-coding RNA which harbors one of the major regulators of pluripotency, SOX2 gene, in its intronic region. SOX2OT gene is mapped to human chromosome 3q26.3 (Chr3q26.3) locus and is extended in a high conserved region of over 700 kb. Little is known about the exact role of SOX2OT; however, recent studies have demonstrated a positive role for it in transcription regulation of SOX2 gene. Similar to SOX2, SOX2OT is highly expressed in embryonic stem cells and down-regulated upon the induction of differentiation. SOX2OT is dynamically regulated during the embryogenesis of vertebrates, and delimited to the brain in adult mice and human. Recently, the disregulation of SOX2OT expression and its concomitant expression with SOX2 have become highlighted in some somatic cancers including esophageal squamous cell carcinoma, lung squamous cell carcinoma, and breast cancer. Interestingly, SOX2OT is differentially spliced into multiple mRNA-like transcripts in stem and cancer cells. In this review, we are describing the structural and functional features of SOX2OT, with an emphasis on its expression signature, its splicing patterns and its critical function in the regulation of SOX2 expression during development and tumorigenesis. PMID:26136768

  7. Evaluation of data discretization methods to derive platform independent isoform expression signatures for multi-class tumor subtyping

    PubMed Central

    2015-01-01

    Background Many supervised learning algorithms have been applied in deriving gene signatures for patient stratification from gene expression data. However, transferring the multi-gene signatures from one analytical platform to another without loss of classification accuracy is a major challenge. Here, we compared three unsupervised data discretization methods--Equal-width binning, Equal-frequency binning, and k-means clustering--in accurately classifying the four known subtypes of glioblastoma multiforme (GBM) when the classification algorithms were trained on the isoform-level gene expression profiles from exon-array platform and tested on the corresponding profiles from RNA-seq data. Results We applied an integrated machine learning framework that involves three sequential steps; feature selection, data discretization, and classification. For models trained and tested on exon-array data, the addition of data discretization step led to robust and accurate predictive models with fewer number of variables in the final models. For models trained on exon-array data and tested on RNA-seq data, the addition of data discretization step dramatically improved the classification accuracies with Equal-frequency binning showing the highest improvement with more than 90% accuracies for all the models with features chosen by Random Forest based feature selection. Overall, SVM classifier coupled with Equal-frequency binning achieved the best accuracy (> 95%). Without data discretization, however, only 73.6% accuracy was achieved at most. Conclusions The classification algorithms, trained and tested on data from the same platform, yielded similar accuracies in predicting the four GBM subgroups. However, when dealing with cross-platform data, from exon-array to RNA-seq, the classifiers yielded stable models with highest classification accuracies on data transformed by Equal frequency binning. The approach presented here is generally applicable to other cancer types for

  8. Outcome-based profiling of astrocytic tumours identifies prognostic gene expression signatures which link molecular and morphology-based pathology.

    PubMed

    Beetz, Christian; Bergner, Sven; Brodoehl, Stefan; Brodhun, Michael; Ewald, Christian; Kalff, Rolf; Krüger, Jutta; Patt, Stephan; Kiehntopf, Michael; Deufel, Thomas

    2006-11-01

    Astrocytomas are intracranial malignancies for which invasive growth and high motility of tumour cells preclude total resection; the tumours usually recur in a more aggressive and, eventually, lethal form. Clinical outcome is highly variable and the accuracy of morphology-based prognostic statements is limited. In order to identify novel molecular markers for prognosis we obtained expression profiles of: i) tumours associated with particularly long recurrence-free intervals, ii) tumours which led to rapid patient death, and iii) tumour-free control brain. Unsupervised data analysis completely separated the three sample entities indicating a strong impact of the selection criteria on general gene expression. Consequently, significant numbers of specifically expressed genes could be identified for each entity. An extended set of tumours was then investigated by RT-PCR targeting 12 selected genes. Data from these experiments were summarised into a sample-specific index which assigns tumours to high- and low-risk groups as successfully as does morphology-based grading. Moreover, this index directly correlates with definite survival suggesting that integrated gene expression data allow individualised prognostic statements. We also analysed localisation of selected marker transcripts by in situ hybridization. Our finding of cell-specificity for some of these outcome-determining genes relates global expression data to the presence of morphological correlates of tumour behaviour and, thus, provides a link between morphology-based and molecular pathology. Our identification of expression signatures that are associated individually with clinical outcome confirms the prognostic relevance of gene expression data and, thus, represents a step towards eventually implementing molecular diagnosis into clinical practice in neuro-oncology.

  9. Transcriptome profiling of the whitefly Bemisia tabaci reveals stage-specific gene expression signatures for thiamethoxam resistance.

    PubMed

    Yang, N; Xie, W; Jones, C M; Bass, C; Jiao, X; Yang, X; Liu, B; Li, R; Zhang, Y

    2013-10-01

    Bemisia tabaci has developed high levels of resistance to many insecticides including the neonicotinoids and there is strong evidence that for some compounds resistance is stage-specific. To investigate the molecular basis of B. tabaci resistance to the neonicotinoid thiamethoxam we used a custom whitefly microarray to compare gene expression in the egg, nymph and adult stages of a thiamethoxam-resistant strain (TH-R) with a susceptible strain (TH-S). Gene ontology and bioinformatic analyses revealed that in all life stages many of the differentially expressed transcripts encoded enzymes involved in metabolic processes and/or metabolism of xenobiotics. Several of these are candidate resistance genes and include the cytochrome P450 CYP6CM1, which has been shown to confer resistance to several neonicotinoids previously, a P450 belonging to the Cytochrome P450s 4 family and a glutathione S-transferase (GST) belonging to the sigma class. Finally several ATP-binding cassette transporters of the ABCG subfamily were highly over-expressed in the adult stage of the TH-R strain and may play a role in resistance by active efflux. Here, we evaluated both common and stage-specific gene expression signatures and identified several candidate resistance genes that may underlie B. tabaci resistance to thiamethoxam.

  10. Epithelial cells captured from ductal carcinoma in situ reveal a gene expression signature associated with progression to invasive breast cancer

    PubMed Central

    Abuázar, Carolina Sens; de Toledo Osorio, Cynthia Aparecida Bueno; Pinilla, Mabel Gigliola; da Silva, Sabrina Daniela; Camargo, Anamaria Aranha; Silva, Wilson Araujo; e Ferreira, Elisa Napolitano; Brentani, Helena Paula; Carraro, Dirce Maria

    2016-01-01

    Breast cancer biomarkers that can precisely predict the risk of progression of non-invasive ductal carcinoma in situ (DCIS) lesions to invasive disease are lacking. The identification of molecular alterations that occur during the invasion process is crucial for the discovery of drivers of transition to invasive disease and, consequently, biomarkers with clinical utility. In this study, we explored differences in gene expression in mammary epithelial cells before and after the morphological manifestation of invasion, i.e., early and late stages, respectively. In the early stage, epithelial cells were captured from both pre-invasive lesions with distinct malignant potential [pure DCIS as well as the in situ component that co-exists with invasive breast carcinoma lesions (DCIS-IBC)]; in the late stage, epithelial cells were captured from the two distinct morphological components of the same sample (in situ and invasive components). Candidate genes were identified using cDNA microarray and rapid subtractive hybridization (RaSH) cDNA libraries and validated by RT-qPCR assay using new samples from each group. These analyses revealed 26 genes, including 20 from the early and 6 from the late stage. The expression profile based on the 20 genes, marked by a preferential decrease in expression level towards invasive phenotype, discriminated the majority of DCIS samples. Thus, this study revealed a gene expression signature with the potential to predict DCIS progression and, consequently, provides opportunities to tailor treatments for DCIS patients. PMID:27708222

  11. Expression of the Bcl-2 apoptotic marker in cats diagnosed with inflammatory bowel disease and gastrointestinal lymphoma.

    PubMed

    Swanson, Christine M; Smedley, Rebecca C; Saavedra, Paulo Vilar; Kiupel, Matti; Kitchell, Barbara E

    2012-10-01

    Immunolabeling for the critical lymphocyte survival factor, Bcl-2, of intestinal biopsies from cats with histologic evidence of inflammatory bowel disease (IBD) or gastrointestinal (GI) lymphoma was evaluated to determine if expression differed significantly between these two disease processes. Immunolabeling for Bcl-2 was performed on small intestinal endoscopic or full thickness biopsy sections from 55 cats. Diagnosis of IBD, T-cell lymphoma or B-cell lymphoma was established previously. The percentage of infiltrating lymphocytes that were positively labeled for Bcl-2 was subjectively determined for each case. Eight cats were diagnosed with IBD and 47 cats with lymphoma. A significantly higher percentage of cells were positively immunolabeled for Bcl-2 in cats with GI lymphoma [median (range); 90 (5-95)%] compared with cats with IBD [60 (15-95)%] (P = 0.029). However, the overall degree of positive immunolabeling in both groups tended to be high. This over-expression of Bcl-2 may prove useful as a therapeutic target for IBD and GI lymphoma in cats.

  12. Matrix Metalloproteinases: The Gene Expression Signatures of Head and Neck Cancer Progression

    PubMed Central

    Iizuka, Shinji; Ishimaru, Naozumi; Kudo, Yasusei

    2014-01-01

    Extracellular matrix degradation by matrix metalloproteinases (MMPs) plays a pivotal role in cancer progression by promoting motility, invasion and angiogenesis. Studies have shown that MMP expression is increased in head and neck squamous cell carcinomas (HNSCCs), one of the most common cancers in the world, and contributes to poor outcome. In this review, we examine the expression pattern of MMPs in HNSCC by microarray datasets and summarize the current knowledge of MMPs, specifically MMP-1, -3, -7 -10, -12, -13, 14 and -19, that are highly expressed in HNSCCs and involved cancer invasion and angiogenesis. PMID:24531055

  13. Expression signature as a biomarker for prenatal diagnosis of trisomy 21.

    PubMed

    Volk, Marija; Maver, Aleš; Lovrečić, Luca; Juvan, Peter; Peterlin, Borut

    2013-01-01

    A universal biomarker panel with the potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptome analysis is a powerful tool to capture differentially expressed genes (DEG), which can be used as biomarker-diagnostic-predictive tool for various conditions in prenatal setting. In search of biomarker set for predicting high-risk pregnancies, we performed global expression profiling to find DEG in Ts21. Subsequently, we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using expression microarrays. Datasets from Ts21 transcriptomic studies from GEO repository were incorporated. DEG were discovered using linear regression modelling and validated using RT-PCR quantification on an independent sample of 16 cases with Ts21 and 32 controls. The classification performance of Ts21 status based on expression profiling was performed using supervised machine learning algorithm and evaluated using a leave-one-out cross validation approach. Global gene expression profiling has revealed significant expression changes between normal and Ts21 samples, which in combination with data from previously performed Ts21 transcriptomic studies, were used to generate a multi-gene biomarker for Ts21, comprising of 9 gene expression profiles. In addition to biomarker's high performance in discriminating samples from global expression profiling, we were also able to show its discriminatory performance on a larger sample set 2, validated using RT-PCR experiment (AUC=0.97), while its performance on data from previously published studies reached discriminatory AUC values of 1.00. Our results show that transcriptomic changes might potentially be used to discriminate trisomy of chromosome 21 in the prenatal setting. As expressional alterations reflect both, causal

  14. Trophic factor-induced activity 'signature' regulates the functional expression of postsynaptic excitatory acetylcholine receptors required for synaptogenesis.

    PubMed

    Luk, Collin C; Lee, Arthur J; Wijdenes, Pierre; Zaidi, Wali; Leung, Andrew; Wong, Noelle Y; Andrews, Joseph; Syed, Naweed I

    2015-04-01

    Highly coordinated and coincidental patterns of activity-dependent mechanisms ("fire together wire together") are thought to serve as inductive signals during synaptogenesis, enabling neuronal pairing between specific sub-sets of excitatory partners. However, neither the nature of activity triggers, nor the "activity signature" of long-term neuronal firing in developing/regenerating neurons have yet been fully defined. Using a highly tractable model system comprising of identified cholinergic neurons from Lymnaea, we have discovered that intrinsic trophic factors present in the Lymnaea brain-conditioned medium (CM) act as a natural trigger for activity patterns in post- but not the presynaptic neuron. Using microelectrode array recordings, we demonstrate that trophic factors trigger stereotypical activity patterns that include changes in frequency, activity and variance. These parameters were reliable indicators of whether a neuron expressed functional excitatory or inhibitory nAChRs and synapse formation. Surprisingly, we found that the post- but not the presynaptic cell exhibits these changes in activity patterns, and that the functional expression of excitatory nAChRs required neuronal somata, de novo protein synthesis and voltage gated calcium channels. In summary, our data provides novel insights into trophic factor mediated actions on neuronal activity and its specific regulation of nAChR expression.

  15. Comprehensive Gene expression meta-analysis and integrated bioinformatic approaches reveal shared signatures between thrombosis and myeloproliferative disorders

    PubMed Central

    Jha, Prabhash Kumar; Vijay, Aatira; Sahu, Anita; Ashraf, Mohammad Zahid

    2016-01-01

    Thrombosis is a leading cause of morbidity and mortality in patients with myeloproliferative disorders (MPDs), particularly polycythemia vera (PV) and essential thrombocythemia (ET). Despite the attempts to establish a link between them, the shared biological mechanisms are yet to be characterized. An integrated gene expression meta-analysis of five independent publicly available microarray data of the three diseases was conducted to identify shared gene expression signatures and overlapping biological processes. Using INMEX bioinformatic tool, based on combined Effect Size (ES) approaches, we identified a total of 1,157 differentially expressed genes (DEGs) (697 overexpressed and 460 underexpressed genes) shared between the three diseases. EnrichR tool’s rich library was used for comprehensive functional enrichment and pathway analysis which revealed “mRNA Splicing” and “SUMO E3 ligases SUMOylate target proteins” among the most enriched terms. Network based meta-analysis identified MYC and FN1 to be the most highly ranked hub genes. Our results reveal that the alterations in biomarkers of the coagulation cascade like F2R, PROS1, SELPLG and ITGB2 were common between the three diseases. Interestingly, the study has generated a novel database of candidate genetic markers, pathways and transcription factors shared between thrombosis and MPDs, which might aid in the development of prognostic therapeutic biomarkers. PMID:27892526

  16. Different Gene Expression Signatures in Children and Adults with Celiac Disease.

    PubMed

    Pascual, V; Medrano, L M; López-Palacios, N; Bodas, A; Dema, B; Fernández-Arquero, M; González-Pérez, B; Salazar, I; Núñez, C

    2016-01-01

    Celiac disease (CD) is developed after gluten ingestion in genetically susceptible individuals. It can appear at any time in life, but some differences are commonly observed between individuals with onset early in life or in adulthood. We aimed to investigate the molecular basis underlying those differences. We collected 19 duodenal biopsies of children and adults with CD and compared the expression of 38 selected genes between each other and with the observed in 13 non-CD controls matched by age. A Bayesian methodology was used to analyze the differences of gene expression between groups. We found seven genes with a similarly altered expression in children and adults with CD when compared to controls (C2orf74, CCR6, FASLG, JAK2, IL23A, TAGAP and UBE2L3). Differences were observed in 13 genes: six genes being altered only in adults (IL1RL1, CD28, STAT3, TMEM187, VAMP3 and ZFP36L1) and two only in children (TNFSF18 and ICOSLG); and four genes showing a significantly higher alteration in adults (CCR4, IL6, IL18RAP and PLEK) and one in children (C1orf106). This is the first extensive study comparing gene expression in children and adults with CD. Differences in the expression level of several genes were found between groups, being notorious the higher alteration observed in adults. Further research is needed to evaluate the possible genetic influence underlying these changes and the specific functional consequences of the reported differences.

  17. Human spontaneous labor without histologic chorioamnionitis is characterized by an acute inflammation gene expression signature

    PubMed Central

    Haddad, Ramsi; Tromp, Gerard; Kuivaniemi, Helena; Chaiworapongsa, Tinnakorn; Kim, Yeon Mee; Mazor, Moshe; Romero, Roberto

    2006-01-01

    OBJECTIVE The purpose of this study was to identify which biological processes may be involved in normal labor. STUDY DESIGN Transcriptional profiles for chorioamniotic membranes (n=24) and blood (n=20) were generated from patients at term with no labor (TNL) and in labor (TIL). RESULTS Expression of 197 transcripts (P≤0.02) differentiated TIL and TNL chorioamniotic membrane samples. Gene Ontology analysis indicated that TIL samples had increased expression of multiple chemokines and transcripts associated with neutrophil and monocyte recruitment. Microarray results were verified using quantitative real-time RT-PCR with independent samples. Transcriptional profiles from blood RNA revealed no Gene Ontology category enrichment of discriminant probe sets. CONCLUSION Labor induces gene expression changes consistent with localized inflammation, despite the absence of histologically detectable inflammation. PMID:16890549

  18. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue

    PubMed Central

    2012-01-01

    Background Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients. Methods Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks. Results In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Conclusions Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for

  19. Blood-Based Gene Expression Signatures of Infants and Toddlers with Autism

    ERIC Educational Resources Information Center

    Glatt, Stephen J.; Tsuang, Ming T.; Winn, Mary; Chandler, Sharon D.; Collins, Melanie; Lopez, Linda; Weinfeld, Melanie; Carter, Cindy; Schork, Nicholas; Pierce, Karen; Courchesne, Eric

    2012-01-01

    Objective: Autism spectrum disorders (ASDs) are highly heritable neurodevelopmental disorders that onset clinically during the first years of life. ASD risk biomarkers expressed early in life could significantly impact diagnosis and treatment, but no transcriptome-wide biomarker classifiers derived from fresh blood samples from children with…

  20. Hantaviruses induce cell type- and viral species-specific host microRNA expression signatures.

    PubMed

    Shin, Ok Sarah; Kumar, Mukesh; Yanagihara, Richard; Song, Jin-Won

    2013-11-01

    The mechanisms of hantavirus-induced modulation of host cellular immunity remain poorly understood. Recently, microRNAs (miRNAs) have emerged as a class of essential regulators of host immune response genes. To ascertain if differential host miRNA expression toward representative hantavirus species correlated with immune response genes, miRNA expression profiles were analyzed in human endothelial cells, macrophages and epithelial cells infected with pathogenic and nonpathogenic rodent- and shrew-borne hantaviruses. Distinct miRNA expression profiles were observed in a cell type- and viral species-specific pattern. A subset of miRNAs, including miR-151-5p and miR-1973, were differentially expressed between Hantaan virus and Prospect Hill virus. Pathway analyses confirmed that the targets of selected miRNAs were associated with inflammatory responses and innate immune receptor-mediated signaling pathways. Our data suggest that differential immune responses following hantavirus infection may be regulated in part by cellular miRNA through dysregulation of genes critical to the inflammatory process.

  1. Gene expression signature in organized and growth arrested mammaryacini predicts good outcome in breast cancer

    SciTech Connect

    Fournier, Marcia V.; Martin, Katherine J.; Kenny, Paraic A.; Xhaja, Kris; Bosch, Irene; Yaswen, Paul; Bissell, Mina J.

    2006-02-08

    To understand how non-malignant human mammary epithelial cells (HMEC) transit from a disorganized proliferating to an organized growth arrested state, and to relate this process to the changes that occur in breast cancer, we studied gene expression changes in non-malignant HMEC grown in three-dimensional cultures, and in a previously published panel of microarray data for 295 breast cancer samples. We hypothesized that the gene expression pattern of organized and growth arrested mammary acini would share similarities with breast tumors with good prognoses. Using Affymetrix HG-U133A microarrays, we analyzed the expression of 22,283 gene transcripts in two HMEC cell lines, 184 (finite life span) and HMT3522 S1 (immortal non-malignant), on successive days post-seeding in a laminin-rich extracellular matrix assay. Both HMECs underwent growth arrest in G0/G1 and differentiated into polarized acini between days 5 and 7. We identified gene expression changes with the same temporal pattern in both lines. We show that genes that are significantly lower in the organized, growth arrested HMEC than in their proliferating counterparts can be used to classify breast cancer patients into poor and good prognosis groups with high accuracy. This study represents a novel unsupervised approach to identifying breast cancer markers that may be of use clinically.

  2. Different Gene Expression Signatures in Children and Adults with Celiac Disease

    PubMed Central

    López-Palacios, N.; Bodas, A.; Dema, B.; Fernández-Arquero, M.; González-Pérez, B.; Salazar, I.; Núñez, C.

    2016-01-01

    Celiac disease (CD) is developed after gluten ingestion in genetically susceptible individuals. It can appear at any time in life, but some differences are commonly observed between individuals with onset early in life or in adulthood. We aimed to investigate the molecular basis underlying those differences. We collected 19 duodenal biopsies of children and adults with CD and compared the expression of 38 selected genes between each other and with the observed in 13 non-CD controls matched by age. A Bayesian methodology was used to analyze the differences of gene expression between groups. We found seven genes with a similarly altered expression in children and adults with CD when compared to controls (C2orf74, CCR6, FASLG, JAK2, IL23A, TAGAP and UBE2L3). Differences were observed in 13 genes: six genes being altered only in adults (IL1RL1, CD28, STAT3, TMEM187, VAMP3 and ZFP36L1) and two only in children (TNFSF18 and ICOSLG); and four genes showing a significantly higher alteration in adults (CCR4, IL6, IL18RAP and PLEK) and one in children (C1orf106). This is the first extensive study comparing gene expression in children and adults with CD. Differences in the expression level of several genes were found between groups, being notorious the higher alteration observed in adults. Further research is needed to evaluate the possible genetic influence underlying these changes and the specific functional consequences of the reported differences. PMID:26859134

  3. Getting Diagnosed

    MedlinePlus

    ... also for those with related disorders. How is Marfan syndrome diagnosed? getting_diagnosed.jpg A Marfan diagnosis ... spinal column). Is there a genetic test for Marfan syndrome? Genetic testing can provide helpful information in ...

  4. Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy.

    PubMed

    Blakely, Collin M; Stoddard, Alexander J; Belka, George K; Dugan, Katherine D; Notarfrancesco, Kathleen L; Moody, Susan E; D'Cruz, Celina M; Chodosh, Lewis A

    2006-06-15

    Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.

  5. Bioinformatic identification of prognostic signature defined by copy number alteration and expression of CCNE1 in non-muscle invasive bladder cancer

    PubMed Central

    Song, Bic-Na; Kim, Seon-Kyu; Chu, In-Sun

    2017-01-01

    Non-muscle invasive bladder cancer (NMIBC) patients frequently fail to respond to treatment and experience disease progression because of their clinical and biological diversity. In this study, we identify a prognostic molecular signature for predicting the heterogeneity of NMIBC by using an integrative analysis of copy number and gene expression data. We analyzed the copy number and gene expression profiles of 404 patients with bladder cancer obtained from The Cancer Genome Atlas (TCGA) consortium. Of the 14 molecules with significant copy number alterations that were previously reported, 13 were significantly correlated with copy number and expression changes. Prognostic gene sets based on the 13 genes were developed, and their prognostic values were verified in three independent patient cohorts (n=501). Among them, a signature of CCNE1 and its coexpressed genes was significantly associated with disease progression and validated in the independent cohorts. The CCNE1 signature was an independent risk factor based on the result of a multivariate analysis (hazard ratio=6.849, 95% confidence interval=1.613–29.092, P=0.009). Finally, gene network and upstream regulator analyses revealed that NMIBC progression is potentially mediated by CCND1-CCNE1-SP1 pathways. The prognostic molecular signature defined by copy number and expression changes of CCNE1 suggests a novel diagnostic tool for predicting the likelihood of NMIBC progression. PMID:28082741

  6. Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity

    PubMed Central

    2016-01-01

    Many mechanisms have been proposed for how heightened aerobic glycolytic metabolism fuels cancer pathogenicity, but there are still many unexplored pathways. Here, we have performed metabolomic profiling to map glucose incorporation into metabolic pathways upon transformation of mammary epithelial cells by 11 commonly mutated human oncogenes. We show that transformation of mammary epithelial cells by oncogenic stimuli commonly shunts glucose-derived carbons into synthesis of sialic acid, a hexosamine pathway metabolite that is converted to CMP-sialic acid by cytidine monophosphate N-acetylneuraminic acid synthase (CMAS) as a precursor to glycoprotein and glycolipid sialylation. We show that CMAS knockdown leads to elevations in intracellular sialic acid levels, a depletion of cellular sialylation, and alterations in the expression of many cancer-relevant genes to impair breast cancer pathogenicity. Our study reveals the heretofore unrecognized role of sialic acid metabolism and protein sialylation in regulating the expression of genes that maintain breast cancer pathogenicity. PMID:27380425

  7. Clinical significance of in vivo cytarabine-induced gene expression signature in AML.

    PubMed

    Lamba, Jatinder K; Pounds, Stanley; Cao, Xueyuan; Crews, Kristine R; Cogle, Christopher R; Bhise, Neha; Raimondi, Susana C; Downing, James R; Baker, Sharyn D; Ribeiro, Raul C; Rubnitz, Jeffrey E

    2016-01-01

    Despite initial remission, ∼60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML; however, the extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy, can trigger adaptive response by influencing leukemic cell transcriptome and, hence, development of resistance or refractory disease. It is, however, challenging to perform such a study due to lack of availability of specimens post-drug treatment. The primary objective of this study was to identify in vivo cytarabine-induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. The results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.

  8. Proteomic analysis of MG132-treated germinating pollen reveals expression signatures associated with proteasome inhibition.

    PubMed

    Vannini, Candida; Bracale, Marcella; Crinelli, Rita; Marconi, Valerio; Campomenosi, Paola; Marsoni, Milena; Scoccianti, Valeria

    2014-01-01

    Chemical inhibition of the proteasome has been previously found to effectively impair pollen germination and tube growth in vitro. However, the mediators of these effects at the molecular level are unknown. By performing 2DE proteomic analysis, 24 differentially expressed protein spots, representing 14 unique candidate proteins, were identified in the pollen of kiwifruit (Actinidia deliciosa) germinated in the presence of the MG132 proteasome inhibitor. qPCR analysis revealed that 11 of these proteins are not up-regulated at the mRNA level, but are most likely stabilized by proteasome inhibition. These differentially expressed proteins are predicted to function in various pathways including energy and lipid metabolism, cell wall synthesis, protein synthesis/degradation and stress responses. In line with this evidence, the MG132-induced changes in the proteome were accompanied by an increase in ATP and ROS content and by an alteration in fatty acid composition.

  9. Protein Sialylation Regulates a Gene Expression Signature that Promotes Breast Cancer Cell Pathogenicity.

    PubMed

    Kohnz, Rebecca A; Roberts, Lindsay S; DeTomaso, David; Bideyan, Lara; Yan, Peter; Bandyopadhyay, Sourav; Goga, Andrei; Yosef, Nir; Nomura, Daniel K

    2016-08-19

    Many mechanisms have been proposed for how heightened aerobic glycolytic metabolism fuels cancer pathogenicity, but there are still many unexplored pathways. Here, we have performed metabolomic profiling to map glucose incorporation into metabolic pathways upon transformation of mammary epithelial cells by 11 commonly mutated human oncogenes. We show that transformation of mammary epithelial cells by oncogenic stimuli commonly shunts glucose-derived carbons into synthesis of sialic acid, a hexosamine pathway metabolite that is converted to CMP-sialic acid by cytidine monophosphate N-acetylneuraminic acid synthase (CMAS) as a precursor to glycoprotein and glycolipid sialylation. We show that CMAS knockdown leads to elevations in intracellular sialic acid levels, a depletion of cellular sialylation, and alterations in the expression of many cancer-relevant genes to impair breast cancer pathogenicity. Our study reveals the heretofore unrecognized role of sialic acid metabolism and protein sialylation in regulating the expression of genes that maintain breast cancer pathogenicity.

  10. Heme-related gene expression signatures of meat intakes in lung cancer tissues.

    PubMed

    Lam, Tram Kim; Rotunno, Melissa; Ryan, Brid M; Pesatori, Angela C; Bertazzi, Pier Alberto; Spitz, Margaret; Caporaso, Neil E; Landi, Maria Teresa

    2014-07-01

    Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus-low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) ≤ 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (∼ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer.

  11. Transcription factor regulation can be accurately predicted from the presence of target gene signatures in microarray gene expression data

    PubMed Central

    Essaghir, Ahmed; Toffalini, Federica; Knoops, Laurent; Kallin, Anders; van Helden, Jacques; Demoulin, Jean-Baptiste

    2010-01-01

    Deciphering transcription factor networks from microarray data remains difficult. This study presents a simple method to infer the regulation of transcription factors from microarray data based on well-characterized target genes. We generated a catalog containing transcription factors associated with 2720 target genes and 6401 experimentally validated regulations. When it was available, a distinction between transcriptional activation and inhibition was included for each regulation. Next, we built a tool (www.tfacts.org) that compares submitted gene lists with target genes in the catalog to detect regulated transcription factors. TFactS was validated with published lists of regulated genes in various models and compared to tools based on in silico promoter analysis. We next analyzed the NCI60 cancer microarray data set and showed the regulation of SOX10, MITF and JUN in melanomas. We then performed microarray experiments comparing gene expression response of human fibroblasts stimulated by different growth factors. TFactS predicted the specific activation of Signal transducer and activator of transcription factors by PDGF-BB, which was confirmed experimentally. Our results show that the expression levels of transcription factor target genes constitute a robust signature for transcription factor regulation, and can be efficiently used for microarray data mining. PMID:20215436

  12. Physical activity-associated gene expression signature in nonhuman primate motor cortex.

    PubMed

    Mitchell, Amanda C; Leak, Rehana K; Garbett, Krassimira; Zigmond, Michael J; Cameron, Judy L; Mirnics, Károly

    2012-03-01

    It has been established that weight gain and weight loss are heavily influenced by activity level. In this study, we hypothesized that the motor cortex exhibits a distinct physical activity-associated gene expression profile, which may underlie changes in weight associated with movement. Using DNA microarrays we profiled gene expression in the motor cortex of a group of 14 female rhesus monkeys (Macaca mulatta) with a wide range of stable physical activity levels. We found that neuronal growth factor signaling and nutrient sensing transcripts in the brain were highly correlated with physical activity. A follow-up of AKT3 expression changes (a gene at the apex of neuronal survival and nutrient sensing) revealed increased protein levels of total AKT, phosphorylated AKT, and forkhead box O3 (FOXO3), one of AKT's main downstream effectors. In addition, we successfully validated three other genes via quantitative polymerase chain reaction (qPCR) (cereblon (CRBN), origin recognition complex subunit 4-like, and pyruvate dehydrogenase 4 (PDK4)). We conclude that these genes are important in the physical activity-associated pathway in the motor cortex, and may be critical for physical activity-associated changes in body weight and neuroprotection.

  13. Gene expression signatures defining fundamental biological processes in pluripotent, early, and late differentiated embryonic stem cells.

    PubMed

    Gaspar, John Antonydas; Doss, Michael Xavier; Winkler, Johannes; Wagh, Vilas; Hescheler, Jürgen; Kolde, Raivo; Vilo, Jaak; Schulz, Herbert; Sachinidis, Agapios

    2012-09-01

    Investigating the molecular mechanisms controlling the in vivo developmental program postembryogenesis is challenging and time consuming. However, the developmental program can be partly recapitulated in vitro by the use of cultured embryonic stem cells (ESCs). Similar to the totipotent cells of the inner cell mass, gene expression and morphological changes in cultured ESCs occur hierarchically during their differentiation, with epiblast cells developing first, followed by germ layers and finally somatic cells. Combination of high throughput -omics technologies with murine ESCs offers an alternative approach for studying developmental processes toward organ-specific cell phenotypes. We have made an attempt to understand differentiation networks controlling embryogenesis in vivo using a time kinetic, by identifying molecules defining fundamental biological processes in the pluripotent state as well as in early and the late differentiation stages of ESCs. Our microarray data of the differentiation of the ESCs clearly demonstrate that the most critical early differentiation processes occur at days 2 and 3 of differentiation. Besides monitoring well-annotated markers pertinent to both self-renewal and potency (capacity to differentiate to different cell lineage), we have identified candidate molecules for relevant signaling pathways. These molecules can be further investigated in gain and loss-of-function studies to elucidate their role for pluripotency and differentiation. As an example, siRNA knockdown of MageB16, a gene highly expressed in the pluripotent state, has proven its influence in inducing differentiation when its function is repressed.

  14. Gene expression signature in peripheral blood cells from medical students exposed to chronic psychological stress.

    PubMed

    Kawai, Tomoko; Morita, Kyoko; Masuda, Kiyoshi; Nishida, Kensei; Shikishima, Michiyo; Ohta, Masayuki; Saito, Toshiro; Rokutan, Kazuhito

    2007-10-01

    To assess response to chronic psychological stress, gene expression profiles in peripheral blood from 18 medical students confronting license examination were analyzed using an original microarray. Total RNA was collected from each subject 9 months before the examination and mixed to be used as a universal control. At that time, most students had normal scores on the state-trait anxiety inventory (STAI). However, STAI scores were significantly elevated at 2 months and at 2 days before the examination. Pattern of the gene expression profile was more uniform 2 days before than 2 months before the examination. We identified 24 genes that significantly and uniformly changed from the universal control 2 days before the examination. Of the 24 genes, real-time PCR validated changes in mRNA levels of 10 (PLCB2, CSF3R, ARHGEF1, DPYD, CTNNB1, PPP3CA, POLM, IRF3, TP53, and CCNI). The identified genes may be useful to assess chronic psychological stress response.

  15. Towards a tolerance toolkit: Gene expression signatures enabling the emergence of resistant bacterial strains

    NASA Astrophysics Data System (ADS)

    Erickson, Keesha; Chatterjee, Anushree

    2014-03-01

    Microbial pathogens are able to rapidly acquire tolerance to chemical toxins. Developing next-generation antibiotics that impede the emergence of resistance will help avoid a world-wide health crisis. Conversely, the ability to induce rapid tolerance gains could lead to high-yielding strains for sustainable production of biofuels and commodity chemicals. Achieving these goals requires an understanding of the general mechanisms allowing microbes to become resistant to diverse toxins. We apply top-down and bottom-up methodologies to identify biological network changes leading to adaptation and tolerance. Using a top-down approach, we perform evolution experiments to isolate resistant strains, collect samples for transcriptomic and proteomic analysis, and use the omics data to inform mathematical gene regulatory models. Using a bottom-up approach, we build and test synthetic genetic devices that enable increased or decreased expression of selected genes. Unique patterns in gene expression are identified in cultures actively gaining resistance, especially in pathways known to be involved with stress response, efflux, and mutagenesis. Genes correlated with tolerance could potentially allow the design of resistance-free antibiotics or robust chemical production strains.

  16. Transcriptomic Signature of the SHATTERPROOF2 Expression Domain Reveals the Meristematic Nature of Arabidopsis Gynoecial Medial Domain1[OPEN

    PubMed Central

    Villarino, Gonzalo H.; Hu, Qiwen; Flores-Vergara, Miguel; Sehra, Bhupinder; Brumos, Javier; Stepanova, Anna N.; Sundberg, Eva; Heber, Steffen

    2016-01-01

    Plant meristems, like animal stem cell niches, maintain a pool of multipotent, undifferentiated cells that divide and differentiate to give rise to organs. In Arabidopsis (Arabidopsis thaliana), the carpel margin meristem is a vital meristematic structure that generates ovules from the medial domain of the gynoecium, the female floral reproductive structure. The molecular mechanisms that specify this meristematic region and regulate its organogenic potential are poorly understood. Here, we present a novel approach to analyze the transcriptional signature of the medial domain of the Arabidopsis gynoecium, highlighting the developmental stages that immediately proceed ovule initiation, the earliest stages of seed development. Using a floral synchronization system and a SHATTERPROOF2 (SHP2) domain-specific reporter, paired with FACS and RNA sequencing, we assayed the transcriptome of the gynoecial medial domain with temporal and spatial precision. This analysis reveals a set of genes that are differentially expressed within the SHP2 expression domain, including genes that have been shown previously to function during the development of medial domain-derived structures, including the ovules, thus validating our approach. Global analyses of the transcriptomic data set indicate a similarity of the pSHP2-expressing cell population to previously characterized meristematic domains, further supporting the meristematic nature of this gynoecial tissue. Our method identifies additional genes including novel isoforms, cis-natural antisense transcripts, and a previously unrecognized member of the REPRODUCTIVE MERISTEM family of transcriptional regulators that are potential novel regulators of medial domain development. This data set provides genome-wide transcriptional insight into the development of the carpel margin meristem in Arabidopsis. PMID:26983993

  17. MicroRNA expression signature and the therapeutic effect of the microRNA-21 antagomir in hypertrophic scarring

    PubMed Central

    Guo, Liang; Xu, Kai; Yan, Hongbo; Feng, Haifeng; Wang, Tao; Chai, Linlin; Xu, Guozheng

    2017-01-01

    Hypertrophic scars (HS) area fibroproliferative disorder of the skin, which causes aesthetic and functional impairment. However, the molecular pathogenesis of this disease remains largely unknown and currently no efficient treatment exists. MicroRNAs (miRNAs) are involved in a variety of pathophysiological processes, however the role of miRNAs in HS development remains unclear. To investigate the miRNA expression signature of HS, microarray analysis was performed and 152 miRNAs were observed to be differentially expressed in HS tissue compared with normal skin tissues. Of the miRNAs identified, miRNA-21 (miR-21) was significantly increased in HS tissues and hypertrophic scar fibroblasts (HSFBs) as determined by reverse transcription-quantitative polymerase chain reaction analysis. It was also observed that, when miR-21 in HSFBs was blocked through use of an antagomir, the phenotype of fibrotic fibroblasts in vitro was reversed, as demonstrated by growth inhibition, induction of apoptosis and suppressed expression of fibrosis-associated genes collagen type I α 1 chain (COL1A1), COL1A2 and fibronectin. Furthermore, miR-21 antagomir administration significantly reduced the severity of HS formation and decreased collagen deposition in a rabbit ear HS model. The total scar area and scar elevation index were calculated and were demonstrated to be significantly decreased in the treatment group compared with control rabbits. These results indicated that the miR-21 antagomir has a therapeutic effect on HS and suggests that targeting miRNAs may be a successful and novel therapeutic strategy in the treatment of fibrotic diseases that are difficult to treat with existing methods. PMID:28075443

  18. EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells.

    PubMed

    Yaguchi, Akinori; Ishibashi, Takeshi; Terada, Kazuki; Ueno-Yokohata, Hitomi; Saito, Yuya; Fujimura, Junya; Shimizu, Toshiaki; Ohki, Kentaro; Manabe, Atsushi; Kiyokawa, Nobutaka

    2017-04-04

    ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3-4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

  19. Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures

    PubMed Central

    Wirapati, Pratyaksha; Sotiriou, Christos; Kunkel, Susanne; Farmer, Pierre; Pradervand, Sylvain; Haibe-Kains, Benjamin; Desmedt, Christine; Ignatiadis, Michail; Sengstag, Thierry; Schütz, Frédéric; Goldstein, Darlene R; Piccart, Martine; Delorenzi, Mauro

    2008-01-01

    Introduction Breast cancer subtyping and prognosis have been studied extensively by gene expression profiling, resulting in disparate signatures with little overlap in their constituent genes. Although a previous study demonstrated a prognostic concordance among gene expression signatures, it was limited to only one dataset and did not fully elucidate how the different genes were related to one another nor did it examine the contribution of well-known biological processes of breast cancer tumorigenesis to their prognostic performance. Method To address the above issues and to further validate these initial findings, we performed the largest meta-analysis of publicly available breast cancer gene expression and clinical data, which are comprised of 2,833 breast tumors. Gene coexpression modules of three key biological processes in breast cancer (namely, proliferation, estrogen receptor [ER], and HER2 signaling) were used to dissect the role of constituent genes of nine prognostic signatures. Results Using a meta-analytical approach, we consolidated the signatures associated with ER signaling, ERBB2 amplification, and proliferation. Previously published expression-based nomenclature of breast cancer 'intrinsic' subtypes can be mapped to the three modules, namely, the ER-/HER2- (basal-like), the HER2+ (HER2-like), and the low- and high-proliferation ER+/HER2- subtypes (luminal A and B). We showed that all nine prognostic signatures exhibited a similar prognostic performance in the entire dataset. Their prognostic abilities are due mostly to the detection of proliferation activity. Although ER- status (basal-like) and ERBB2+ expression status correspond to bad outcome, they seem to act through elevated expression of proliferation genes and thus contain only indirect information about prognosis. Clinical variables measuring the extent of tumor progression, such as tumor size and nodal status, still add independent prognostic information to proliferation genes. Conclusion

  20. Gene expression signature for early prediction of late occurring pancytopenia in irradiated baboons.

    PubMed

    Port, Matthias; Hérodin, Francis; Valente, Marco; Drouet, Michel; Lamkowski, Andreas; Majewski, Matthäus; Abend, Michael

    2017-02-24

    Based on gene expression changes measured in the peripheral blood within the first 2 days after irradiation, we predicted a pancytopenia in a baboon model. Eighteen baboons were irradiated with 2.5 or 5 Gy. According to changes in blood cell counts, the surviving baboons (n = 17) exhibited a hematological acute radiation syndrome (HARS) either with or without a pancytopenia. We used a two stage study design where stage I was a whole genome screen (microarrays) for mRNA combined with a qRT-PCR platform for simultaneous detection of 667 miRNAs using a part of the samples. Candidate mRNAs and miRNAs differentially upregulated or downregulated (>2-fold, p < 0.05) during the first 2 days after irradiation were chosen for validation in stage II using the remaining samples and using throughout more sensitive qRT-PCR. We detected about twice as many upregulated (mean 2128) than downregulated genes (mean 789) in baboons developing an HARS either with or without a pancytopenia. From 51 candidate mRNAs altogether, 11 mRNAs were validated using qRT-PCR. These mRNAs showed only significant differences between HARS groups and H0, but not between HARS groups with and without pancytopenia. Six miRNA species (e.g., miR-574-3p, p = 0.009, ROC = 0.94) revealed significant gene expression differences between HARS groups with and without pancytopenia and are known to sensitize irradiated cells. Hence, in particular, the newly identified miRNA species for prediction of pancytopenia will support the medical management decision making.

  1. Identification of Novel Cholesteatoma-Related Gene Expression Signatures Using Full-Genome Microarrays

    PubMed Central

    Klenke, Christin; Janowski, Sebastian; Borck, Daniela; Widera, Darius; Ebmeyer, Jörg; Kalinowski, Jörn; Leichtle, Anke; Hofestädt, Ralf; Upile, Tahwinder; Kaltschmidt, Christian; Kaltschmidt, Barbara; Sudhoff, Holger

    2012-01-01

    Background Cholesteatoma is a gradually expanding destructive epithelial lesion within the middle ear. It can cause extensive local tissue destruction in the temporal bone and can initially lead to the development of conductive hearing loss via ossicular erosion. As the disease progresses, sensorineural hearing loss, vertigo or facial palsy may occur. Cholesteatoma may promote the spread of infection through the tegmen of the middle ear and cause meningitis or intracranial infections with abscess formation. It must, therefore, be considered as a potentially life-threatening middle ear disease. Methods and Findings In this study, we investigated differentially expressed genes in human cholesteatomas in comparison to regular auditory canal skin using Whole Human Genome Microarrays containing 19,596 human genes. In addition to already described up-regulated mRNAs in cholesteatoma, such as MMP9, DEFB2 and KRT19, we identified 3558 new cholesteatoma-related transcripts. 811 genes appear to be significantly differentially up-regulated in cholesteatoma. 334 genes were down-regulated more than 2-fold. Significantly regulated genes with protein metabolism activity include matrix metalloproteinases as well as PI3, SERPINB3 and SERPINB4. Genes like SPP1, KRT6B, PRPH, SPRR1B and LAMC2 are known as genes with cell growth and/or maintenance activity. Transport activity genes and signal transduction genes are LCN2, GJB2 and CEACAM6. Three cell communication genes were identified; one CDH19 and two from the S100 family. Conclusions This study demonstrates that the expression profile of cholesteatoma is similar to a metastatic tumour and chronically inflamed tissue. Based on the investigated profiles we present novel protein-protein interaction and signal transduction networks, which include cholesteatoma-regulated transcripts and may be of great value for drug targeting and therapy development. PMID:23285167

  2. Expression signature of lncRNAs and their potential roles in cardiac fibrosis of post-infarct mice

    PubMed Central

    Qu, Xuefeng; Song, Xiaotong; Yuan, Wei; Shu, You; Wang, Yuying; Zhao, Xuyun; Gao, Ming; Lu, Renzhong; Luo, Shenjian; Zhao, Wei; Zhang, Yue; Sun, Lihua; Lu, Yanjie

    2016-01-01

    The present study aimed to investigate whether long non-coding RNAs (lncRNAs) are involved in cardiac fibrogenesis induced by myocardial infarction (MI). The differentially expressed lncRNAs and mRNAs in peri-infarct region of mice 4 weeks after MI were selected for bioinformatic analysis including gene ontology (GO) enrichment, pathway and network analysis. Left ventricular tissue levels of lncRNAs and mRNAs were compared between MI and sham control mice, using a false discovery rate (FDR) of <5%. Out of 55000 lncRNAs detected, 263 were significantly up-regulated and 282 down-regulated. Out of 23000 mRNAs detected, 142 were significantly up-regulated and 67 down-regulated. Among the differentially expressed lncRNAs, 53 were up-regulated by ≥2.0-fold change and 37 down-regulated by ≤0.5-fold change. Nine up-regulated and five down-regulated lncRNAs were randomly selected for quantitative real-time PCR (qRT-PCR) verification. GO and pathway analyses revealed 173 correlated lncRNA–mRNA pairs for 57 differentially expressed lncRNAs and 20 differentially expressed genes which are related to the development of cardiac fibrosis. We identified TGF-β3 as the top-ranked gene, a critical component of the transforming growth factor-β (TGF-β) and mitogen activated protein kinase (MAPK) signalling pathways in cardiac fibrosis. NONMMUT022554 was identified as the top-ranked lncRNA, positively correlated with six up-regulated genes, which are involved in the extracellular matrix (ECM)–receptor interactions and the phosphoinositid-3 kinase/protein kinase B (PI3K-Akt) signalling pathway. Our study has identified the expression signature of lncRNAs in cardiac fibrosis induced by MI and unravelled the possible involvement of the deregulated lncRNAs in cardiac fibrosis and the associated pathological processes. PMID:27129287

  3. Gene expression signature based screening identifies ribonucleotide reductase as a candidate therapeutic target in Ewing sarcoma

    PubMed Central

    Goss, Kelli L.; Gordon, David J.

    2016-01-01

    There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies. We used gene expression data derived from a genetically defined model of Ewing sarcoma to interrogate the Connectivity Map and identify a class of drugs, iron chelators, that downregulate a significant number of EWS-FLI1 target genes. We then identified ribonucleotide reductase M2 (RRM2), the iron-dependent subunit of ribonucleotide reductase (RNR), as one mediator of iron chelator toxicity in Ewing sarcoma cells. Inhibition of RNR in Ewing sarcoma cells caused apoptosis in vitro and attenuated tumor growth in an in vivo, xenograft model. Additionally, we discovered that the sensitivity of Ewing sarcoma cells to inhibition or suppression of RNR is mediated, in part, by high levels of SLFN11, a protein that sensitizes cells to DNA damage. This work demonstrates a unique dependency of Ewing sarcoma cells on RNR and supports further investigation of RNR inhibitors, which are currently used in clinical practice, as a novel approach for treating Ewing sarcoma. PMID:27557498

  4. Molecular Signature of HPV-Induced Carcinogenesis: pRb, p53 and Gene Expression Profiling

    PubMed Central

    Buitrago-Pérez, Águeda; Garaulet, Guillermo; Vázquez-Carballo, Ana; Paramio, Jesús M; García-Escudero, Ramón

    2009-01-01

    The infection by mucosal human papillomavirus (HPV) is causally associated with tumor development in cervix and oropharynx. The mechanisms responsible for this oncogenic potential are mainly due to the product activities of two early viral oncogenes: E6 and E7. Although a large number of cellular targets have been described for both oncoproteins, the interaction with tumor suppressors p53 and retinoblastoma protein (pRb) emerged as the key functional activities. E6 degrades tumor suppressor p53, thus inhibiting p53-dependent functions, whereas E7 binds and degrades pRb, allowing the transcription of E2F-dependent genes. Since these two tumor suppressors exert their actions through transcriptional modulation, functional genomics has provided a large body of data that reflects the altered gene expression of HPVinfected cells or tissues. Here we will review the similarities and differences of these findings, and we also compare them with those obtained with transgenic mouse models bearing the deletion of some of the viral oncogene targets. The comparative analysis supports molecular evidences about the role of oncogenes E6 and E7 in the interference with the mentioned cellular functions, and also suggests that the mentioned transgenic mice can be used as models for HPV-associated diseases such as human cervical, oropharynx, and skin carcinomas. PMID:19721808

  5. Molecular Signature of HPV-Induced Carcinogenesis: pRb, p53 and Gene Expression Profiling.

    PubMed

    Buitrago-Pérez, Agueda; Garaulet, Guillermo; Vázquez-Carballo, Ana; Paramio, Jesús M; García-Escudero, Ramón

    2009-03-01

    The infection by mucosal human papillomavirus (HPV) is causally associated with tumor development in cervix and oropharynx. The mechanisms responsible for this oncogenic potential are mainly due to the product activities of two early viral oncogenes: E6 and E7. Although a large number of cellular targets have been described for both oncoproteins, the interaction with tumor suppressors p53 and retinoblastoma protein (pRb) emerged as the key functional activities. E6 degrades tumor suppressor p53, thus inhibiting p53-dependent functions, whereas E7 binds and degrades pRb, allowing the transcription of E2F-dependent genes. Since these two tumor suppressors exert their actions through transcriptional modulation, functional genomics has provided a large body of data that reflects the altered gene expression of HPVinfected cells or tissues. Here we will review the similarities and differences of these findings, and we also compare them with those obtained with transgenic mouse models bearing the deletion of some of the viral oncogene targets. The comparative analysis supports molecular evidences about the role of oncogenes E6 and E7 in the interference with the mentioned cellular functions, and also suggests that the mentioned transgenic mice can be used as models for HPV-associated diseases such as human cervical, oropharynx, and skin carcinomas.

  6. Dynamic classification using case-specific training cohorts outperforms static gene expression signatures in breast cancer

    PubMed Central

    Győrffy, Balázs; Karn, Thomas; Sztupinszki, Zsófia; Weltz, Boglárka; Müller, Volkmar; Pusztai, Lajos

    2015-01-01

    The molecular diversity of breast cancer makes it impossible to identify prognostic markers that are applicable to all breast cancers. To overcome limitations of previous multigene prognostic classifiers, we propose a new dynamic predictor: instead of using a single universal training cohort and an identical list of informative genes to predict the prognosis of new cases, a case-specific predictor is developed for each test case. Gene expression data from 3,534 breast cancers with clinical annotation including relapse-free survival is analyzed. For each test case, we select a case-specific training subset including only molecularly similar cases and a case-specific predictor is generated. This method yields different training sets and different predictors for each new patient. The model performance was assessed in leave-one-out validation and also in 325 independent cases. Prognostic discrimination was high for all cases (n = 3,534, HR = 3.68, p = 1.67 E−56). The dynamic predictor showed higher overall accuracy (0.68) than genomic surrogates for Oncotype DX (0.64), Genomic Grade Index (0.61) or MammaPrint (0.47). The dynamic predictor was also effective in triple-negative cancers (n = 427, HR = 3.08, p = 0.0093) where the above classifiers all failed. Validation in independent patients yielded similar classification power (HR = 3.57). The dynamic classifier is available online at http://www.recurrenceonline.com/?q=Re_training. In summary, we developed a new method to make personalized prognostic prediction using case-specific training cohorts. The dynamic predictors outperform static models developed from single historical training cohorts and they also predict well in triple-negative cancers. PMID:25274406

  7. Gene expression signatures associated with suppression of TRAMP prostate carcinogenesis by a kavalactone-rich Kava fraction.

    PubMed

    Tang, Su-Ni; Zhang, Jinhui; Jiang, Peixin; Datta, Palika; Leitzman, Pablo; O'Sullivan, M Gerard; Jiang, Cheng; Xing, Chengguo; Lü, Junxuan

    2016-12-01

    Kava (Piper methysticum Forster) extract and its major kavalactones have been shown to block chemically induced lung tumor initiation in mouse models. Here we evaluated the chemopreventive effect of a kavalactone-rich Kava fraction B (KFB), free of flavokavains, on carcinogenesis in a transgenic adenocarcinoma of mouse prostate (TRAMP) model and characterized the prostate gene expression signatures. Male C57BL/6 TRAMP mice were fed AIN93M diet with or without 0.4% KFB from 8 wk of age. Mice were euthanized at 16 or 28 wk. The growth of the dorsolateral prostate (DLP) lobes in KFB-treated TRAMP mice was inhibited by 66% and 58% at the respective endpoint. Anterior and ventral prostate lobes in KFB-treated TRAMP mice were suppressed by 40% and 49% at 28 wk, respectively. KFB consumption decreased cell proliferation biomarker Ki-67 and epithelial lesion severity in TRAMP DLP, without detectable apoptosis enhancement. Real time qRT-PCR detection of mRNA from DLP at 28 wk showed decreased expression of cell cycle regulatory genes congruent with Ki-67 suppression. Microarray profiling of DLP mRNA indicated that "oncogene-like" genes related to angiogenesis and cell proliferation were suppressed by KFB but tumor suppressor, immunity, muscle/neuro, and metabolism-related genes were upregulated by KFB in both TRAMP and WT DLP. TRAMP mice fed KFB diet developed lower incidence of neuroendocrine carcinomas (NECa) (2 out of 14 mice) than those fed the basal diet (8 out of 14 mice, χ(2)  = 5.6, P < 0.025). KFB may, therefore, inhibit not only TRAMP DLP epithelial lesions involving multiple molecular pathways, but also NECa. © 2016 Wiley Periodicals, Inc.

  8. Diagnosing ALS

    MedlinePlus

    ... that a person diagnosed with ALS seek a second opinion from an ALS "expert" - someone who diagnoses and treats many ALS patients and has training in this medical specialty. The ALS Association maintains a list of recognized experts in the field of ALS. See ALS Association Certified Centers of ...

  9. High Expression of Three-Gene Signature Improves Prediction of Relapse-Free Survival in Estrogen Receptor-Positive and Node-Positive Breast Tumors

    PubMed Central

    Thakkar, Arvind; Raj, Hemanth; Ravishankar; Muthuvelan, Bhaskaran; Balakrishnan, Arun; Padigaru, Muralidhara

    2015-01-01

    The objective of the present study was to validate prognostic gene signature for estrogen receptor alpha-positive (ER03B1+) and lymph node (+) breast cancer for improved selection of patients for adjuvant therapy. In our previous study, we identified a group of seven genes (GATA3, NTN4, SLC7A8, ENPP1, MLPH, LAMB2, and PLAT) that show elevated messenger RNA (mRNA) expression levels in ERα (+) breast cancer patient samples. The prognostic values of these genes were evaluated using gene expression data from three public data sets of breast cancer patients (n = 395). Analysis of ERα (+) breast cancer cohort (n = 195) showed high expression of GATA3, NTN4, and MLPH genes significantly associated with longer relapse-free survival (RFS). Next cohort of ERα (+) and node (+) samples (n = 109) revealed high mRNA expression of GATA3, SLC7A8, and MLPH significantly associated with longer RFS. Multivariate analysis of combined three-gene signature for ERα (+) cohort, and ERα (+) and node (+) cohorts showed better hazard ratio than individual genes. The validated three-gene signature sets for ERα (+) cohort, and ERα (+) and node (+) cohort may have potential clinical utility since they demonstrated predictive and prognostic ability in three independent public data sets. PMID:26648682

  10. Unique long non-coding RNA expression signature in ETV6/RUNX1-driven B-cell precursor acute lymphoblastic leukemia

    PubMed Central

    Ghazavi, Farzaneh; Moerloose, Barbara De; Loocke, Wouter Van; Wallaert, Annelynn; Helsmoortel, Hetty H.; Ferster, Alina; Bakkus, Marleen; Plat, Geneviève; Delabesse, Eric; Uyttebroeck, Anne; Nieuwerburgh, Filip Van; Deforce, Dieter; Roy, Nadine Van; Speleman, Frank; Benoit, Yves

    2016-01-01

    Overwhelming evidence indicates that long non-coding RNAs have essential roles in tumorigenesis. Nevertheless, their role in the molecular pathogenesis of pediatric B-cell precursor acute lymphoblastic leukemia has not been extensively explored. Here, we conducted a comprehensive analysis of the long non-coding RNA transcriptome in ETV6/RUNX1-positive BCP-ALL, one of the most frequent subtypes of pediatric leukemia. First, we used primary leukemia patient samples to identify an ETV6/RUNX1 specific expression signature consisting of 596 lncRNA transcripts. Next, integration of this lncRNA signature with RNA sequencing of BCP-ALL cell lines and lncRNA profiling of an in vitro model system of ETV6/RUNX1 knockdown, revealed that lnc-NKX2-3-1, lnc-TIMM21-5, lnc-ASTN1-1 and lnc-RTN4R-1 are truly regulated by the oncogenic fusion protein. Moreover, sustained inactivation of lnc-RTN4R-1 and lnc-NKX2-3-1 in ETV6/RUNX1 positive cells caused profound changes in gene expression. All together, our study defined a unique lncRNA expression signature associated with ETV6/RUNX1-positive BCP-ALL and identified lnc-RTN4R-1 and lnc-NKX2-3-1 as lncRNAs that might be functionally implicated in the biology of this prevalent subtype of human leukemia. PMID:27650541

  11. Newly Diagnosed?

    MedlinePlus

    ... Suggestions Examine Your Skin Newly Diagnosed? Understanding Your Pathology Biopsy: The First Step Sentinel Node Biopsy Melanoma ... start this journey: Get a copy of your pathology report. We can help you understand the report ...

  12. Newly Diagnosed

    MedlinePlus

    ... of transmitting HIV to others. Do I Have AIDS? Being HIV-positive does NOT necessarily mean you ... Children Newly Diagnosed: Older Adults Related Topics on AIDS.gov Stages of HIV Infection Immune System 101 ...

  13. Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration

    PubMed Central

    2012-01-01

    Introduction Acquired tamoxifen resistance involves complex signaling events that are not yet fully understood. Successful therapeutic intervention to delay the onset of hormone resistance depends critically on mechanistic elucidation of viable molecular targets associated with hormone resistance. This study was undertaken to investigate the global proteomic alterations in a tamoxifen resistant MCF-7 breast cancer cell line obtained by long term treatment of the wild type MCF-7 cell line with 4-hydroxytamoxifen (4-OH Tam). Methods We cultured MCF-7 cells with 4-OH Tam over a period of 12 months to obtain the resistant cell line. A gel-free, quantitative proteomic method was used to identify and quantify the proteome of the resistant cell line. Nano-flow high-performance liquid chromatography coupled to high resolution Fourier transform mass spectrometry was used to analyze fractionated peptide mixtures that were isobarically labeled from the resistant and control cell lysates. Real time quantitative PCR and Western blots were used to verify selected proteomic changes. Lentiviral vector transduction was used to generate MCF-7 cells stably expressing S100P. Online pathway analysis was performed to assess proteomic signatures in tamoxifen resistance. Survival analysis was done to evaluate clinical relevance of altered proteomic expressions. Results Quantitative proteomic analysis revealed a wide breadth of signaling events during transition to acquired tamoxifen resistance. A total of 629 proteins were found significantly changed with 364 up-regulated and 265 down-regulated. Collectively, these changes demonstrated the suppressed state of estrogen receptor (ER) and ER-regulated genes, activated survival signaling and increased migratory capacity of the resistant cell line. The protein S100P was found to play a critical role in conferring tamoxifen resistance and enhanced cell motility. Conclusions Our data demonstrate that the adaptive changes in the proteome of

  14. Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis.

    PubMed

    Bhatlekar, Seema; Addya, Sankar; Salunek, Moreh; Orr, Christopher R; Surrey, Saul; McKenzie, Steven; Fields, Jeremy Z; Boman, Bruce M

    2014-01-15

    Our goal was to identify a unique gene expression signature for human colonic stem cells (SCs). Accordingly, we determined the gene expression pattern for a known SC-enriched region--the crypt bottom. Colonic crypts and isolated crypt subsections (top, middle, and bottom) were purified from fresh, normal, human, surgical specimens. We then used an innovative strategy that used two-color microarrays (∼18,500 genes) to compare gene expression in the crypt bottom with expression in the other crypt subsections (middle or top). Array results were validated by PCR and immunostaining. About 25% of genes analyzed were expressed in crypts: 88 preferentially in the bottom, 68 in the middle, and 131 in the top. Among genes upregulated in the bottom, ∼30% were classified as growth and/or developmental genes including several in the PI3 kinase pathway, a six-transmembrane protein STAMP1, and two homeobox (HOXA4, HOXD10) genes. qPCR and immunostaining validated that HOXA4 and HOXD10 are selectively expressed in the normal crypt bottom and are overexpressed in colon carcinomas (CRCs). Immunostaining showed that HOXA4 and HOXD10 are co-expressed with the SC markers CD166 and ALDH1 in cells at the normal crypt bottom, and the number of these co-expressing cells is increased in CRCs. Thus, our findings show that these two HOX genes are selectively expressed in colonic SCs and that HOX overexpression in CRCs parallels the SC overpopulation that occurs during CRC development. Our study suggests that developmental genes play key roles in the maintenance of normal SCs and crypt renewal, and contribute to the SC overpopulation that drives colon tumorigenesis.

  15. Ion signatures of magnetic flux ropes in the Venusian ionosphere as observed by APSERA-4 and MAG onboard Venus Express

    NASA Astrophysics Data System (ADS)

    Guymer, G.; Grande, M.; Whittaker, I.

    2008-09-01

    Abstract Venus has a negligible intrinsic magnetic moment with an upper limit a factor 10-5 of earth's [1]. This entails that the ionosphere is vulnerable to scavenging by the solar wind. However, magnetic fields may be induced in the ionosphere by interaction with the interplanetary magnetic field frozen-in to the solar wind. The presence of small scale magnetic structures in the dayside ionosphere of the planet Venus has been long established and were first observed in Pioneer Venus Orbiter (PVO) data in 1979 [2] during the run up to solar maximum. These ionospheric `flux ropes' were observed in over 70% of passes in which the orbit of PVO intersected the dayside ionosphere [3]. Magnetic flux ropes are identified as brief, discrete disturbances from any background magnetic field, lasting a few seconds with a magnitude of up to many 10's of nano-Teslas in strength [3, 4]. Flux ropes have a strong central, axial field, that is wrapped with field lines of weakening strength and increased helical angle with distance from the central field lines [4]. Due to this particular structure, flux ropes present a specific signature in the three variance projections (also known as a hodogram) when minimum variance analysis is applied to the magnetic data set [2]. With Venus Express now in operational orbit around the planet, flux ropes are being observed in the data retrieved by the magnetometers (MAG [5]) onboard. The magnetic data used in this analysis is the 1Hz data set provided by H. Wei (of UCLA). Variance projections have been produced for several structures in 2006, revealing them to be flux ropes (see figure 1). Using the Ion Mass Analyser (IMA; part of the ASPERA-4 package [6]) and MAG, the ion composition within the ropes and the effect of such magnetic structures upon ionospheric erosion is being studied. Where flux ropes have been evident in the magnetic data, ion spectra have been produced in an attempt to deduce any compositional differences between a flux rope

  16. miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness.

    PubMed

    Lerebours, Florence; Cizeron-Clairac, Geraldine; Susini, Aurelie; Vacher, Sophie; Mouret-Fourme, Emmanuelle; Belichard, Catherine; Brain, Etienne; Alberini, Jean-Louis; Spyratos, Frédérique; Lidereau, Rosette; Bieche, Ivan

    2013-10-01

    IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT-PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non-stage-matched non-IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non-IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non-IBC. Among these, a 5-miRNA signature comprising miR-421, miR-486, miR-503, miR-720 and miR-1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis-Free Survival in non-IBC patients.

  17. Signature control

    NASA Astrophysics Data System (ADS)

    Pyati, Vittal P.

    The reduction of vehicle radar signature is accomplished by means of vehicle shaping, the use of microwave frequencies-absorbent materials, and either passive or active cancellation techniques; such techniques are also useful in the reduction of propulsion system-associated IR emissions. In some anticipated scenarios, the objective is not signature-reduction but signature control, for deception, via decoy vehicles that mimic the signature characteristics of actual weapons systems. As the stealthiness of airframes and missiles increases, their propulsion systems' exhaust plumes assume a more important role in detection by an adversary.

  18. Expression signature based on TP53 target genes doesn't predict response to TP53-MDM2 inhibitor in wild type TP53 tumors.

    PubMed

    Sonkin, Dmitriy

    2015-10-22

    A number of TP53-MDM2 inhibitors are currently under investigation as therapeutic agents in a variety of clinical trials in patients with TP53 wild type tumors. Not all wild type TP53 tumors are sensitive to such inhibitors. In an attempt to improve selection of patients with TP53 wild type tumors, an mRNA expression signature based on 13 TP53 transcriptional target genes was recently developed (Jeay et al. 2015). Careful reanalysis of TP53 status in the study validation data set of cancer cell lines considered to be TP53 wild type detected TP53 inactivating alterations in 23% of cell lines. The subsequent reanalysis of the remaining TP53 wild type cell lines clearly demonstrated that unfortunately the 13-gene signature cannot predict response to TP53-MDM2 inhibitor in TP53 wild type tumors.

  19. Factors Associated with Expressive and Receptive Language in French-Speaking Toddlers Clinically Diagnosed with Language Delay

    ERIC Educational Resources Information Center

    Sylvestre, Audette; Desmarais, Chantal; Meyer, Francois; Bairati, Isabelle; Rouleau, Nancie; Merette, Chantal

    2012-01-01

    The purpose of this exploratory study was to examine child and environmental factors known to be associated to language development and how they relate to results in expressive vocabulary, expressive language, and receptive language in language-delayed toddlers. The cross-sectional data on 96 French-speaking children aged 18-36 months were…

  20. Diagnosing Flu

    MedlinePlus

    ... your symptoms and their clinical judgment. Will my health care provider test me for flu if I have flu-like ... flu symptoms do not require testing because the test results usually do not change how you are treated. Your health care provider may diagnose you with flu based on ...

  1. Discriminating Gene Expression Signature of Radiation-Induced Thyroid Tumors after Either External Exposure or Internal Contamination

    PubMed Central

    Ory, Catherine; Ugolin, Nicolas; Schlumberger, Martin; Hofman, Paul; Chevillard, Sylvie

    2011-01-01

    Both external radiation exposure and internal radionuclide contamination are well known risk factors in the development of thyroid epithelial tumors. The identification of specific molecular markers deregulated in radiation-induced thyroid tumors is important for the etiological diagnosis since neither histological features nor genetic alterations can discriminate between sporadic and radiation-induced tumors. Identification of highly discriminating markers in radiation-induced tumors is challenging as it relies on the ability to identify marker deregulation which is associated with a cellular stress that occurred many years before in the thyroid cells. The existence of such a signature is still controversial, as it was not found in several studies while a highly discriminating signature was found in both post-radiotherapy and post-Chernobyl series in other studies. Overall, published studies searching for radiation-induced thyroid tumor specificities, using transcriptomic, proteomic and comparative genomic hybridization approaches, and bearing in mind the analytical constraints required to analyze such small series of tumors, suggest that such a molecular signature could be found. In comparison with sporadic tumors, we highlight molecular similarities and specificities in tumors occurring after high-dose external radiation exposure, such as radiotherapy, and in post-Chernobyl tumors that occurred after internal 131I contamination. We discuss the relevance of signature extrapolation from series of tumors developing after high and low doses in the identification of tumors induced at very low doses of radiation. PMID:24704841

  2. Whither the "signature wounds of the war" after the war: estimates of incidence rates and proportions of TBI and PTSD diagnoses attributable to background risk, enhanced ascertainment, and active war zone service, active component, U.S. Armed Forces, 2003-2014.

    PubMed

    Brundage, John F; Taubman, Stephen B; Hunt, Devin J; Clark, Leslie L

    2015-02-01

    Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are "signature wounds" of the Afghanistan/Iraq wars; however, many TBI/PTSD cases are not war related. During the wars, diagnoses of TBI/PTSD among military members increased because risks of TBI/PTSD, and capabilities to detect cases, increased. This report summarizes TBI/PTSD diagnosis experiences of three cohorts of overseas deployers in relation to the natures of their exposures to active war service and enhanced case ascertainment efforts. The findings suggest that, during the war, the proportions of PTSD diagnoses attributable to war zone service decreased from approximately 80% to less than 50%, while the proportions attributable to enhanced case ascertainment increased from less than 10% to nearly 50%. The proportions of TBI diagnoses attributable to war zone service more than tripled from 2003-2005 (13.1%) through 2007-2009 (44.8%); the proportions attributable to enhanced ascertainment also markedly increased, but not until after 2007. By the end of the war, war zone service and enhanced ascertainment accounted for similar proportions of all PTSD and TBI diagnoses. If programs and resources currently focused on TBI and PTSD continue, rates of diagnoses post-war will greatly exceed those pre-war.

  3. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

    PubMed Central

    Hu, Shimin; Xu-Monette, Zijun Y.; Balasubramanyam, Aarthi; Manyam, Ganiraju C.; Visco, Carlo; Tzankov, Alexander; Liu, Wei-min; Miranda, Roberto N.; Zhang, Li; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W. L.; Han van Krieken, J.; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J. M.; Zhao, Xiaoying; Winter, Jane N.; Zhang, Mingzhi; Li, Ling; Møller, Michael B.; Piris, Miguel A.; Li, Yong; Go, Ronald S.; Wu, Lin; Medeiros, L. Jeffrey; Young, Ken H.

    2013-01-01

    CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30+ DLBCL had superior 5-year overall survival (CD30+, 79% vs CD30–, 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30+ DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30+ DLBCL as a distinct subgroup of DLBCL. PMID:23343832

  4. CCR 20th Anniversary Commentary: Gene-Expression Signature in Breast Cancer--Where Did It Start and Where Are We Now?

    PubMed

    Gingras, Isabelle; Desmedt, Christine; Ignatiadis, Michail; Sotiriou, Christos

    2015-11-01

    Desmedt and colleagues published two articles, one in the June 1, 2007 issue, and the other in the August 15, 2008, issue of Clinical Cancer Research, that showed gene-expression signatures to be proliferation driven and time dependent, with their prognostic power decreasing with increasing follow-up years. Moreover, the articles showed that immune response is a crucial determinant of prognosis in the HER2-positive and estrogen receptor-negative/HER2-negative subtypes, providing a rationale to further explore the role of the antitumor immune response in these breast cancer subtypes.

  5. Conditional entropy in variation-adjusted windows detects selection signatures associated with expression quantitative trait loci (eQTLs)

    PubMed Central

    2015-01-01

    Background Over the past 50,000 years, shifts in human-environmental or human-human interactions shaped genetic differences within and among human populations, including variants under positive selection. Shaped by environmental factors, such variants influence the genetics of modern health, disease, and treatment outcome. Because evolutionary processes tend to act on gene regulation, we test whether regulatory variants are under positive selection. We introduce a new approach to enhance detection of genetic markers undergoing positive selection, using conditional entropy to capture recent local selection signals. Results We use conditional logistic regression to compare our Adjusted Haplotype Conditional Entropy (H|H) measure of positive selection to existing positive selection measures. H|H and existing measures were applied to published regulatory variants acting in cis (cis-eQTLs), with conditional logistic regression testing whether regulatory variants undergo stronger positive selection than the surrounding gene. These cis-eQTLs were drawn from six independent studies of genotype and RNA expression. The conditional logistic regression shows that, overall, H|H is substantially more powerful than existing positive-selection methods in identifying cis-eQTLs against other Single Nucleotide Polymorphisms (SNPs) in the same genes. When broken down by Gene Ontology, H|H predictions are particularly strong in some biological process categories, where regulatory variants are under strong positive selection compared to the bulk of the gene, distinct from those GO categories under overall positive selection. . However, cis-eQTLs in a second group of genes lack positive selection signatures detectable by H|H, consistent with ancient short haplotypes compared to the surrounding gene (for example, in innate immunity GO:0042742); under such other modes of selection, H|H would not be expected to be a strong predictor.. These conditional logistic regression models are

  6. Blood-based gene expression signatures of medication-free outpatients with major depressive disorder: integrative genome-wide and candidate gene analyses.

    PubMed

    Hori, Hiroaki; Sasayama, Daimei; Teraishi, Toshiya; Yamamoto, Noriko; Nakamura, Seiji; Ota, Miho; Hattori, Kotaro; Kim, Yoshiharu; Higuchi, Teruhiko; Kunugi, Hiroshi

    2016-01-05

    Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the "synaptic transmission" pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research.

  7. Blood-based gene expression signatures of medication-free outpatients with major depressive disorder: integrative genome-wide and candidate gene analyses

    PubMed Central

    Hori, Hiroaki; Sasayama, Daimei; Teraishi, Toshiya; Yamamoto, Noriko; Nakamura, Seiji; Ota, Miho; Hattori, Kotaro; Kim, Yoshiharu; Higuchi, Teruhiko; Kunugi, Hiroshi

    2016-01-01

    Several microarray-based studies have investigated gene expression profiles in major depressive disorder (MDD), yet with highly variable findings. We examined blood-based genome-wide expression signatures of MDD, focusing on molecular pathways and networks underlying differentially expressed genes (DEGs) and behaviours of hypothesis-driven, evidence-based candidate genes for depression. Agilent human whole-genome arrays were used to measure gene expression in 14 medication-free outpatients with MDD who were at least moderately ill and 14 healthy controls matched pairwise for age and sex. After filtering, we compared expression of entire probes between patients and controls and identified DEGs. The DEGs were evaluated by pathway and network analyses. For the candidate gene analysis, we utilized 169 previously prioritized genes and examined their case-control separation efficiency and correlational co-expression network in patients relative to controls. The 317 screened DEGs mapped to a significantly over-represented pathway, the “synaptic transmission” pathway. The protein-protein interaction network was also significantly enriched, in which a number of key molecules for depression were included. The co-expression network of candidate genes was markedly disrupted in patients. This study provided evidence for an altered molecular network along with several key molecules in MDD and confirmed that the candidate genes are worthwhile targets for depression research. PMID:26728011

  8. A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable

    PubMed Central

    van Kessel, Kim E. M.; van de Werken, Harmen J. G.; Lurkin, Irene; Ziel – van der Made, Angelique C. J.; Zwarthoff, Ellen C.; Boormans, Joost L.

    2017-01-01

    Background Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) provides a small but significant survival benefit. Nevertheless, controversies on applying NAC remain because the limited benefit must be weight against chemotherapy-related toxicity and the delay of definitive local treatment. Therefore, there is a clear clinical need for tools to guide treatment decisions on NAC in MIBC. Here, we aimed to validate a previously reported 20-gene expression signature that predicted lymph node-positive disease at radical cystectomy in clinically node-negative MIBC patients, which would be a justification for upfront chemotherapy. Methods We studied diagnostic transurethral resection of bladder tumors (dTURBT) of 150 MIBC patients (urothelial carcinoma) who were subsequently treated by radical cystectomy and pelvic lymph node dissection. RNA was isolated and the expression level of the 20 genes was determined on a qRT-PCR platform. Normalized Ct values were used to calculate a risk score to predict the presence of node-positive disease. The Cancer Genome Atlas (TCGA) RNA expression data was analyzed to subsequently validate the results. Results In a univariate regression analysis, none of the 20 genes significantly correlated with node-positive disease. The area under the curve of the risk score calculated by the 20-gene expression signature was 0.54 (95% Confidence Interval: 0.44-0.65) versus 0.67 for the model published by Smith et al. Node-negative patients had a significantly lower tumor grade at TURBT (p = 0.03), a lower pT stage (p<0.01) and less frequent lymphovascular invasion (13% versus 38%, p<0.01) at radical cystectomy than node-positive patients. In addition, in the TCGA data, none of the 20 genes was differentially expressed in node-negative versus node-positive patients. Conclusions We conclude that a 20-gene expression signature developed for nodal staging of MIBC at radical cystectomy could not be validated on a qRT-PCR platform in a

  9. MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker

    PubMed Central

    Goto, Yusuke; Kojima, Satoko; Nishikawa, Rika; Kurozumi, Akira; Kato, Mayuko; Enokida, Hideki; Matsushita, Ryosuke; Yamazaki, Kazuto; Ishida, Yasuo; Nakagawa, Masayuki; Naya, Yukio; Ichikawa, Tomohiko; Seki, Naohiko

    2015-01-01

    Background: Our present study of the microRNA (miRNA) expression signature in castration-resistant prostate cancer (CRPC) revealed that the clustered miRNAs microRNA-221 (miR-221) and microRNA-222 (miR-222) are significantly downregulated in cancer tissues. The aim of this study was to investigate the functional roles of miR-221 and miR-222 in prostate cancer (PCa) cells. Methods: A CRPC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were analysed using PCa cells. The association between miRNA expression and overall survival was estimated by the Kaplan–Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster. Results: miR-221 and miR-222 were significantly downregulated in PCa and CRPC specimens. Kaplan–Meier survival curves showed that low expression of miR-222 predicted a short duration of progression to CRPC. Restoration of miR-221 or miR-222 in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Ecm29 was directly regulated by the miR-221/222 cluster in PCa cells. Conclusions: Loss of the tumour-suppressive miR-221/222 cluster enhanced migration and invasion in PCa cells. Our data describing targets regulated by the tumour-suppressive miR-221/222 cluster provide insights into the mechanisms of PCa and CRPC progression. PMID:26325107

  10. Basic Fibroblast Growth Factor-2/beta3 Integrin Expression Profile: Signature of Local Progression After Chemoradiotherapy for Patients With Locally Advanced Non-Small-Cell Lung Cancer

    SciTech Connect

    Massabeau, Carole; Rouquette, Isabelle; Lauwers-Cances, Valerie; Mazieres, Julien; Bachaud, Jean-Marc; Armand, Jean-Pierre; Delisle, Marie-Bernadette; Favre, Gilles; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth

    2009-11-01

    Purpose: No biologic signature of chemoradiotherapy sensitivity has been reported for patients with locally advanced non-small-cell lung cancer (NSCLC). We have previously demonstrated that basic fibroblast growth factor (FGF-2) and alphavbeta3 integrin pathways control tumor radioresistance. We investigated whether the expression of the proteins involved in these pathways might be associated with the response to treatment and, therefore, the clinical outcome. Methods and Materials: FGF-2, beta3 integrin, angiopoietin-2, and syndecan-1 expression was studied using immunohistochemistry performed on biopsies obtained, before any treatment, from 65 patients exclusively treated with chemoradiotherapy for locally advanced NSCLC. The response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria using computed tomography at least 6 weeks after the end of the chemoradiotherapy. Local progression-free survival, metastasis-free survival, and disease-free survival were studied using the log-rank test and Cox proportional hazard analysis. Results: Among this NSCLC biopsy population, 43.7% overexpressed beta3 integrin (beta3{sup +}), 43% FGF-2 (FGF-2{sup +}), 41.5% syndecan-1, and 59.4% angiopoietin-2. Our results showed a strong association between FGF-2 and beta3 integrin expression (p = .001). The adjusted hazard ratio of local recurrence for FGF-2{sup +}/beta3{sup +} tumors compared with FGF-2{sup -}/beta3{sup -} tumors was 6.1 (95% confidence interval, 2.6-14.6, p = .005). However, the risk of local recurrence was not increased when tumors overexpressed beta3 integrin or FGF-2 alone. Moreover, the co-expression of these two proteins was marginally associated with the response to chemoradiotherapy and metastasis-free survival. Conclusion: The results of this study have identified the combined profile FGF-2/beta3 integrin expression as a signature of local control in patients treated with chemoradiotherapy for locally advanced

  11. Differential gene expression pattern in human mammary epithelial cells induced by realistic organochlorine mixtures described in healthy women and in women diagnosed with breast cancer.

    PubMed

    Rivero, Javier; Henríquez-Hernández, Luis Alberto; Luzardo, Octavio P; Pestano, José; Zumbado, Manuel; Boada, Luis D; Valerón, Pilar F

    2016-03-30

    Organochlorine pesticides (OCs) have been associated with breast cancer development and progression, but the mechanisms underlying this phenomenon are not well known. In this work, we evaluated the effects exerted on normal human mammary epithelial cells (HMEC) by the OC mixtures most frequently detected in healthy women (H-mixture) and in women diagnosed with breast cancer (BC-mixture), as identified in a previous case-control study developed in Spain. Cytotoxicity and gene expression profile of human kinases (n=68) and non-kinases (n=26) were tested at concentrations similar to those described in the serum of those cases and controls. Although both mixtures caused a down-regulation of genes involved in the ATP binding process, our results clearly indicate that both mixtures may exert a very different effect on the gene expression profile of HMEC. Thus, while BC-mixture up-regulated the expression of oncogenes associated to breast cancer (GFRA1 and BHLHB8), the H-mixture down-regulated the expression of tumor suppressor genes (EPHA4 and EPHB2). Our results indicate that the composition of the OC mixture could play a role in the initiation processes of breast cancer. In addition, the present results suggest that subtle changes in the composition and levels of pollutants involved in environmentally relevant mixtures might induce very different biological effects, which explain, at least partially, why some mixtures seem to be more carcinogenic than others. Nonetheless, our findings confirm that environmentally relevant pollutants may modulate the expression of genes closely related to carcinogenic processes in the breast, reinforcing the role exerted by environment in the regulation of genes involved in breast carcinogenesis.

  12. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors

    PubMed Central

    Savelyeva, Natalia; McCann, Katy J.; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S.; Ward, Matthew; Martin, Eva Garrido

    2016-01-01

    Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(−)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(−) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(−) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment. PMID:27462861

  13. Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors.

    PubMed

    Wood, Oliver; Woo, Jeongmin; Seumois, Gregory; Savelyeva, Natalia; McCann, Katy J; Singh, Divya; Jones, Terry; Peel, Lailah; Breen, Michael S; Ward, Matthew; Garrido Martin, Eva; Sanchez-Elsner, Tilman; Thomas, Gareth; Vijayanand, Pandurangan; Woelk, Christopher H; King, Emma; Ottensmeier, Christian

    2016-08-30

    Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than it's HPV negative (HPV(-)) counterpart. This may be due to the higher numbers of tumor-infiltrating lymphocytes (TILs) in HPV positive (HPV(+)) tumors. RNA-Sequencing (RNA-Seq) was used to evaluate whether the differences in clinical behaviour simply reflect a numerical difference in TILs or whether there is a fundamental behavioural difference between TILs in these two settings. Thirty-nine HNSCC tumors were scored for TIL density by immunohistochemistry. After the removal of 16 TILlow tumors, RNA-Seq analysis was performed on 23 TILhigh/med tumors (HPV(+) n=10 and HPV(-) n=13). Using EdgeR, differentially expressed genes (DEG) were identified. Immune subset analysis was performed using Functional Analysis of Individual RNA-Seq/ Microarray Expression (FAIME) and immune gene RNA transcript count analysis. In total, 1,634 DEGs were identified, with a dominant immune signature observed in HPV(+) tumors. After normalizing the expression profiles to account for differences in B- and T-cell number, 437 significantly DEGs remained. A B-cell associated signature distinguished HPV(+) from HPV(-) tumors, and included the DEGs CD200, GGA2, ADAM28, STAG3, SPIB, VCAM1, BCL2 and ICOSLG; the immune signal relative to T-cells was qualitatively similar between TILs of both tumor cohorts. Our findings were validated and confirmed in two independent cohorts using TCGA data and tumor-infiltrating B-cells from additional HPV(+) HNSCC patients. A B-cell associated signal segregated tumors relative to HPV status. Our data suggests that the role of B-cells in the adaptive immune response to HPV(+) HNSCC requires re-assessment.

  14. University of Texas Southwestern Medical Center: Functional Signature Ontology Tool: Triplicate Measurements of Reporter Gene Expression in Response to Individual Genetic and Chemical Perturbations in HCT116 Cells | Office of Cancer Genomics

    Cancer.gov

    The goal of this project is to use an eight-gene expression profile to define functional signatures for small molecules and natural products with heretofore undefined mechanism of action. Two genes in the eight gene set are used as internal controls and do not vary across gene expression array data collected from the public domain. The remaining six genes are found to vary independently across a large collection of publically available gene expression array datasets.  Read the abstract

  15. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

    PubMed Central

    Brown, P J; Wong, K K; Felce, S L; Lyne, L; Spearman, H; Soilleux, E J; Pedersen, L M; Møller, M B; Green, T M; Gascoyne, D M; Banham, A H

    2016-01-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco–Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID:26500140

  16. Determining epithelial contribution to in vivo mesenchymal tumour expression signature using species-specific microarray profiling analysis of xenografts.

    PubMed

    Purdom, E; Restall, C; Busuttil, R A; Schluter, H; Boussioutas, A; Thompson, E W; Anderson, R L; Speed, T P; Haviv, I

    2013-02-01

    Gene expression profiling using microarrays and xenograft transplants of human cancer cell lines are both popular tools to investigate human cancer. However, the undefined degree of cross hybridization between the mouse and human genomes hinders the use of microarrays to characterize gene expression of both the host and the cancer cell within the xenograft. Since an increasingly recognized aspect of cancer is the host response (or cancer-stroma interaction), we describe here a bioinformatic manipulation of the Affymetrix profiling that allows interrogation of the gene expression of both the mouse host and the human tumour. Evidence of microenvironmental regulation of epithelial mesenchymal transition of the tumour component in vivo is resolved against a background of mesenchymal gene expression. This tool could allow deeper insight to the mechanism of action of anti-cancer drugs, as typically novel drug efficacy is being tested in xenograft systems.

  17. MicroRNA expression signatures for the prediction of BRCA1/2 mutation-associated hereditary breast cancer in paraffin-embedded formalin-fixed breast tumors.

    PubMed

    Tanic, Miljana; Yanowski, Kira; Gómez-López, Gonzalo; Rodriguez-Pinilla, María Socorro; Marquez-Rodas, Iván; Osorio, Ana; Pisano, David G; Martinez-Delgado, Beatriz; Benítez, Javier

    2015-02-01

    Screening for germline mutations in breast cancer-associated genes BRCA1 and BRCA2 is indicated for patients with breast cancer from high-risk breast cancer families and influences both treatment options and clinical management. However, only 25% of selected patients test positive for BRCA1/2 mutation, indicating that additional diagnostic biomarkers are necessary. We analyzed 124 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients with hereditary (104) and sporadic (20) invasive breast cancer, divided into two series (A and B). Microarray expression profiling of 829 human miRNAs was performed on 76 samples (Series A), and bioinformatics tool Prophet was used to develop and test a microarray classifier. Samples were stratified into a training set (n = 38) for microarray classifier generation and a test set (n = 38) for signature validation. A 35-miRNA microarray classifier was generated for the prediction of BRCA1/2 mutation status with a reported 95% (95% CI = 0.88-1.0) and 92% (95% CI: 0.84-1.0) accuracy in the training and the test set, respectively. Differential expression of 12 miRNAs between BRCA1/2 mutation carriers versus noncarriers was validated by qPCR in an independent tumor series B (n = 48). Logistic regression model based on the expression of six miRNAs (miR-142-3p, miR-505*, miR-1248, miR-181a-2*, miR-25* and miR-340*) discriminated between tumors from BRCA1/2 mutation carriers and noncarriers with 92% (95% CI: 0.84-0.99) accuracy. In conclusion, we identified miRNA expression signatures predictive of BRCA1/2 mutation status in routinely available FFPE breast tumor samples, which may be useful to complement current patient selection criteria for gene testing by identifying individuals with high likelihood of being BRCA1/2 mutation carriers.

  18. A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide.

    PubMed

    Di Narzo, Antonio Fabio; Kozlenkov, Alexey; Roussos, Panos; Hao, Ke; Hurd, Yasmin; Lewis, David A; Sibille, Etienne; Siever, Larry J; Koonin, Eugene; Dracheva, Stella

    2014-09-15

    Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5-HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5-HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide.

  19. Identification of co-expressed gene signatures in mouse B1, marginal zone and B2 B-cell populations

    PubMed Central

    Mabbott, Neil A; Gray, David

    2014-01-01

    In mice, three major B-cell subsets have been identified with distinct functionalities: B1 B cells, marginal zone B cells and follicular B2 B cells. Here, we used the growing body of publicly available transcriptomics data to create an expression atlas of 84 gene expression microarray data sets of distinct mouse B-cell subsets. These data were subjected to network-based cluster analysis using BioLayout Express3D. Using this analysis tool, genes with related functions clustered together in discrete regions of the network graph and enabled the identification of transcriptional networks that underpinned the functional activity of distinct cell populations. Some gene clusters were expressed highly by most of the cell populations included in this analysis (such as those with activity related to house-keeping functions). Others contained genes with expression patterns specific to distinct B-cell subsets. While these clusters contained many genes typically associated with the activity of the cells they were specifically expressed in, many novel B-cell-subset-specific candidate genes were identified. A large number of uncharacterized genes were also represented in these B-cell lineage-specific clusters. Further analysis of the activities of these uncharacterized candidate genes will lead to the identification of novel B-cell lineage-specific transcription factors and regulators of B-cell function. We also analysed 36 microarray data sets from distinct human B-cell populations. These data showed that mouse and human germinal centre B cells shared similar transcriptional features, whereas mouse B1 B cells were distinct from proposed human B1 B cells. PMID:24032749

  20. A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine

    PubMed Central

    Lee, Kuen-Haur; Lo, Hsiang-Ling; Tang, Wan-Chun; Hsiao, Heidi Hao-yun; Yang, Pei-Ming

    2014-01-01

    Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy. PMID:25227736

  1. Signatures of selection and host-adapted gene expression of the Phytophthora infestans RNA silencing suppressor PSR2.

    PubMed

    de Vries, Sophie; von Dahlen, Janina K; Uhlmann, Constanze; Schnake, Anika; Kloesges, Thorsten; Rose, Laura E

    2017-01-01

    Phytophthora infestans is a devastating pathogen in agricultural systems. Recently, an RNA silencing suppressor (PSR2, 'Phytophthora suppressor of RNA silencing 2') has been described in P. infestans. PSR2 has been shown to increase the virulence of Phytophthora pathogens on their hosts. This gene is one of the few effectors present in many economically important Phytophthora species. In this study, we investigated: (i) the evolutionary history of PSR2 within and between species of Phytophthora; and (ii) the interaction between sequence variation, gene expression and virulence. In P. infestans, the highest PiPSR2 expression was correlated with decreased symptom expression. The highest gene expression was observed in the biotrophic phase of the pathogen, suggesting that PSR2 is important during early infection. Protein sequence conservation was negatively correlated with host range, suggesting host range as a driver of PSR2 evolution. Within species, we detected elevated amino acid variation, as observed for other effectors; however, the frequency spectrum of the mutations was inconsistent with strong balancing selection. This evolutionary pattern may be related to the conservation of the host target(s) of PSR2 and the absence of known corresponding R genes. In summary, our study indicates that PSR2 is a conserved effector that acts as a master switch to modify plant gene regulation early during infection for the pathogen's benefit. The conservation of PSR2 and its important role in virulence make it a promising target for pathogen management.

  2. Identify signature regulatory network for glioblastoma prognosis by integrative mRNA and miRNA co-expression analysis.

    PubMed

    Bing, Zhi-Tong; Yang, Guang-Hui; Xiong, Jie; Guo, Ling; Yang, Lei

    2016-12-01

    Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults. Patients with this disease have a poor prognosis. The objective of this study is to identify survival-related individual genes (or miRNAs) and miRNA -mRNA pairs in GBM using a multi-step approach. First, the weighted gene co-expression network analysis and survival analysis are applied to identify survival-related modules from mRNA and miRNA expression profiles, respectively. Subsequently, the role of individual genes (or miRNAs) within these modules in GBM prognosis are highlighted using survival analysis. Finally, the integration analysis of miRNA and mRNA expression as well as miRNA target prediction is used to identify survival-related miRNA -mRNA regulatory network. In this study, five genes and two miRNA modules that significantly correlated to patient's survival. In addition, many individual genes (or miRNAs) assigned to these modules were found to be closely linked with survival. For instance, increased expression of neuropilin-1 gene (a member of module turquoise) indicated poor prognosis for patients and a group of miRNA -mRNA regulatory networks that comprised 38 survival-related miRNA -mRNA pairs. These findings provide a new insight into the underlying molecular regulatory mechanisms of GBM.

  3. A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine.

    PubMed

    Lee, Kuen-Haur; Lo, Hsiang-Ling; Tang, Wan-Chun; Hsiao, Heidi Hao-yun; Yang, Pei-Ming

    2014-09-17

    Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy.

  4. Laser Capture Microdissection Assisted Identification of Epithelial MicroRNA Expression Signatures for Prognosis of Stage I NSCLC

    DTIC Science & Technology

    2013-10-01

    et al: A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401-14, 2007 6. Sica A, Mantovani A: Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787-95, 2012  

  5. MMP-13 Regulates Growth of Wound Granulation Tissue and Modulates Gene Expression Signatures Involved in Inflammation, Proteolysis, and Cell Viability

    PubMed Central

    Toriseva, Mervi; Laato, Matti; Carpén, Olli; Ruohonen, Suvi T.; Savontaus, Eriika; Inada, Masaki; Krane, Stephen M.; Kähäri, Veli-Matti

    2012-01-01

    Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (Mmp13−/−) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in Mmp13−/− mice. Granulation tissue in Mmp13−/− mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in Mmp13−/− mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13−/− mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13−/− granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13−/− mice compared to WT mice. Mmp13−/− mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis. PMID:22880047

  6. WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma.

    PubMed

    Sun, Yuting; Bell, Jessica L; Carter, Daniel; Gherardi, Samuele; Poulos, Rebecca C; Milazzo, Giorgio; Wong, Jason W H; Al-Awar, Rima; Tee, Andrew E; Liu, Pei Y; Liu, Bing; Atmadibrata, Bernard; Wong, Matthew; Trahair, Toby; Zhao, Quan; Shohet, Jason M; Haupt, Ygal; Schulte, Johannes H; Brown, Peter J; Arrowsmith, Cheryl H; Vedadi, Masoud; MacKenzie, Karen L; Hüttelmaier, Stefan; Perini, Giovanni; Marshall, Glenn M; Braithwaite, Antony; Liu, Tao

    2015-12-01

    MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, we investigated the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. We showed that WDR5 could form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis. Similarly, a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, our results identify WDR5 as a key cofactor for N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastomas.

  7. Behaviorally activated mRNA expression profiles produce signatures of learning and enhanced inhibition in aged rats with preserved memory.

    PubMed

    Haberman, Rebecca P; Colantuoni, Carlo; Koh, Ming Teng; Gallagher, Michela

    2013-01-01

    Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally-induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to

  8. Tumor suppressive microRNAs (miR-222 and miR-31) regulate molecular pathways based on microRNA expression signature in prostate cancer.

    PubMed

    Fuse, Miki; Kojima, Satoko; Enokida, Hideki; Chiyomaru, Takeshi; Yoshino, Hirofumi; Nohata, Nijiro; Kinoshita, Takashi; Sakamoto, Shinichi; Naya, Yukio; Nakagawa, Masayuki; Ichikawa, Tomohiko; Seki, Naohiko

    2012-11-26

    microRNAs (miRNAs) have key roles in human tumorigenesis, tumor progression and metastasis. miRNAs are aberrantly expressed in many human cancers and can function as tumor suppressors or oncogenes that target many cancer-related genes. This study seeks to identify novel miRNA-regulated molecular pathways in prostate cancer (PCa). The miRNA expression signature in clinical specimens of PCa showed that 56 miRNAs were significantly downregulated in PCa compared with non-PCa tissues. We focused on the top four downregulated miRNAs (miR-187, miR-205, miR-222 and miR-31) to investigate their functional significance in PCa cells. Expression levels of these four miRNAs were validated in PCa specimens (15 PCa tissues and 17 non-PCa tissues) to confirm that they were significantly reduced in these PCa tissues. Gain-of-function analysis demonstrated that miR-222 and miR-31 inhibited cell proliferation, invasion and migration in PCa cell lines (PC3 and DU145), suggesting that miR-222 and miR-31 may act as tumor suppressors in PCa. Genome-wide gene expression analysis using miR-222 or miR-31 transfectants to identify the pathways they affect showed that many cancer-related genes are regulated by these miRNAs in PC3 cells. Identification and categorization of the molecular pathways regulated by tumor suppressive miRNAs could provide new information about the molecular mechanisms of PCa tumorigenesis.

  9. Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

    PubMed Central

    Bolisetty, Mohan; Kursawe, Romy; Sun, Lili; Sivakamasundari, V.; Kycia, Ina

    2017-01-01

    Blood glucose levels are tightly controlled by the coordinated action of at least four cell types constituting pancreatic islets. Changes in the proportion and/or function of these cells are associated with genetic and molecular pathophysiology of monogenic, type 1, and type 2 (T2D) diabetes. Cellular heterogeneity impedes precise understanding of the molecular components of each islet cell type that govern islet (dys)function, particularly the less abundant delta and gamma/pancreatic polypeptide (PP) cells. Here, we report single-cell transcriptomes for 638 cells from nondiabetic (ND) and T2D human islet samples. Analyses of ND single-cell transcriptomes identified distinct alpha, beta, delta, and PP/gamma cell-type signatures. Genes linked to rare and common forms of islet dysfunction and diabetes were expressed in the delta and PP/gamma cell types. Moreover, this study revealed that delta cells specifically express receptors that receive and coordinate systemic cues from the leptin, ghrelin, and dopamine signaling pathways implicating them as integrators of central and peripheral metabolic signals into the pancreatic islet. Finally, single-cell transcriptome profiling revealed genes differentially regulated between T2D and ND alpha, beta, and delta cells that were undetectable in paired whole islet analyses. This study thus identifies fundamental cell-type–specific features of pancreatic islet (dys)function and provides a critical resource for comprehensive understanding of islet biology and diabetes pathogenesis. PMID:27864352

  10. Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease

    PubMed Central

    Hensman Moss, Davina J.; Flower, Michael D.; Lo, Kitty K.; Miller, James R. C.; van Ommen, Gert-Jan B.; ’t Hoen, Peter A. C.; Stone, Timothy C.; Guinee, Amelia; Langbehn, Douglas R.; Jones, Lesley; Plagnol, Vincent; van Roon-Mom, Willeke M. C.; Holmans, Peter; Tabrizi, Sarah J.

    2017-01-01

    There is widespread transcriptional dysregulation in Huntington’s disease (HD) brain, but analysis is inevitably limited by advanced disease and postmortem changes. However, mutant HTT is ubiquitously expressed and acts systemically, meaning blood, which is readily available and contains cells that are dysfunctional in HD, could act as a surrogate for brain tissue. We conducted an RNA-Seq transcriptomic analysis using whole blood from two HD cohorts, and performed gene set enrichment analysis using public databases and weighted correlation network analysis modules from HD and control brain datasets. We identified dysregulated gene sets in blood that replicated in the independent cohorts, correlated with disease severity, corresponded to the most significantly dysregulated modules in the HD caudate, the most prominently affected brain region, and significantly overlapped with the transcriptional signature of HD myeloid cells. High-throughput sequencing technologies and use of gene sets likely surmounted the limitations of previously inconsistent HD blood expression studies. Our results suggest transcription is disrupted in peripheral cells in HD through mechanisms that parallel those in brain. Immune upregulation in HD overlapped with Alzheimer’s disease, suggesting a common pathogenic mechanism involving macrophage phagocytosis and microglial synaptic pruning, and raises the potential for shared therapeutic approaches. PMID:28322270

  11. Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis

    PubMed Central

    Mohamad Yusof, Azliana; Abdullah Suhaimi, Shahrun Niza; Muhammad, Rohaizak; Jamal, Rahman

    2016-01-01

    Background. Papillary thyroid carcinoma (PTC) is the commonest thyroid malignancy originating from the follicle cells in the thyroid. Despite a good overall prognosis, certain high-risk cases as in those with lymph node metastasis (LNM) have progressive disease and poorer prognosis. MicroRNAs are a class of non-protein-coding, 19–24 nucleotides single-stranded RNAs which regulate gene expression and these molecules have been shown to play a role in LNM. The integrated analysis of miRNAs and gene expression profiles together with transcription factors (TFs) has been shown to improve the identification of functional miRNA-target gene-TF relationships, providing a more complete view of molecular events underlying metastasis process. Objectives. We reanalyzed The Cancer Genome Atlas (TCGA) datasets on PTC to identify differentially expressed miRNAs/genes in PTC patients with LNM-positive (LNM-P) versus lymph node negative (LNN) PTC patients and to investigate the miRNA-gene-TF regulatory circuit that regulate LNM in PTC. Results. PTC patients with LNM (PTC LNM-P) have a significantly shorter disease-free survival rate compared to PTC patients without LNM (PTC LNN) (Log-rank Mantel Cox test, p = 0.0049). We identified 181 significantly differentially expressed miRNAs in PTC LNM-P versus PTC LNN; 110 were upregulated and 71 were downregulated. The five topmost deregulated miRNAs were hsa-miR-146b, hsa-miR-375, hsa-miR-31, hsa-miR-7-2 and hsa-miR-204. In addition, 395 miRNAs were differentially expressed between PTC LNM-P and normal thyroid while 400 miRNAs were differentially expressed between PTC LNN and normal thyroid. We found four significant enrichment pathways potentially involved in metastasis to the lymph nodes, namely oxidative phosphorylation (OxPhos), cell adhesion molecules (CAMs), leukocyte transendothelial migration and cytokine–cytokine receptor interaction. OxPhos was the most significantly perturbed pathway (p = 4.70E−06) involving downregulation

  12. High-resolution transcriptome analysis reveals neuropathic pain gene-expression signatures in spinal microglia after nerve injury.

    PubMed

    Jeong, Heejin; Na, Young-Ji; Lee, Kihwan; Kim, Yong Ho; Lee, Yunsin; Kang, Minho; Jiang, Bao-Chun; Yeom, Young Il; Wu, Long-Jun; Gao, Yong-Jing; Kim, Junhyong; Oh, Seog Bae

    2016-04-01

    Microglial cells, the resident immune cells of the spinal cord, become activated in response to peripheral nerve injury. Microglia activation contributes to the development of neuropathic pain. Here we employed microarray analysis of individually collected pools of 10 spinal microglia cells to identify changes of levels and cell-to-cell expression variance of microglial genes during their activation after peripheral nerve injury. The analysis of microglia on postoperative day 1 (POD1) identified miR-29c as a critical factor for microglial activation and the development of neuropathic pain. Early POD1 microglia exhibited a very distinct expression profile compared to late POD7 microglia, possibly leading to the transition from initiation to maintenance of neuropathic pain. We found sample variance patterns that were consistent with the hypothesis that microglia were highly heterogeneous at the level of individual cells, and variation analysis identified 56 microglial genes potentially linked to the maintenance of neuropathic pain which included Gria1. This study provides insights into spinal microglial biology and reveals novel microglial targets for the treatment of neuropathic pain.

  13. The gene expression signature of relapse in paediatric acute lymphoblastic leukaemia: implications for mechanisms of therapy failure.

    PubMed

    Beesley, Alex H; Cummings, Aaron J; Freitas, Joseph R; Hoffmann, Katrin; Firth, Martin J; Ford, Jette; de Klerk, Nicolas H; Kees, Ursula R

    2005-11-01

    Despite significant improvements in the treatment of childhood acute lymphoblastic leukaemia (ALL), the prognosis for relapsing patients remains poor. The aim of this study was to generate a transcriptional profile of relapsed ALL to increase our understanding of the mechanisms involved in therapy failure. RNA was extracted from 11 pairs of cryopreserved pre-B ALL bone marrow specimens taken from the same patients at diagnosis and relapse, and analysed using HG-U133A microarrays. Relapse specimens overexpressed genes that are involved with cell growth and proliferation, in keeping with their aggressive phenotype. When tested in 72 independent specimens of pre-B ALL and T-ALL, the identified genes could successfully differentiate between diagnosis and relapse in either lineage, indicating the existence of relapse mechanisms common to both. These genes have functions relevant for oncogenesis, drug resistance and metastasis, but are not related to classical multidrug-resistance pathways. Increased expression of the top-ranked gene (BSG) at diagnosis was significantly associated with adverse outcome. Several chromosomal loci, including 19p13, were identified as potential hotspots for aberrant gene expression in relapsed ALL. Our results provide evidence for a link between drug resistance and the microenvironment that has previously only been considered in the context of solid tumour biology.

  14. Gene expression signatures in CD34+-progenitor-derived dendritic cells exposed to the chemical contact allergen nickel sulfate

    SciTech Connect

    Schoeters, Elke . E-mail: elke.schoeters@vito.be; Nuijten, Jean-Marie; Heuvel, Rosette L. van den; Nelissen, Inge; Witters, Hilda; Schoeters, Greet E.R.; Tendeloo, Vigor F.I. van; Berneman, Zwi N.; Verheyen, Geert R.

    2006-10-01

    The detection of the sensitizing potential of chemicals is of great importance to industry. A promising in vitro alternative to the currently applied animal assays for sensitization testing makes use of dendritic cells (DCs) that have the capability to process and present antigens to naive T cells and induce their proliferation. Here, we studied changes in gene expression profiles after exposing DCs to the contact allergen nickel sulfate. CD34+-progenitor-derived DCs, initiated from 3 different donors, were exposed to 60 {mu}M nickel sulfate, during 0.5, 1, 3, 6, 12 and 24 h. cDNA microarrays were used to assess the transcriptional activity of about 11,000 genes. Significant changes in the expression of 283 genes were observed; 178 genes were up-regulated and 93 down-regulated. These genes were involved in metabolism, cell structure, immune response, transcription, signal transduction, transport, and apoptosis. No functional information was found for 74 genes. Real-time RT-PCR was used to confirm the microarray results of 12 genes. In addition, 3 DC maturation markers not present on the microarrays (DEC205, DC LAMP and CCR7) were analyzed using real-time RT-PCR and found to be up-regulated at several time points. Our data indicate that a broad range of biological processes is influenced by nickel. Some processes are clearly linked to the immune response and DC maturation, others may indicate a toxic effect of nickel.

  15. First Generation Gene Expression Signature for Early Prediction of Late Occurring Hematological Acute Radiation Syndrome in Baboons.

    PubMed

    Port, M; Herodin, F; Valente, M; Drouet, M; Lamkowski, A; Majewski, M; Abend, M

    2016-07-01

    We implemented a two-stage study to predict late occurring hematologic acute radiation syndrome (HARS) in a baboon model based on gene expression changes measured in peripheral blood within the first two days after irradiation. Eighteen baboons were irradiated to simulate different patterns of partial-body and total-body exposure, which corresponded to an equivalent dose of 2.5 or 5 Gy. According to changes in blood cell counts the surviving baboons (n = 17) exhibited mild (H1-2, n = 4) or more severe (H2-3, n = 13) HARS. Blood samples taken before irradiation served as unexposed control (H0, n = 17). For stage I of this study, a whole genome screen (mRNA microarrays) was performed using a portion of the samples (H0, n = 5; H1-2, n = 4; H2-3, n = 5). For stage II, using the remaining samples and the more sensitive methodology, qRT-PCR, validation was performed on candidate genes that were differentially up- or down-regulated during the first two days after irradiation. Differential gene expression was defined as significant (P < 0.05) and greater than or equal to a twofold difference above a H0 classification. From approximately 20,000 genes, on average 46% appeared to be expressed. On day 1 postirradiation for H2-3, approximately 2-3 times more genes appeared up-regulated (1,418 vs. 550) or down-regulated (1,603 vs. 735) compared to H1-2. This pattern became more pronounced at day 2 while the number of differentially expressed genes decreased. The specific genes showed an enrichment of biological processes coding for immune system processes, natural killer cell activation and immune response (P = 1 × E-06 up to 9 × E-14). Based on the P values, magnitude and sustained differential gene expression over time, we selected 89 candidate genes for validation using qRT-PCR. Ultimately, 22 genes were confirmed for identification of H1-3 classifications and seven genes for identification of H2-3 classifications using qRT-PCR. For H1-3 classifications, most genes were

  16. Analysis of Post-Traumatic Brain Injury Gene Expression Signature Reveals Tubulins, Nfe2l2, Nfkb, Cd44, and S100a4 as Treatment Targets

    PubMed Central

    Lipponen, Anssi; Paananen, Jussi; Puhakka, Noora; Pitkänen, Asla

    2016-01-01

    We aimed to define the chronically altered gene expression signature of traumatic brain injury (TBI-sig) to discover novel treatments to reverse pathologic gene expression or reinforce the expression of recovery-related genes. Genome-wide RNA-sequencing was performed at 3 months post-TBI induced by lateral fluid-percussion injury in rats. We found 4964 regulated genes in the perilesional cortex and 1966 in the thalamus (FDR < 0.05). TBI-sig was used for a LINCS analysis which identified 11 compounds that showed a strong connectivity with the TBI-sig in neuronal cell lines. Of these, celecoxib and sirolimus were recently reported to have a disease-modifying effect in in vivo animal models of epilepsy. Other compounds revealed by the analysis were BRD-K91844626, BRD-A11009626, NO-ASA, BRD-K55260239, SDZ-NKT-343, STK-661558, BRD-K75971499, ionomycin, and desmethylclomipramine. Network analysis of overlapping genes revealed the effects on tubulins (Tubb2a, Tubb3, Tubb4b), Nfe2l2, S100a4, Cd44, and Nfkb2, all of which are linked to TBI-relevant outcomes, including epileptogenesis and tissue repair. Desmethylclomipramine modulated most of the gene targets considered favorable for TBI outcome. Our data demonstrate long-lasting transcriptomics changes after TBI. LINCS analysis predicted that these changes could be modulated by various compounds, some of which are already in clinical use but never tested in TBI. PMID:27530814

  17. T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

    PubMed

    Zhao, Bin-Bin; Zheng, Su-Jun; Gong, Lu-Lu; Wang, Yu; Chen, Cai-Feng; Jin, Wen-Jing; Zhang, Ding; Yuan, Xiao-Hui; Guo, Jian; Duan, Zhong-Ping; He, You-Wen

    2013-01-01

    Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

  18. "Fibrous nests" in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome.

    PubMed

    Désert, Romain; Mebarki, Sihem; Desille, Mireille; Sicard, Marie; Lavergne, Elise; Renaud, Stéphanie; Bergeat, Damien; Sulpice, Laurent; Perret, Christine; Turlin, Bruno; Clément, Bruno; Musso, Orlando

    2016-12-01

    Hepatocellular carcinoma (HCC) is the 3rd cause of cancer-related death worldwide. Most cases arise in a background of chronic inflammation, extracellular matrix (ECM) remodeling, severe fibrosis and stem/progenitor cell amplification. Although HCCs are soft cellular tumors, they may contain fibrous nests within the tumor mass. Thus, the aim of this study was to explore cancer cell phenotypes in fibrous nests. Combined anatomic pathology, tissue microarray and real-time PCR analyses revealed that HCCs (n=82) containing fibrous nests were poorly differentiated, expressed Wnt pathway components and target genes, as well as markers of stem/progenitor cells, such as CD44, LGR5 and SOX9. Consistently, in severe liver fibroses (n=66) and in HCCs containing fibrous nests, weighted correlation analysis revealed a gene network including the myofibroblast marker ACTA2, the basement membrane components COL4A1 and LAMC1, the Wnt pathway members FZD1; FZD7; WNT2; LEF1; DKK1 and the Secreted Frizzled Related Proteins (SFRPs) 1; 2 and 5. Moreover, unbiased random survival forest analysis of a transcriptomic dataset of 247 HCC patients revealed high DKK1, COL4A1, SFRP1 and LAMC1 to be associated with advanced tumor staging as well as with bad overall and disease-free survival. In vitro, these genes were upregulated in liver cancer stem/progenitor cells upon Wnt-induced mesenchymal commitment and myofibroblast differentiation. In conclusion, fibrous nests express Wnt target genes, as well as markers of cancer stem cells and mesenchymal commitment. Fibrous nests embody the specific microenvironment of the cancer stem cell niche and can be detected by routine anatomic pathology analyses.

  19. Spatio-Temporal Gene Expression Profiling during In Vivo Early Ovarian Folliculogenesis: Integrated Transcriptomic Study and Molecular Signature of Early Follicular Growth

    PubMed Central

    Bonnet, Agnes; Servin, Bertrand; Mulsant, Philippe; Mandon-Pepin, Beatrice

    2015-01-01

    Background The successful achievement of early ovarian folliculogenesis is important for fertility and reproductive life span. This complex biological process requires the appropriate expression of numerous genes at each developmental stage, in each follicular compartment. Relatively little is known at present about the molecular mechanisms that drive this process, and most gene expression studies have been performed in rodents and without considering the different follicular compartments. Results We used RNA-seq technology to explore the sheep transcriptome during early ovarian follicular development in the two main compartments: oocytes and granulosa cells. We documented the differential expression of 3,015 genes during this phase and described the gene expression dynamic specific to these compartments. We showed that important steps occurred during primary/secondary transition in sheep. We also described the in vivo molecular course of a number of pathways. In oocytes, these pathways documented the chronology of the acquisition of meiotic competence, migration and cellular organization, while in granulosa cells they concerned adhesion, the formation of cytoplasmic projections and steroid synthesis. This study proposes the involvement in this process of several members of the integrin and BMP families. The expression of genes such as Kruppel-like factor 9 (KLF9) and BMP binding endothelial regulator (BMPER) was highlighted for the first time during early follicular development, and their proteins were also predicted to be involved in gene regulation. Finally, we selected a data set of 24 biomarkers that enabled the discrimination of early follicular stages and thus offer a molecular signature of early follicular growth. This set of biomarkers includes known genes such as SPO11 meiotic protein covalently bound to DSB (SPO11), bone morphogenetic protein 15 (BMP15) and WEE1 homolog 2 (S. pombe)(WEE2) which play critical roles in follicular development but other

  20. An Integrated Analysis of MicroRNA and mRNA Expression Profiles to Identify RNA Expression Signatures in Lambskin Hair Follicles in Hu Sheep

    PubMed Central

    Lv, Xiaoyang; Sun, Wei; Yin, Jinfeng; Ni, Rong; Su, Rui; Wang, Qingzeng; Gao, Wen; Bao, Jianjun; Yu, Jiarui; Wang, Lihong; Chen, Ling

    2016-01-01

    Wave patterns in lambskin hair follicles are an important factor determining the quality of sheep’s wool. Hair follicles in lambskin from Hu sheep, a breed unique to China, have 3 types of waves, designated as large, medium, and small. The quality of wool from small wave follicles is excellent, while the quality of large waves is considered poor. Because no molecular and biological studies on hair follicles of these sheep have been conducted to date, the molecular mechanisms underlying the formation of different wave patterns is currently unknown. The aim of this article was to screen the candidate microRNAs (miRNA) and genes for the development of hair follicles in Hu sheep. Two-day-old Hu lambs were selected from full-sib individuals that showed large, medium, and small waves. Integrated analysis of microRNA and mRNA expression profiles employed high-throughout sequencing technology. Approximately 13, 24, and 18 differentially expressed miRNAs were found between small and large waves, small and medium waves, and medium and large waves, respectively. A total of 54, 190, and 81 differentially expressed genes were found between small and large waves, small and medium waves, and medium and large waves, respectively, by RNA sequencing (RNA-seq) analysis. Differentially expressed genes were classified using gene ontology and pathway analyses. They were found to be mainly involved in cell differentiation, proliferation, apoptosis, growth, immune response, and ion transport, and were associated with MAPK and the Notch signaling pathway. Reverse transcription-polymerase chain reaction (RT-PCR) analyses of differentially-expressed miRNA and genes were consistent with sequencing results. Integrated analysis of miRNA and mRNA expression indicated that, compared to small waves, large waves included 4 downregulated miRNAs that had regulatory effects on 8 upregulated genes and 3 upregulated miRNAs, which in turn influenced 13 downregulated genes. Compared to small waves

  1. Osteopontin Modulates Inflammation, Mucin Production, and Gene Expression Signatures After Inhalation of Asbestos in a Murine Model of Fibrosis

    PubMed Central

    Sabo-Attwood, Tara; Ramos-Nino, Maria E.; Eugenia-Ariza, Maria; MacPherson, Maximilian B.; Butnor, Kelly J.; Vacek, Pamela C.; McGee, Sean P.; Clark, Jessica C.; Steele, Chad; Mossman, Brooke T.

    2011-01-01

    Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN+/+) inhaling asbestos, OPN null mice (OPN−/−) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1β, and eotaxin) also were significantly less in asbestos-exposed OPN−/− mice. Microarrays performed on lung tissues from asbestos-exposed OPN+/+ and OPN−/− mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1β and epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression. PMID:21514415

  2. How Are Arrhythmias Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Are Arrhythmias Diagnosed? Arrhythmias can be hard to diagnose, especially the types ... symptoms every once in a while. Doctors diagnose arrhythmias based on medical and family histories, a physical ...

  3. Prolonged expression of the BX1 signature enzyme is associated with a recombination hotspot in the benzoxazinoid gene cluster in Zea mays.

    PubMed

    Zheng, Linlin; McMullen, Michael D; Bauer, Eva; Schön, Chris-Carolin; Gierl, Alfons; Frey, Monika

    2015-07-01

    Benzoxazinoids represent preformed protective and allelopathic compounds. The main benzoxazinoid in maize (Zea mays L.) is 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA). DIMBOA confers resistance to herbivores and microbes. Protective concentrations are found predominantly in young plantlets. We made use of the genetic diversity present in the maize nested association mapping (NAM) panel to identify lines with significant benzoxazinoid concentrations at later developmental stages. At 24 d after imbibition (dai), only three lines, including Mo17, showed effective DIMBOA concentrations of 1.5mM or more; B73, by contrast, had low a DIMBOA content. Mapping studies based on Mo17 and B73 were performed to reveal mechanisms that influence the DIMBOA level in 24 dai plants. A major quantitative trait locus mapped to the Bx gene cluster located on the short arm of chromosome 4, which encodes the DIMBOA biosynthetic genes. Mo17 was distinguished from all other NAM lines by high transcriptional expression of the Bx1 gene at later developmental stages. Bx1 encodes the signature enzyme of the pathway. In Mo17×B73 hybrids at 24 dai, only the Mo17 Bx1 allele transcript was detected. A 3.9kb cis-element, termed DICE (distal cis-element), that is located in the Bx gene cluster approximately 140 kb upstream of Bx1, was required for high Bx1 transcript levels during later developmental stages in Mo17. The DICE region was a hotspot of meiotic recombination. Genetic analysis revealed that high 24 dai DIMBOA concentrations were not strictly dependent on high Bx1 transcript levels. However, constitutive expression of Bx1 in transgenics increased DIMBOA levels at 24 dai, corroborating a correlation between DIMBOA content and Bx1 transcription.

  4. Age-Specific Gene Expression Signatures for Breast Tumors and Cross-Species Conserved Potential Cancer Progression Markers in Young Women

    PubMed Central

    Colak, Dilek; Nofal, Asmaa; AlBakheet, AlBandary; Nirmal, Maimoona; Jeprel, Hatim; Eldali, Abdelmoneim; AL-Tweigeri, Taher; Tulbah, Asma; Ajarim, Dahish; Malik, Osama Al; Kaya, Namik; Park, Ben H.; Bin Amer, Suad M.

    2013-01-01

    Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross

  5. Forensic handwriting examiners' expertise for signature comparison.

    PubMed

    Sita, Jodi; Found, Bryan; Rogers, Douglas K

    2002-09-01

    This paper reports on the performance of forensic document examiners (FDEs) in a signature comparison task that was designed to address the issue of expertise. The opinions of FDEs regarding 150 genuine and simulated questioned signatures were compared with a control group of non-examiners' opinions. On the question of expertise, results showed that FDEs were statistically better than the control group at accurately determining the genuineness or non-genuineness of questioned signatures. The FDE group made errors (by calling a genuine signature simulated or by calling a simulated signature genuine) in 3.4% of their opinions while 19.3% of the control group's opinions were erroneous. The FDE group gave significantly more inconclusive opinions than the control group. Analysis of FDEs' responses showed that more correct opinions were expressed regarding simulated signatures and more inconclusive opinions were made on genuine signatures. Further, when the complexity of a signature was taken into account, FDEs made more correct opinions on high complexity signatures than on signatures of lower complexity. There was a wide range of skill amongst FDEs and no significant relationship was found between the number of years FDEs had been practicing and their correct, inconclusive and error rates.

  6. How Is Sarcoidosis Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Sarcoidosis Diagnosed? Your doctor will diagnose sarcoidosis based on ... Content: NEXT >> Featured Video Living With and Managing Sarcoidosis 05/18/2011 This video—presented by the ...

  7. How Is Atherosclerosis Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Atherosclerosis Diagnosed? Your doctor will diagnose atherosclerosis based on ... Rate This Content: NEXT >> Featured Video What is atherosclerosis? 05/22/2014 Describes how the build-up ...

  8. Developing a prognostic micro-RNA signature for human cervical carcinoma.

    PubMed

    How, Christine; Pintilie, Melania; Bruce, Jeff P; Hui, Angela B Y; Clarke, Blaise A; Wong, Philip; Yin, Shaoming; Yan, Rui; Waggott, Daryl; Boutros, Paul C; Fyles, Anthony; Hedley, David W; Hill, Richard P; Milosevic, Michael; Liu, Fei-Fei

    2015-01-01

    Cervical cancer remains the third most frequently diagnosed and fourth leading cause of cancer death in women worldwide. We sought to develop a micro-RNA signature that was prognostic for disease-free survival, which could potentially allow tailoring of treatment for cervical cancer patients. A candidate prognostic 9-micro-RNA signature set was identified in the training set of 79 frozen specimens. However, three different approaches to validate this signature in an independent cohort of 87 patients with formalin-fixed paraffin-embedded (FFPE) specimens, were unsuccessful. There are several challenges and considerations associated with developing a prognostic micro-RNA signature for cervical cancer, namely: tumour heterogeneity, lack of concordance between frozen and FFPE specimens, and platform selection for global micro-RNA expression profiling in this disease. Our observations provide an important cautionary tale for future miRNA signature studies for cervical cancer, which can also be potentially applicable to miRNA profiling studies involving other types of human malignancies.

  9. Significance Analysis of Prognostic Signatures

    PubMed Central

    Beck, Andrew H.; Knoblauch, Nicholas W.; Hefti, Marco M.; Kaplan, Jennifer; Schnitt, Stuart J.; Culhane, Aedin C.; Schroeder, Markus S.; Risch, Thomas; Quackenbush, John; Haibe-Kains, Benjamin

    2013-01-01

    A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that “random” gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated

  10. Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

    PubMed Central

    Langer, Christian; Marcucci, Guido; Holland, Kelsi B.; Radmacher, Michael D.; Maharry, Kati; Paschka, Peter; Whitman, Susan P.; Mrózek, Krzysztof; Baldus, Claudia D.; Vij, Ravi; Powell, Bayard L.; Carroll, Andrew J.; Kolitz, Jonathan E.; Caligiuri, Michael A.; Larson, Richard A.; Bloomfield, Clara D.

    2009-01-01

    Purpose To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. Conclusion MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets. PMID:19451432

  11. Signatures support program

    NASA Astrophysics Data System (ADS)

    Hawley, Chadwick T.

    2009-05-01

    The Signatures Support Program (SSP) leverages the full spectrum of signature-related activities (collections, processing, development, storage, maintenance, and dissemination) within the Department of Defense (DOD), the intelligence community (IC), other Federal agencies, and civil institutions. The Enterprise encompasses acoustic, seismic, radio frequency, infrared, radar, nuclear radiation, and electro-optical signatures. The SSP serves the war fighter, the IC, and civil institutions by supporting military operations, intelligence operations, homeland defense, disaster relief, acquisitions, and research and development. Data centers host and maintain signature holdings, collectively forming the national signatures pool. The geographically distributed organizations are the authoritative sources and repositories for signature data; the centers are responsible for data content and quality. The SSP proactively engages DOD, IC, other Federal entities, academia, and industry to locate signatures for inclusion in the distributed national signatures pool and provides world-wide 24/7 access via the SSP application.

  12. Immunohistochemistry Study of P53 and C-erbB-2 Expression in Trophoblastic Tissue and Their Predictive Values in Diagnosing Malignant Progression of Simple Molar Pregnancy

    PubMed Central

    Hasanzadeh, Malihe; Sharifi, Norrie; Farazestanian, Marjaneh; Nazemian, Seyed Saman; Madani Sani, Faezeh

    2016-01-01

    Background Finding a tumor marker to predict the aggressive behavior of molar pregnancy in early stages has yet been a topic for studies. Objectives In this survey we planned to study patients with molar pregnancy to 1) assess the p53 and c-erbB-2 expression in trophoblastic tissue, 2) to study the relationship between their expression intensity and progression of a molar pregnancy to gestational trophoblastic neoplasia, and 3) to determine a cut off value for the amount of p53 and c-erbB-2 expression which might correlate with aggressive behavior of molar pregnancy. Patients and Methods In a prospective cross sectional study by using a high accuracy technique EnVision Tm system for immunohistochemistry staining of molar pregnancy samples, we evaluated p53 and c-erbB-2 expression in cytotrophoblast and syncytiotrophoblast and the correlation of their expression with progression of molar pregnancy to gestational trophoblastic neoplasia (GTN). Normal prostatic tissue and Breast cancer tissue were used as positive controls. Results We studied 28 patients with simple molar pregnancy (SMP) and 30 with GTN. Cytotrophobalst had significantly higher expression of p53 and c-erbB-2 and syncytiotrophoblast had greater expression of p53 in GTN group as compared to SMP group. The cut off values for percentage of p53 positive immunostained cytotrophoblast and syncytiotrophoblast were 5.5% and 2.5%. In c-erbB-2 positive membranous stained cytotrophoblast the cut off was 12.5%. Conclusions Our data suggests that over expression of p53 and c-erbB-2 is associated with malignant progression of molar pregnancy. We encountered that high expression of p53 and c-erbB-2 in trophoblastic cells could predict gestational trophoblastic neoplasia during the early stages. PMID:27703642

  13. Improving Multiple Fault Diagnosability using Possible Conflicts

    NASA Technical Reports Server (NTRS)

    Daigle, Matthew J.; Bregon, Anibal; Biswas, Gautam; Koutsoukos, Xenofon; Pulido, Belarmino

    2012-01-01

    Multiple fault diagnosis is a difficult problem for dynamic systems. Due to fault masking, compensation, and relative time of fault occurrence, multiple faults can manifest in many different ways as observable fault signature sequences. This decreases diagnosability of multiple faults, and therefore leads to a loss in effectiveness of the fault isolation step. We develop a qualitative, event-based, multiple fault isolation framework, and derive several notions of multiple fault diagnosability. We show that using Possible Conflicts, a model decomposition technique that decouples faults from residuals, we can significantly improve the diagnosability of multiple faults compared to an approach using a single global model. We demonstrate these concepts and provide results using a multi-tank system as a case study.

  14. Evaluation of a Minimally Invasive Cell Sampling Device Coupled with Assessment of Trefoil Factor 3 Expression for Diagnosing Barrett's Esophagus: A Multi-Center Case–Control Study

    PubMed Central

    Ross-Innes, Caryn S.; Debiram-Beecham, Irene; O'Donovan, Maria; Walker, Elaine; Varghese, Sibu; Lao-Sirieix, Pierre; Lovat, Laurence; Griffin, Michael; Ragunath, Krish; Haidry, Rehan; Sami, Sarmed S.; Kaye, Philip; Novelli, Marco; Disep, Babett; Ostler, Richard; Aigret, Benoit; North, Bernard V.; Bhandari, Pradeep; Haycock, Adam; Morris, Danielle; Attwood, Stephen; Dhar, Anjan; Rees, Colin; Rutter, Matthew D. D.; Sasieni, Peter D.; Fitzgerald, Rebecca C.

    2015-01-01

    Background Barrett's esophagus (BE) is a commonly undiagnosed condition that predisposes to esophageal adenocarcinoma. Routine endoscopic screening for BE is not recommended because of the burden this would impose on the health care system. The objective of this study was to determine whether a novel approach using a minimally invasive cell sampling device, the Cytosponge, coupled with immunohistochemical staining for the biomarker Trefoil Factor 3 (TFF3), could be used to identify patients who warrant endoscopy to diagnose BE. Methods and Findings A case–control study was performed across 11 UK hospitals between July 2011 and December 2013. In total, 1,110 individuals comprising 463 controls with dyspepsia and reflux symptoms and 647 BE cases swallowed a Cytosponge prior to endoscopy. The primary outcome measures were to evaluate the safety, acceptability, and accuracy of the Cytosponge-TFF3 test compared with endoscopy and biopsy. In all, 1,042 (93.9%) patients successfully swallowed the Cytosponge, and no serious adverse events were attributed to the device. The Cytosponge was rated favorably, using a visual analogue scale, compared with endoscopy (p < 0.001), and patients who were not sedated for endoscopy were more likely to rate the Cytosponge higher than endoscopy (Mann-Whitney test, p < 0.001). The overall sensitivity of the test was 79.9% (95% CI 76.4%–83.0%), increasing to 87.2% (95% CI 83.0%–90.6%) for patients with ≥3 cm of circumferential BE, known to confer a higher cancer risk. The sensitivity increased to 89.7% (95% CI 82.3%–94.8%) in 107 patients who swallowed the device twice during the study course. There was no loss of sensitivity in patients with dysplasia. The specificity for diagnosing BE was 92.4% (95% CI 89.5%–94.7%). The case–control design of the study means that the results are not generalizable to a primary care population. Another limitation is that the acceptability data were limited to a single measure. Conclusions The

  15. How Is Raynaud's Diagnosed?

    MedlinePlus

    ... diagnose primary Raynaud's (Raynaud's disease) or secondary Raynaud's (Raynaud's phenomenon) based on your medical history, a physical exam, and test results. Specialists Involved Primary care doctors and internists often diagnose and treat Raynaud's. If you have the disorder, you also may ...

  16. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM).

    PubMed

    Krönke, J; Kuchenbauer, F; Kull, M; Teleanu, V; Bullinger, L; Bunjes, D; Greiner, A; Kolmus, S; Köpff, S; Schreder, M; Mügge, L-O; Straka, C; Engelhardt, M; Döhner, H; Einsele, H; Bassermann, F; Bargou, R; Knop, S; Langer, C

    2017-01-20

    Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.Leukemia advance online publication, 20 January 2017; doi:10.1038/leu.2016.384.

  17. Effectiveness of Cognitive Behavioral and Supportive-Expressive Group Therapy for Women Diagnosed with Breast Cancer: A Review of the Literature

    ERIC Educational Resources Information Center

    Boutin, Daniel L.

    2007-01-01

    A review of the literature revealed 20 studies that examined the extent to which cognitive behavioral therapy (CBT), supportive-expressive group therapy (SEGT), and a combination of these two treatments impact women with breast cancer. Based on this review, it is determined that CBT and SEGT have repeated experimental support for positively…

  18. Uncertainty in hydrological signatures

    NASA Astrophysics Data System (ADS)

    Westerberg, I. K.; McMillan, H. K.

    2015-09-01

    Information about rainfall-runoff processes is essential for hydrological analyses, modelling and water-management applications. A hydrological, or diagnostic, signature quantifies such information from observed data as an index value. Signatures are widely used, e.g. for catchment classification, model calibration and change detection. Uncertainties in the observed data - including measurement inaccuracy and representativeness as well as errors relating to data management - propagate to the signature values and reduce their information content. Subjective choices in the calculation method are a further source of uncertainty. We review the uncertainties relevant to different signatures based on rainfall and flow data. We propose a generally applicable method to calculate these uncertainties based on Monte Carlo sampling and demonstrate it in two catchments for common signatures including rainfall-runoff thresholds, recession analysis and basic descriptive signatures of flow distribution and dynamics. Our intention is to contribute to awareness and knowledge of signature uncertainty, including typical sources, magnitude and methods for its assessment. We found that the uncertainties were often large (i.e. typical intervals of ±10-40 % relative uncertainty) and highly variable between signatures. There was greater uncertainty in signatures that use high-frequency responses, small data subsets, or subsets prone to measurement errors. There was lower uncertainty in signatures that use spatial or temporal averages. Some signatures were sensitive to particular uncertainty types such as rating-curve form. We found that signatures can be designed to be robust to some uncertainty sources. Signature uncertainties of the magnitudes we found have the potential to change the conclusions of hydrological and ecohydrological analyses, such as cross-catchment comparisons or inferences about dominant processes.

  19. RUNX1 Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Signatures

    PubMed Central

    Mendler, Jason H.; Maharry, Kati; Radmacher, Michael D.; Mrózek, Krzysztof; Becker, Heiko; Metzeler, Klaus H.; Schwind, Sebastian; Whitman, Susan P.; Khalife, Jihane; Kohlschmidt, Jessica; Nicolet, Deedra; Powell, Bayard L.; Carter, Thomas H.; Wetzler, Meir; Moore, Joseph O.; Kolitz, Jonathan E.; Baer, Maria R.; Carroll, Andrew J.; Larson, Richard A.; Caligiuri, Michael A.; Marcucci, Guido; Bloomfield, Clara D.

    2012-01-01

    Purpose To determine the association of RUNX1 mutations with therapeutic outcome in younger and older patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) and with gene/microRNA expression signatures. Patients and Methods Younger (< 60 years; n = 175) and older (≥ 60 years; n = 225) patients with CN-AML treated with intensive cytarabine/anthracycline-based first-line therapy on Cancer and Leukemia Group B protocols were centrally analyzed for RUNX1 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene/microRNA expression profiles were derived using microarrays. Results RUNX1 mutations were found in 8% and 16% of younger and older patients, respectively (P = .02). They were associated with ASXL1 mutations (P < .001) and inversely associated with NPM1 (P < .001) and CEBPA (P = .06) mutations. RUNX1-mutated patients had lower complete remission rates (P = .005 in younger; P = .006 in older) and shorter disease-free survival (P = .058 in younger; P < .001 in older), overall survival (P = .003 in younger; P < .001 in older), and event-free survival (P < .001 for younger and older) than RUNX1 wild-type patients. Because RUNX1 mutations were more common in older patients and almost never coexisted with NPM1 mutations, RUNX1 mutation–associated expression signatures were derived in older, NPM1 wild-type patients and featured upregulation of genes normally expressed in primitive hematopoietic cells and B-cell progenitors, including DNTT, BAALC, BLNK, CD109, RBPMS, and FLT3, and downregulation of promoters of myelopoiesis, including CEBPA and miR-223. Conclusion RUNX1 mutations are twice as common in older than younger patients with CN-AML and negatively impact outcome in both age groups. RUNX1-mutated blasts have molecular features of primitive hematopoietic and lymphoid progenitors, potentially leading to novel therapeutic approaches. PMID:22753902

  20. The lincRNA HOTAIRM1, located in the HOXA genomic region, is expressed in acute myeloid leukemia, impacts prognosis in patients in the intermediate-risk cytogenetic category, and is associated with a distinctive microRNA signature

    PubMed Central

    Díaz-Beyá, Marina; Brunet, Salut; Nomdedéu, Josep; Pratcorona, Marta; Cordeiro, Anna; Gallardo, David; Escoda, Lourdes; Tormo, Mar; Heras, Inmaculada; Ribera, Josep Maria; Duarte, Rafael; de Llano, María Paz Queipo; Bargay, Joan; Sampol, Antonia; Nomdedeu, Mertixell; Risueño, Ruth M.; Hoyos, Montserrat; Sierra, Jorge; Monzo, Mariano; Navarro, Alfons; Esteve, Jordi

    2015-01-01

    Long non-coding RNAs (lncRNAs) are deregulated in several tumors, although their role in acute myeloid leukemia (AML) is mostly unknown. We have examined the expression of the lncRNA HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in 241 AML patients. We have correlated HOTAIRM1 expression with a miRNA expression profile. We have also analyzed the prognostic value of HOTAIRM1 expression in 215 intermediate-risk AML (IR-AML) patients. The lowest expression level was observed in acute promyelocytic leukemia (P < 0.001) and the highest in t(6;9) AML (P = 0.005). In 215 IR-AML patients, high HOTAIRM1 expression was independently associated with shorter overall survival (OR:2.04;P = 0.001), shorter leukemia-free survival (OR:2.56; P < 0.001) and a higher cumulative incidence of relapse (OR:1.67; P = 0.046). Moreover, HOTAIRM1 maintained its independent prognostic value within the favorable molecular subgroup (OR: 3.43; P = 0.009). Interestingly, HOTAIRM1 was overexpressed in NPM1-mutated AML (P < 0.001) and within this group retained its prognostic value (OR: 2.21; P = 0.01). Moreover, HOTAIRM1 expression was associated with a specific 33- microRNA signature that included miR-196b (P < 0.001). miR-196b is located in the HOX genomic region and has previously been reported to have an independent prognostic value in AML. miR-196b and HOTAIRM1 in combination as a prognostic factor can classify patients as high-, intermediate-, or low-risk (5-year OS: 24% vs 42% vs 70%; P = 0.004). Determination of HOTAIRM1 level at diagnosis provided relevant prognostic information in IR-AML and allowed refinement of risk stratification based on common molecular markers. The prognostic information provided by HOTAIRM1 was strengthened when combined with miR-196b expression. Furthermore, HOTAIRM1 correlated with a 33-miRNA signature. PMID:26436590

  1. Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix

    PubMed Central

    Rieke, Damian T.; Ochsenreither, Sebastian; Klinghammer, Konrad; Seiwert, Tanguy Y.; Klauschen, Frederick; Tinhofer, Inge; Keilholz, Ulrich

    2016-01-01

    Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression. A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma. A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC. Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition. PMID:27683114

  2. How Is Neuroblastoma Diagnosed?

    MedlinePlus

    ... Neuroblastoma Early Detection, Diagnosis, and Staging How Is Neuroblastoma Diagnosed? Neuroblastomas are usually found when a child ... Ask Your Child’s Doctor About Neuroblastoma? More In Neuroblastoma About Neuroblastoma Causes, Risk Factors, and Prevention Early ...

  3. How Is Hemophilia Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Hemophilia Diagnosed? If you or your child appears to ... have bleeding problems. However, some people who have hemophilia have no recent family history of the disease. ...

  4. How Is Lymphocytopenia Diagnosed?

    MedlinePlus

    ... of lymphocytes—T cells, B cells, and natural killer cells. The test can help diagnose the underlying ... cause low levels of B cells or natural killer cells. Tests for Underlying Conditions Many diseases and ...

  5. Cardiac expression of deiodinase type 3 (Dio3) following myocardial infarction is associated with the induction of a pluripotency microRNA signature from the Dlk1-Dio3 genomic region.

    PubMed

    Janssen, Rob; Zuidwijk, Marian; Muller, Alice; Mulders, Joyce; Oudejans, Cees B M; Simonides, Warner S

    2013-06-01

    The adult heart has almost completely lost the proliferative potential of the fetal heart. Instead, loss of cardiomyocytes due to myocardial infarction (MI) leads to a limited, and often insufficient, hypertrophic response of cardiomyocytes in the spared myocardium. This response is still characterized by a partial reexpression of the fetal gene program. Because of the suggested involvement of microRNAs (miRNAs) in cardiac remodeling, we examined the miRNA expression profile of the spared left ventricular myocardium using a MI mouse model. C57Bl/6J mice of either sex were randomly assigned to the sham-operated group or MI group. MI was induced by ligation of the left coronary artery. One week after surgery RNA was isolated from the left ventricle. MiRNA analysis was performed using the Taqman Megaplex rodent array. Unexpectedly, we found a set of 29 up-regulated miRNAs originating from the Dlk1-Dio3 genomic imprinted region, which has been identified as a hallmark of pluripotency and proliferation. This miRNA signature was associated with a 6-fold increase in expression of the deiodinase type 3 gene (Dio3) located in this region. Dio3 is a fetally expressed thyroid hormone-inactivating enzyme associated with cell proliferation, which was shown to be up-regulated in cardiomyocytes creating a local hypothyroid condition in the spared myocardium in this model. These data suggest that a regenerative process is initiated, but not completed, in adult cardiomyocytes after MI. The identified miRNA signature could provide new ways to manipulate the in vivo response of adult cardiomyocytes to stress and to increase the regenerative capacity of the injured myocardium.

  6. Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein.

    PubMed

    Schweizer, Leonille; Koelsche, Christian; Sahm, Felix; Piro, Rosario M; Capper, David; Reuss, David E; Pusch, Stefan; Habel, Antje; Meyer, Jochen; Göck, Tanja; Jones, David T W; Mawrin, Christian; Schittenhelm, Jens; Becker, Albert; Heim, Stephanie; Simon, Matthias; Herold-Mende, Christel; Mechtersheimer, Gunhild; Paulus, Werner; König, Rainer; Wiestler, Otmar D; Pfister, Stefan M; von Deimling, Andreas

    2013-05-01

    Non-central nervous system hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) are considered by pathologists as two variants of a single tumor entity now subsumed under the entity SFT. Recent detection of frequent NAB2-STAT6 fusions in both, HPC and SFT, provided additional support for this view. On the other hand, current neuropathological practice still distinguishes between HPC and SFT. The present study set out to identify genes involved in the formation of meningeal HPC. We performed exome sequencing and detected the NAB2-STAT6 fusion in DNA of 8/10 meningeal HPC thereby providing evidence of close relationship of these tumors with peripheral SFT. Due to the considerable effort required for exome sequencing, we sought to explore surrogate markers for the NAB2-STAT6 fusion protein. We adopted the Duolink proximity ligation assay and demonstrated the presence of NAB2-STAT6 fusion protein in 17/17 HPC and the absence in 15/15 meningiomas. More practical, presence of the NAB2-STAT6 fusion protein resulted in a strong nuclear signal in STAT6 immunohistochemistry. The nuclear reallocation of STAT6 was detected in 35/37 meningeal HPC and 25/25 meningeal SFT but not in 87 meningiomas representing the most important differential diagnosis. Tissues not harboring the NAB2-STAT6 fusion protein presented with nuclear expression of NAB2 and cytoplasmic expression of STAT6 proteins. In conclusion, we provide strong evidence for meningeal HPC and SFT to constitute variants of a single entity which is defined by NAB2-STAT6 fusion. In addition, we demonstrate that this fusion can be rapidly detected by STAT6 immunohistochemistry which shows a consistent nuclear reallocation. This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms.

  7. Can specific transcriptional regulators assemble a universal cancer signature?

    NASA Astrophysics Data System (ADS)

    Roy, Janine; Isik, Zerrin; Pilarsky, Christian; Schroeder, Michael

    2013-10-01

    Recently, there is a lot of interest in using biomarker signatures derived from gene expression data to predict cancer progression. We assembled signatures of 25 published datasets covering 13 types of cancers. How do these signatures compare with each other? On one hand signatures answering the same biological question should overlap, whereas signatures predicting different cancer types should differ. On the other hand, there could also be a Universal Cancer Signature that is predictive independently of the cancer type. Initially, we generate signatures for all datasets using classical approaches such as t-test and fold change and then, we explore signatures resulting from a network-based method, that applies the random surfer model of Google's PageRank algorithm. We show that the signatures as published by the authors and the signatures generated with classical methods do not overlap - not even for the same cancer type - whereas the network-based signatures strongly overlap. Selecting 10 out of 37 universal cancer genes gives the optimal prediction for all cancers thus taking a first step towards a Universal Cancer Signature. We furthermore analyze and discuss the involved genes in terms of the Hallmarks of cancer and in particular single out SP1, JUN/FOS and NFKB1 and examine their specific role in cancer progression.

  8. What Signatures Dominantly Associate with Gene Age?

    PubMed Central

    Yin, Hongyan; Wang, Guangyu; Ma, Lina; Yi, Soojin V.; Zhang, Zhang

    2016-01-01

    As genes originate at different evolutionary times, they harbor distinctive genomic signatures of evolutionary ages. Although previous studies have investigated different gene age-related signatures, what signatures dominantly associate with gene age remains unresolved. Here we address this question via a combined approach of comprehensive assignment of gene ages, gene family identification, and multivariate analyses. We first provide a comprehensive and improved gene age assignment by combining homolog clustering with phylogeny inference and categorize human genes into 26 age classes spanning the whole tree of life. We then explore the dominant age-related signatures based on a collection of 10 potential signatures (including gene composition, gene length, selection pressure, expression level, connectivity in protein–protein interaction network and DNA methylation). Our results show that GC content and connectivity in protein–protein interaction network (PPIN) associate dominantly with gene age. Furthermore, we investigate the heterogeneity of dominant signatures in duplicates and singletons. We find that GC content is a consistent primary factor of gene age in duplicates and singletons, whereas PPIN is more strongly associated with gene age in singletons than in duplicates. Taken together, GC content and PPIN are two dominant signatures in close association with gene age, exhibiting heterogeneity in duplicates and singletons and presumably reflecting complex differential interplays between natural selection and mutation. PMID:27609935

  9. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

    PubMed

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

    2016-09-13

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

  10. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer

    PubMed Central

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D.; Verardo, Roberto; Leo, Angelo Di; Migliaccio, Ilenia

    2016-01-01

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 − 3.2] p = 1.87e−08 and HR = 2.62 [1.9− 3.5] p = 8.6e−11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted. PMID:27634906

  11. Digital Signature Management.

    ERIC Educational Resources Information Center

    Hassler, Vesna; Biely, Helmut

    1999-01-01

    Describes the Digital Signature Project that was developed in Austria to establish an infrastructure for applying smart card-based digital signatures in banking and electronic-commerce applications. Discusses the need to conform to international standards, an international certification infrastructure, and security features for a public directory…

  12. Connectivity mapping using a combined gene signature from multiple colorectal cancer datasets identified candidate drugs including existing chemotherapies

    PubMed Central

    2015-01-01

    Background While the discovery of new drugs is a complex, lengthy and costly process, identifying new uses for existing drugs is a cost-effective approach to therapeutic discovery. Connectivity mapping integrates gene expression profiling with advanced algorithms to connect genes, diseases and small molecule compounds and has been applied in a large number of studies to identify potential drugs, particularly to facilitate drug repurposing. Colorectal cancer (CRC) is a commonly diagnosed cancer with high mortality rates, presenting a worldwide health problem. With the advancement of high throughput omics technologies, a number of large scale gene expression profiling studies have been conducted on CRCs, providing multiple datasets in gene expression data repositories. In this work, we systematically apply gene expression connectivity mapping to multiple CRC datasets to identify candidate therapeutics to this disease. Results We developed a robust method to compile a combined gene signature for colorectal cancer across multiple datasets. Connectivity mapping analysis with this signature of 148 genes identified 10 candidate compounds, including irinotecan and etoposide, which are chemotherapy drugs currently used to treat CRCs. These results indicate that we have discovered high quality connections between the CRC disease state and the candidate compounds, and that the gene signature we created may be used as a potential therapeutic target in treating the disease. The method we proposed is highly effective in generating quality gene signature through multiple datasets; the publication of the combined CRC gene signature and the list of candidate compounds from this work will benefit both cancer and systems biology research communities for further development and investigations. PMID:26356760

  13. Expression and purification of Suid Herpesvirus-1 glycoprotein E in the baculovirus system and its use to diagnose Aujeszky's disease in infected pigs.

    PubMed

    Serena, María Soledad; Geisler, Christoph; Metz, Germán Ernesto; Corva, Santiago Gerardo; Mórtola, Eduardo Carlos; Larsen, Alejandra; Jarvis, Donald L; Echeverría, María Gabriela

    2013-07-01

    Suid Herpesvirus 1 (SHV-1) is the etiological agent of Aujeszky's disease (AD), which affects swine herds worldwide and causes substantial economic losses due to animal mortality and lost productivity. In order to eradicate SHV-1, vaccination programs using viruses lacking the gene encoding glycoprotein E (gE) are ongoing in several countries. These eradication programs have generated a currently unmet demand for affordable and sensitive tests that can detect SHV-1 infection, yet distinguish between infected and vaccinated pigs. To meet this demand, we used the baculovirus-insect cell system to produce immunologically authentic full-length recombinant gE protein for use in a serum ELISA assay. As previous efforts to clone the gE gene had failed due to its extremely high GC-content (75% average), we used betaine as a PCR enhancer to facilitate amplification of the entire gE gene from the Argentinian CL15 strain of SHV-1. The cloned gE gene was expressed at high levels in recombinant baculovirus-infected insect cells and reacted strongly with sera from SHV-1 infected pigs. We used the recombinant gE protein to develop a local indirect ELISA test with sensitivity and specificity comparable to currently available commercial tests. Thus, recombinant gE produced in baculovirus-infected insect cells is a viable source of antigen for the detection of SHV-1 in ELISA tests. We also provide evidence supporting a potential application of this recombinant form of gE as a SHV-1 subunit vaccine.

  14. How a Stroke Is Diagnosed

    MedlinePlus

    ... News About Neurology Image Library Search The Internet Stroke Center Patients & Families About Stroke Stroke Diagnosis Stroke ... Diagnosis » How a Stroke is Diagnosed How a Stroke is Diagnosed How a Stroke is Diagnosed Lab ...

  15. How Is Cardiogenic Shock Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Cardiogenic Shock Diagnosed? The first step in diagnosing cardiogenic shock ... is cardiogenic shock. Tests and Procedures To Diagnose Shock and Its Underlying Causes Blood Pressure Test Medical ...

  16. How Are Genetic Conditions Diagnosed?

    MedlinePlus

    ... Consultation How are genetic conditions diagnosed? How are genetic conditions diagnosed? A doctor may suspect a diagnosis ... and advocacy resources. For more information about diagnosing genetic conditions: Genetics Home Reference provides information about genetic ...

  17. UV Signature Mutations †

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  18. An archaeal genomic signature

    NASA Technical Reports Server (NTRS)

    Graham, D. E.; Overbeek, R.; Olsen, G. J.; Woese, C. R.

    2000-01-01

    Comparisons of complete genome sequences allow the most objective and comprehensive descriptions possible of a lineage's evolution. This communication uses the completed genomes from four major euryarchaeal taxa to define a genomic signature for the Euryarchaeota and, by extension, the Archaea as a whole. The signature is defined in terms of the set of protein-encoding genes found in at least two diverse members of the euryarchaeal taxa that function uniquely within the Archaea; most signature proteins have no recognizable bacterial or eukaryal homologs. By this definition, 351 clusters of signature proteins have been identified. Functions of most proteins in this signature set are currently unknown. At least 70% of the clusters that contain proteins from all the euryarchaeal genomes also have crenarchaeal homologs. This conservative set, which appears refractory to horizontal gene transfer to the Bacteria or the Eukarya, would seem to reflect the significant innovations that were unique and fundamental to the archaeal "design fabric." Genomic protein signature analysis methods may be extended to characterize the evolution of any phylogenetically defined lineage. The complete set of protein clusters for the archaeal genomic signature is presented as supplementary material (see the PNAS web site, www.pnas.org).

  19. Twin Signature Schemes, Revisited

    NASA Astrophysics Data System (ADS)

    Schäge, Sven

    In this paper, we revisit the twin signature scheme by Naccache, Pointcheval and Stern from CCS 2001 that is secure under the Strong RSA (SRSA) assumption and improve its efficiency in several ways. First, we present a new twin signature scheme that is based on the Strong Diffie-Hellman (SDH) assumption in bilinear groups and allows for very short signatures and key material. A big advantage of this scheme is that, in contrast to the original scheme, it does not require a computationally expensive function for mapping messages to primes. We prove this new scheme secure under adaptive chosen message attacks. Second, we present a modification that allows to significantly increase efficiency when signing long messages. This construction uses collision-resistant hash functions as its basis. As a result, our improvements make the signature length independent of the message size. Our construction deviates from the standard hash-and-sign approach in which the hash value of the message is signed in place of the message itself. We show that in the case of twin signatures, one can exploit the properties of the hash function as an integral part of the signature scheme. This improvement can be applied to both the SRSA based and SDH based twin signature scheme.

  20. Diagnosing Abiotic Degradation

    EPA Science Inventory

    The abiotic degradation of chlorinated solvents in ground water can be difficult to diagnose. Under current practice, most of the “evidence” is negative; specifically the apparent disappearance of chlorinated solvents with an accumulation of vinyl chloride, ethane, ethylene, or ...

  1. Newly Diagnosed: Older Adults

    MedlinePlus

    ... Children Newly Diagnosed: Older Adults Related Topics on AIDS.gov Aging with HIV/AIDS National HIV/AIDS ... an Emerging Challenge Last revised: 07/10/2015 AIDS.gov HIV/AIDS Basics • Federal Resources • Using New ...

  2. Altered gene expression signature of early stages of the germ line supports the pre-meiotic origin of human spermatogenic failure.

    PubMed

    Bonache, S; Algaba, F; Franco, E; Bassas, L; Larriba, S

    2014-07-01

    The molecular basis of spermatogenic failure (SpF) is still largely unknown. Accumulating evidence suggests that a series of specific events such as meiosis, are determined at the early stage of spermatogenesis. This study aims to assess the expression profile of pre-meiotic genes of infertile testicular biopsies that might help to define the molecular phenotype associated with human deficiency of sperm production. An accurate quantification of testicular mRNA levels of genes expressed in spermatogonia was carried out by RT-qPCR in individuals showing SpF owing to germ cell maturation defects, Sertoli cell-only syndrome or conserved spermatogenesis. In addition, the gene expression profile of SpF was compared with that of testicular tumour, which is considered to be a severe developmental disease of germ cell differentiation. Protein expression from selected genes was evaluated by immunohistochemistry. Our results indicate that SpF is accompanied by differences in expression of certain genes associated with spermatogonia in the absence of any apparent morphological and/or numerical change in this specific cell type. In SpF testicular samples, we observed down-regulation of genes involved in cell cycle (CCNE1 and POLD1), transcription and post-transcription regulation (DAZL, RBM15 and DICER1), protein degradation (FBXO32 and TM9SF2) and homologous recombination in meiosis (MRE11A and RAD50) which suggests that the expression of these genes is critical for a proper germ cell development. Interestingly, a decrease in the CCNE1, DAZL, RBM15 and STRA8 cellular transcript levels was also observed, suggesting that the gene expression capacity of spermatogonia is altered in SpF contributing to an unsuccessful sperm production. Altogether, these data point to the spermatogenic derangement being already determined at, or arising in, the initial stages of the germ line.

  3. Are there molecular signatures?

    SciTech Connect

    Bennett, W.P.

    1995-10-01

    This report describes molecular signatures and mutational spectrum analysis. The mutation spectrum is defined as the type and location of DNA base change. There are currently about five well documented cases. Mutations and radon-associated tumors are discussed.

  4. Meteor signature interpretation

    SciTech Connect

    Canavan, G.H.

    1997-01-01

    Meteor signatures contain information about the constituents of space debris and present potential false alarms to early warnings systems. Better models could both extract the maximum scientific information possible and reduce their danger. Accurate predictions can be produced by models of modest complexity, which can be inverted to predict the sizes, compositions, and trajectories of object from their signatures for most objects of interest and concern.

  5. Different patterns of Epstein-Barr virus latency in endemic Burkitt lymphoma (BL) lead to distinct variants within the BL-associated gene expression signature.

    PubMed

    Kelly, Gemma L; Stylianou, Julianna; Rasaiyaah, Jane; Wei, Wenbin; Thomas, Wendy; Croom-Carter, Deborah; Kohler, Christian; Spang, Rainer; Woodman, Ciaran; Kellam, Paul; Rickinson, Alan B; Bell, Andrew I

    2013-03-01

    Epstein-Barr virus (EBV) is present in all cases of endemic Burkitt lymphoma (BL) but in few European/North American sporadic BLs. Gene expression arrays of sporadic tumors have defined a consensus BL profile within which tumors are classifiable as "molecular BL" (mBL). Where endemic BLs fall relative to this profile remains unclear, since they not only carry EBV but also display one of two different forms of virus latency. Here, we use early-passage BL cell lines from different tumors, and BL subclones from a single tumor, to compare EBV-negative cells with EBV-positive cells displaying either classical latency I EBV infection (where EBNA1 is the only EBV antigen expressed from the wild-type EBV genome) or Wp-restricted latency (where an EBNA2 gene-deleted virus genome broadens antigen expression to include the EBNA3A, -3B, and -3C proteins and BHRF1). Expression arrays show that both types of endemic BL fall within the mBL classification. However, while EBV-negative and latency I BLs show overlapping profiles, Wp-restricted BLs form a distinct subgroup, characterized by a detectable downregulation of the germinal center (GC)-associated marker Bcl6 and upregulation of genes marking early plasmacytoid differentiation, notably IRF4 and BLIMP1. Importantly, these same changes can be induced in EBV-negative or latency I BL cells by infection with an EBNA2-knockout virus. Thus, we infer that the distinct gene profile of Wp-restricted BLs does not reflect differences in the identity of the tumor progenitor cell per se but differences imposed on a common progenitor by broadened EBV gene expression.

  6. Genetic signatures of heroin addiction.

    PubMed

    Chen, Shaw-Ji; Liao, Ding-Lieh; Shen, Tsu-Wang; Yang, Hsin-Chou; Chen, Kuang-Chi; Chen, Chia-Hsiang

    2016-08-01

    Heroin addiction is a complex psychiatric disorder with a chronic course and a high relapse rate, which results from the interaction between genetic and environmental factors. Heroin addiction has a substantial heritability in its etiology; hence, identification of individuals with a high genetic propensity to heroin addiction may help prevent the occurrence and relapse of heroin addiction and its complications. The study aimed to identify a small set of genetic signatures that may reliably predict the individuals with a high genetic propensity to heroin addiction. We first measured the transcript level of 13 genes (RASA1, PRKCB, PDK1, JUN, CEBPG, CD74, CEBPB, AUTS2, ENO2, IMPDH2, HAT1, MBD1, and RGS3) in lymphoblastoid cell lines in a sample of 124 male heroin addicts and 124 male control subjects using real-time quantitative PCR. Seven genes (PRKCB, PDK1, JUN, CEBPG, CEBPB, ENO2, and HAT1) showed significant differential expression between the 2 groups. Further analysis using 3 statistical methods including logistic regression analysis, support vector machine learning analysis, and a computer software BIASLESS revealed that a set of 4 genes (JUN, CEBPB, PRKCB, ENO2, or CEBPG) could predict the diagnosis of heroin addiction with the accuracy rate around 85% in our dataset. Our findings support the idea that it is possible to identify genetic signatures of heroin addiction using a small set of expressed genes. However, the study can only be considered as a proof-of-concept study. As the establishment of lymphoblastoid cell line is a laborious and lengthy process, it would be more practical in clinical settings to identify genetic signatures for heroin addiction directly from peripheral blood cells in the future study.

  7. Diagnosing Deep Venous Thrombosis

    PubMed Central

    Doyle, D. Lynn

    1992-01-01

    Patients often present with unexplained lower limb pain and swelling. It is important to exclude deep venous thrombosis in the diagnosis because of the threat of sudden death. Simple clinical diagnosis is unacceptable, and noninvasive tests should be used initially. Serial testing detects proximal extension of isolated calf thrombi. Multiple diagnostic modalities are employed to diagnose a new deep venous thrombosis in patients with postphlebitic syndrome. PMID:21221369

  8. Ginger and turmeric expressed sequence tags identify signature genes for rhizome identity and development and the biosynthesis of curcuminoids, gingerols and terpenoids

    PubMed Central

    2013-01-01

    Background Ginger (Zingiber officinale) and turmeric (Curcuma longa) accumulate important pharmacologically active metabolites at high levels in their rhizomes. Despite their importance, relatively little is known regarding gene expression in the rhizomes of ginger and turmeric. Results In order to identify rhizome-enriched genes and genes encoding specialized metabolism enzymes and pathway regulators, we evaluated an assembled collection of expressed sequence tags (ESTs) from eight different ginger and turmeric tissues. Comparisons to publicly available sorghum rhizome ESTs revealed a total of 777 gene transcripts expressed in ginger/turmeric and sorghum rhizomes but apparently absent from other tissues. The list of rhizome-specific transcripts was enriched for genes associated with regulation of tissue growth, development, and transcription. In particular, transcripts for ethylene response factors and AUX/IAA proteins appeared to accumulate in patterns mirroring results from previous studies regarding rhizome growth responses to exogenous applications of auxin and ethylene. Thus, these genes may play important roles in defining rhizome growth and development. Additional associations were made for ginger and turmeric rhizome-enriched MADS box transcription factors, their putative rhizome-enriched homologs in sorghum, and rhizomatous QTLs in rice. Additionally, analysis of both primary and specialized metabolism genes indicates that ginger and turmeric rhizomes are primarily devoted to the utilization of leaf supplied sucrose for the production and/or storage of specialized metabolites associated with the phenylpropanoid pathway and putative type III polyketide synthase gene products. This finding reinforces earlier hypotheses predicting roles of this enzyme class in the production of curcuminoids and gingerols. Conclusion A significant set of genes were found to be exclusively or preferentially expressed in the rhizome of ginger and turmeric. Specific

  9. Transcriptional Signatures in Huntington's Disease

    PubMed Central

    2007-01-01

    While selective neuronal death has been an influential theme in Huntington's disease (HD), there is now a preponderance of evidence that significant neuronal dysfunction precedes frank neuronal death. The best evidence for neuronal dysfunction is the observation that gene expression is altered in HD brain, suggesting that transcriptional dysregulation is a central mechanism. Studies of altered gene expression began with careful observations of post-mortem human HD brain and subsequently were accelerated by the development of transgenic mouse models. The application of DNA microarray technology has spurred tremendous progress with respect to the altered transcriptional processes that occur in HD, through gene expression studies of both transgenic mouse models as well as cellular models of HD. Gene expression profiles are remarkably comparable across these models, bolstering the idea that transcriptional signatures reflect an essential feature of disease pathogenesis. Finally, gene expression studies have been applied to human HD, thus not only validating the approach of using model systems, but also solidifying the idea that altered transcription is a key mechanism in HD pathogenesis. In the future, gene expression profiling will be used as a readout in clinical trials aimed at correcting transcriptional dysregulation in Huntington's disease. PMID:17467140

  10. RNA-Seq reveals expression signatures of genes involved in oxygen transport, protein synthesis, folding, and degradation in response to heat stress in catfish.

    PubMed

    Liu, Shikai; Wang, Xiuli; Sun, Fanyue; Zhang, Jiaren; Feng, Jianbin; Liu, Hong; Rajendran, K V; Sun, Luyang; Zhang, Yu; Jiang, Yanliang; Peatman, Eric; Kaltenboeck, Ludmilla; Kucuktas, Huseyin; Liu, Zhanjiang

    2013-06-17

    Temperature is one of the most prominent abiotic factors affecting ectotherms. Most fish species, as ectotherms, have extraordinary ability to deal with a wide range of temperature changes. While the molecular mechanism underlying temperature adaptation has long been of interest, it is still largely unexplored with fish. Understanding of the fundamental mechanisms conferring tolerance to temperature fluctuations is a topic of increasing interest as temperature may continue to rise as a result of global climate change. Catfish have a wide natural habitat and possess great plasticity in dealing with environmental variations in temperature. However, no studies have been conducted at the transcriptomic level to determine heat stress-induced gene expression. In the present study, we conducted an RNA-Seq analysis to identify heat stress-induced genes in catfish at the transcriptome level. Expression analysis identified a total of 2,260 differentially expressed genes with a cutoff of twofold change. qRT-PCR validation suggested the high reliability of the RNA-Seq results. Gene ontology, enrichment, and pathway analyses were conducted to gain insight into physiological and gene pathways. Specifically, genes involved in oxygen transport, protein folding and degradation, and metabolic process were highly induced, while general protein synthesis was dramatically repressed in response to the lethal temperature stress. This is the first RNA-Seq-based expression study in catfish in response to heat stress. The candidate genes identified should be valuable for further targeted studies on heat tolerance, thereby assisting the development of heat-tolerant catfish lines for aquaculture.

  11. Invisibly Sanitizable Signature without Pairings

    NASA Astrophysics Data System (ADS)

    Yum, Dae Hyun; Lee, Pil Joong

    Sanitizable signatures allow sanitizers to delete some pre-determined parts of a signed document without invalidating the signature. While ordinary sanitizable signatures allow verifiers to know how many subdocuments have been sanitized, invisibly sanitizable signatures do not leave any clue to the sanitized subdocuments; verifiers do not know whether or not sanitizing has been performed. Previous invisibly sanitizable signature scheme was constructed based on aggregate signature with pairings. In this article, we present the first invisibly sanitizable signature without using pairings. Our proposed scheme is secure under the RSA assumption.

  12. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study.

    PubMed

    Jardin, Fabrice; Jais, Jean-Philippe; Molina, Thierry-Jo; Parmentier, Françoise; Picquenot, Jean-Michel; Ruminy, Philippe; Tilly, Hervé; Bastard, Christian; Salles, Gilles-André; Feugier, Pierre; Thieblemont, Catherine; Gisselbrecht, Christian; de Reynies, Aurelien; Coiffier, Bertrand; Haioun, Corinne; Leroy, Karen

    2010-08-19

    Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

  13. Genomic and gene regulatory signatures of cryptozoic adaptation: Loss of blue sensitive photoreceptors through expansion of long wavelength-opsin expression in the red flour beetle Tribolium castaneum

    PubMed Central

    Jackowska, Magdalena; Bao, Riyue; Liu, Zhenyi; McDonald, Elizabeth C; Cook, Tiffany A; Friedrich, Markus

    2007-01-01

    Background Recent genome sequence analysis in the red flour beetle Tribolium castaneum indicated that this highly crepuscular animal encodes only two single opsin paralogs: a UV-opsin and a long wavelength (LW)-opsin; however, these animals do not encode a blue (B)-opsin as most other insects. Here, we studied the spatial regulation of the Tribolium single LW- and UV-opsin gene paralogs in comparison to that of the five opsin paralogs in the retina of Drosophila melanogaster. Results In situ hybridization analysis reveals that the Tribolium retina, in contrast with other insect retinas, constitutes a homogenous field of ommatidia that have seven LW-opsin expressing photoreceptors and one UV-/LW-opsin co-expressing photoreceptor per eye unit. This pattern is consistent with the loss of photoreceptors sensitive to blue wavelengths. It also identifies Tribolium as the first example of a species in insects that co-expresses two different opsins across the entire retina in violation of the widely observed "one receptor rule" of sensory cells. Conclusion Broader studies of opsin evolution in darkling beetles and other coleopteran groups have the potential to pinpoint the permissive and adaptive forces that played a role in the evolution of vision in Tribolium castaneum. PMID:18154648

  14. A comparison of host gene expression signatures associated with infection in vitro by the Makona and Ecran (Mayinga) variants of Ebola virus

    PubMed Central

    Bosworth, Andrew; Dowall, Stuart D.; Garcia-Dorival, Isabel; Rickett, Natasha Y.; Bruce, Christine B.; Matthews, David A.; Fang, Yongxiang; Aljabr, Waleed; Kenny, John; Nelson, Charlotte; Laws, Thomas R.; Williamson, E. Diane; Stewart, James P.; Carroll, Miles W.; Hewson, Roger; Hiscox, Julian A.

    2017-01-01

    The Ebola virus (EBOV) variant Makona (which emerged in 2013) was the causative agent of the largest outbreak of Ebola Virus Disease recorded. Differences in virus-host interactions between viral variants have potential consequences for transmission, disease severity and mortality. A detailed profile of the cellular changes induced by the Makona variant compared with other Ebola virus variants was lacking. In this study, A549 cells, a human cell line with a robust innate response, were infected with the Makona variant or with the Ecran variant originating from the 1976 outbreak in Central Africa. The abundance of viral and cellular mRNA transcripts was profiled using RNASeq and differential gene expression analysis performed. Differences in effects of each virus on the expression of interferon-stimulated genes were also investigated in A549 NPro cells where the type 1 interferon response had been attenuated. Cellular transcriptomic changes were compared with those induced by human respiratory syncytial virus (HRSV), a virus with a similar genome organisation and replication strategy to EBOV. Pathway and gene ontology analysis revealed differential expression of functionally important genes; including genes involved in the inflammatory response, cell proliferation, leukocyte extravasation and cholesterol biosynthesis. Whilst there was overlap with HRSV, there was unique commonality to the EBOV variants. PMID:28240256

  15. Hyperspectral signature analysis of skin parameters

    NASA Astrophysics Data System (ADS)

    Vyas, Saurabh; Banerjee, Amit; Garza, Luis; Kang, Sewon; Burlina, Philippe

    2013-02-01

    The temporal analysis of changes in biological skin parameters, including melanosome concentration, collagen concentration and blood oxygenation, may serve as a valuable tool in diagnosing the progression of malignant skin cancers and in understanding the pathophysiology of cancerous tumors. Quantitative knowledge of these parameters can also be useful in applications such as wound assessment, and point-of-care diagnostics, amongst others. We propose an approach to estimate in vivo skin parameters using a forward computational model based on Kubelka-Munk theory and the Fresnel Equations. We use this model to map the skin parameters to their corresponding hyperspectral signature. We then use machine learning based regression to develop an inverse map from hyperspectral signatures to skin parameters. In particular, we employ support vector machine based regression to estimate the in vivo skin parameters given their corresponding hyperspectral signature. We build on our work from SPIE 2012, and validate our methodology on an in vivo dataset. This dataset consists of 241 signatures collected from in vivo hyperspectral imaging of patients of both genders and Caucasian, Asian and African American ethnicities. In addition, we also extend our methodology past the visible region and through the short-wave infrared region of the electromagnetic spectrum. We find promising results when comparing the estimated skin parameters to the ground truth, demonstrating good agreement with well-established physiological precepts. This methodology can have potential use in non-invasive skin anomaly detection and for developing minimally invasive pre-screening tools.

  16. Construction of protein profile classification model and screening of proteomic signature of acute leukemia

    PubMed Central

    Xu, Yun; Zhuo, Jiacai; Duan, Yonggang; Shi, Benhang; Chen, Xuhong; Zhang, Xiaoli; Xiao, Liang; Lou, Jin; Huang, Ruihong; Zhang, Qiongli; Du, Xin; Li, Ming; Wang, Daping; Shi, Dunyun

    2014-01-01

    The French-American-British (FAB) and WHO classifications provide important guidelines for the diagnosis, treatment, and prognostic prediction of acute leukemia, but are incapable of accurately differentiating all subtypes, and not well correlated with the clinical outcomes. In this study, we performed the protein profiling of the bone marrow mononuclear cells from the patients with acute leukemia and the health volunteers (control) by surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI_TOF_MS). The patients with acute leukemia were analyzed as unitary by the profiling that were grouped into acute promyelocytic leukemia (APL), acute myeloid leukemia-granulocytic (AML-Gran), acute myeloid leukemia-monocytic (AML-Mon) acute lymphocytic leukemia (ALL), and control. Based on 109 proteomic signatures, the classification models of acute leukemia were constructed to screen the predictors by the improvement of the proteomic signatures and to detect their expression characteristics. According to the improvement and the expression characteristics of the predictors, the proteomic signatures (M3829, M1593, M2121, M2536, M1016) characterized successively each group (CON, APL, AML-Gra, AML-Mon, ALL) were screened as target molecules for identification. Meanwhile, the proteomic-based class of determinant samples could be made by the classification models. The credibility of the proteomic-based classification passed the evaluation of Biomarker Patterns Software 5.0 (BPS 5.0) scoring and validated application in clinical practice. The results suggested that the proteomic signatures characterized by different blasts were potential for developing new treatment and monitoring approaches of leukemia blasts. Moreover, the classification model was potential in serving as new diagnose approach of leukemia. PMID:25337199

  17. Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS).

    PubMed

    Plasilova, Martina; Chattopadhyay, Chandon; Ghosh, Apurba; Wenzel, Friedel; Demougin, Philippe; Noppen, Christoph; Schaub, Nathalie; Szinnai, Gabor; Terracciano, Luigi; Heinimann, Karl

    2011-01-01

    Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N) patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.

  18. Metabolic Signatures of Bacterial Vaginosis

    PubMed Central

    Morgan, Martin T.; Fiedler, Tina L.; Djukovic, Danijel; Hoffman, Noah G.; Raftery, Daniel; Marrazzo, Jeanne M.

    2015-01-01

    ABSTRACT Bacterial vaginosis (BV) is characterized by shifts in the vaginal microbiota from Lactobacillus dominant to a microbiota with diverse anaerobic bacteria. Few studies have linked specific metabolites with bacteria found in the human vagina. Here, we report dramatic differences in metabolite compositions and concentrations associated with BV using a global metabolomics approach. We further validated important metabolites using samples from a second cohort of women and a different platform to measure metabolites. In the primary study, we compared metabolite profiles in cervicovaginal lavage fluid from 40 women with BV and 20 women without BV. Vaginal bacterial representation was determined using broad-range PCR with pyrosequencing and concentrations of bacteria by quantitative PCR. We detected 279 named biochemicals; levels of 62% of metabolites were significantly different in women with BV. Unsupervised clustering of metabolites separated women with and without BV. Women with BV have metabolite profiles marked by lower concentrations of amino acids and dipeptides, concomitant with higher levels of amino acid catabolites and polyamines. Higher levels of the signaling eicosanoid 12-hydroxyeicosatetraenoic acid (12-HETE), a biomarker for inflammation, were noted in BV. Lactobacillus crispatus and Lactobacillus jensenii exhibited similar metabolite correlation patterns, which were distinct from correlation patterns exhibited by BV-associated bacteria. Several metabolites were significantly associated with clinical signs and symptoms (Amsel criteria) used to diagnose BV, and no metabolite was associated with all four clinical criteria. BV has strong metabolic signatures across multiple metabolic pathways, and these signatures are associated with the presence and concentrations of particular bacteria. PMID:25873373

  19. Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia

    PubMed Central

    Wagner, Allon; Cohen, Noa; Kelder, Thomas; Amit, Uri; Liebman, Elad; Steinberg, David M; Radonjic, Marijana; Ruppin, Eytan

    2015-01-01

    High-throughput omics have proven invaluable in studying human disease, and yet day-to-day clinical practice still relies on physiological, non-omic markers. The metabolic syndrome, for example, is diagnosed and monitored by blood and urine indices such as blood cholesterol levels. Nevertheless, the association between the molecular and the physiological manifestations of the disease, especially in response to treatment, has not been investigated in a systematic manner. To this end, we studied a mouse model of diet-induced dyslipidemia and atherosclerosis that was subject to various drug treatments relevant to the disease in question. Both physiological data and gene expression data (from the liver and white adipose) were analyzed and compared. We find that treatments that restore gene expression patterns to their norm are associated with the successful restoration of physiological markers to their baselines. This holds in a tissue-specific manner—treatments that reverse the transcriptomic signatures of the disease in a particular tissue are associated with positive physiological effects in that tissue. Further, treatments that introduce large non-restorative gene expression alterations are associated with unfavorable physiological outcomes. These results provide a sound basis to in silico methods that rely on omic metrics for drug repurposing and drug discovery by searching for compounds that reverse a disease's omic signatures. Moreover, they highlight the need to develop drugs that restore the global cellular state to its healthy norm rather than rectify particular disease phenotypes. PMID:26148350

  20. Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell-Renal-Cell-Carcinoma: Proof-of-Concept Study.

    PubMed

    Yin, Qingbo; Hung, Sheng-Che; Wang, Li; Lin, Weili; Fielding, Julia R; Rathmell, W Kimryn; Khandani, Amir H; Woods, Michael E; Milowsky, Matthew I; Brooks, Samira A; Wallen, Eric M; Shen, Dinggang

    2017-03-03

    Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone.

  1. Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell–Renal-Cell-Carcinoma: Proof-of-Concept Study

    PubMed Central

    Yin, Qingbo; Hung, Sheng-Che; Wang, Li; Lin, Weili; Fielding, Julia R.; Rathmell, W. Kimryn; Khandani, Amir H.; Woods, Michael E.; Milowsky, Matthew I.; Brooks, Samira A.; Wallen, Eric. M.; Shen, Dinggang

    2017-01-01

    Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone. PMID:28256615

  2. Practical quantum digital signature

    NASA Astrophysics Data System (ADS)

    Yin, Hua-Lei; Fu, Yao; Chen, Zeng-Bing

    2016-03-01

    Guaranteeing nonrepudiation, unforgeability as well as transferability of a signature is one of the most vital safeguards in today's e-commerce era. Based on fundamental laws of quantum physics, quantum digital signature (QDS) aims to provide information-theoretic security for this cryptographic task. However, up to date, the previously proposed QDS protocols are impractical due to various challenging problems and most importantly, the requirement of authenticated (secure) quantum channels between participants. Here, we present the first quantum digital signature protocol that removes the assumption of authenticated quantum channels while remaining secure against the collective attacks. Besides, our QDS protocol can be practically implemented over more than 100 km under current mature technology as used in quantum key distribution.

  3. Factor models for cancer signatures

    NASA Astrophysics Data System (ADS)

    Kakushadze, Zura; Yu, Willie

    2016-11-01

    We present a novel method for extracting cancer signatures by applying statistical risk models (http://ssrn.com/abstract=2732453) from quantitative finance to cancer genome data. Using 1389 whole genome sequenced samples from 14 cancers, we identify an "overall" mode of somatic mutational noise. We give a prescription for factoring out this noise and source code for fixing the number of signatures. We apply nonnegative matrix factorization (NMF) to genome data aggregated by cancer subtype and filtered using our method. The resultant signatures have substantially lower variability than those from unfiltered data. Also, the computational cost of signature extraction is cut by about a factor of 10. We find 3 novel cancer signatures, including a liver cancer dominant signature (96% contribution) and a renal cell carcinoma signature (70% contribution). Our method accelerates finding new cancer signatures and improves their overall stability. Reciprocally, the methods for extracting cancer signatures could have interesting applications in quantitative finance.

  4. Current signature sensor

    NASA Technical Reports Server (NTRS)

    Perotti, Jose M. (Inventor); Lucena, Angel (Inventor); Ihlefeld, Curtis (Inventor); Burns, Bradley (Inventor); Bassignani, Karin E. (Inventor)

    2005-01-01

    A solenoid health monitoring system uses a signal conditioner and controller assembly in one embodiment that includes analog circuitry and a DSP controller. The analog circuitry provides signal conditioning to the low-level raw signal coming from a signal acquisition assembly. Software running in a DSP analyzes the incoming data (recorded current signature) and determines the state of the solenoid whether it is energized, de-energized, or in a transitioning state. In one embodiment, the software identifies key features in the current signature during the transition phase and is able to determine the health of the solenoid.

  5. Current Signature Sensor

    NASA Technical Reports Server (NTRS)

    Perotti, Jose M. (Inventor); Lucena, Angel (Inventor); Ihlefeld, Curtis (Inventor); Burns, Bradley (Inventor); Bassignani, Mario (Inventor); Bassignani, Karin E. (Inventor)

    2005-01-01

    A solenoid health monitoring system uses a signal conditioner and controller assembly in one embodiment that includes analog circuitry and a DSP controller. The analog circuitry provides signal conditioning to the low-level raw signal coming from a signal acquisition assembly. Software running in a DSP analyzes the incoming data (recorded current signature) and determines the state of the solenoid whether it is energized, de-energized, or in a transitioning state. In one embodiment, the software identifies key features in the current signature during the transition phase and is able to determine the health of the solenoid.

  6. Molecular signature in HCV-positive lymphomas.

    PubMed

    De Re, Valli; Caggiari, Laura; Garziera, Marica; De Zorzi, Mariangela; Repetto, Ombretta

    2012-01-01

    Hepatitis C virus (HCV) is a positive, single-stranded RNA virus, which has been associated to different subtypes of B-cell non-Hodgkin lymphoma (B-NHL). Cumulative evidence suggests an HCV-related antigen driven process in the B-NHL development. The underlying molecular signature associated to HCV-related B-NHL has to date remained obscure. In this review, we discuss the recent developments in this field with a special mention to different sets of genes whose expression is associated with BCR coupled to Blys signaling which in turn was found to be linked to B-cell maturation stages and NF-κb transcription factor. Even if recent progress on HCV-B-NHL signature has been made, the precise relationship between HCV and lymphoma development and phenotype signature remain to be clarified.

  7. Looking for protein expression signatures in European eel peripheral blood mononuclear cells after in vivo exposure to perfluorooctane sulfonate and a real world field study.

    PubMed

    Roland, Kathleen; Kestemont, Patrick; Loos, Robert; Tavazzi, Simona; Paracchini, Bruno; Belpaire, Claude; Dieu, Marc; Raes, Martine; Silvestre, Frédéric

    2014-01-15

    The decline of European eel population can be attributed to many factors such as pollution by xenobiotics present in domestic and industrial effluents. Perfluorooctane sulfonate (PFOS) is a ubiquitous compound of a particular concern in Europe. PFOS can reach high concentrations in tissues of organisms and many toxic effects have been reported in fish. This study aimed at evaluating the toxicological effects of PFOS in European eel peripheral blood mononuclear cells (PBMCs) at the protein expression level. To identify proteins whose expression was modified by PFOS, we performed a proteomic analysis on the post-nuclear fraction of PBMCs after a chronic exposure (28 days) of yellow eels to zero, 1 or 10 μg/L PFOS. This in vivo study was completed by a proteomic field study on eels sampled in Belgian rivers presenting different PFOS pollution degrees. Proteins were separated by two-dimensional in-gel electrophoresis (2D-DIGE) to compare the post-nuclear fraction of PBMCs from the reference group with cells from fish exposed to the pollutant of interest. On the 28 spots that were significantly (p < 0.05; ANOVA followed by a Dunnett post-hoc test) affected by PFOS in the in vivo experiment, a total of 17 different proteins were identified using nano-LC ESI-MS/MS and the Peptide and Protein Prophet of Scaffold software. In the field experiment, 18 significantly (p < 0.05; ANOVA followed by Dunnett's test) affected spots conducted to the identification of 16 different proteins. Interestingly, only three proteins were found in common between in vivo and in situ experiments: plastin-2, alpha-enolase and glyceraldehyde 3-phosphate dehydrogenase. Comparing the results with a previous study, plastin-2 and alpha-enolase were also been found to be affected after in vitro exposure of PBMCs during 48 h to either 10 μg or 1 mg PFOS/L. Potential use of these proteins as biomarkers of PFOS exposure in European eel could indicate early warning signals.

  8. How Is Kawasaki Disease Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Kawasaki Disease Diagnosed? Kawasaki disease is diagnosed based on your child's signs and ... are the first to suspect a child has Kawasaki disease. Pediatricians are doctors who specialize in treating children. ...

  9. How Is Pulmonary Hypertension Diagnosed?

    MedlinePlus

    ... Hypertension Diagnosed? Your doctor will diagnose pulmonary hypertension (PH) based on your medical and family histories, a ... exam, and the results from tests and procedures. PH can develop slowly. In fact, you may have ...

  10. Diagnosing Dementia--Positive Signs

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues Diagnosing Dementia—Positive Signs Past Issues / Fall 2007 Table of ... easy, affordable blood test that could accurately diagnose Alzheimer's disease (AD)—even before symptoms began to show? Researchers ...

  11. Gene expression profiling signatures for the diagnosis and prevention of oral cavity carcinogenesis-genome-wide analysis using RNA-seq technology.

    PubMed

    Tang, Xiao-Han; Urvalek, Alison M; Osei-Sarfo, Kwame; Zhang, Tuo; Scognamiglio, Theresa; Gudas, Lorraine J

    2015-09-15

    We compared the changes in global gene expression between an early stage (the termination of the carcinogen treatment and prior to the appearance of frank tumors) and a late stage (frank squamous cell carcinoma (SCC)) of tongue carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral cavity and esophageal squamous cell carcinoma. Gene ontology and pathway analyses show that increases in "cell cycle progression" and "degradation of basement membrane and ECM pathways" are early events during SCC carcinogenesis and that changes in these pathways are even greater in the actual tumors. Myc, NFκB complex (NFKB1/RELA), and FOS transcription networks are the major transcriptional networks induced in early stage tongue carcinogenesis. Decreases in metabolism pathways, such as in "tricarboxylic acid cycle" and "oxidative phosphorylation", occurred only in the squamous cell carcinomas and not in the early stages of carcinogenesis. We detected increases in ALDH1A3, PTGS2, and KRT1 transcripts in both the early and late stages of carcinogenesis. The identification of the transcripts and pathways that change at an early stage of carcinogenesis provides potentially useful information for early diagnosis and for prevention strategies for human tongue squamous cell carcinomas.

  12. A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis

    PubMed Central

    Skov, Vibe; Burton, Mark; Thomassen, Mads; Stauffer Larsen, Thomas; Riley, Caroline H.; Brinch Madelung, Ann; Kjær, Lasse; Bondo, Henrik; Stamp, Inger; Ehinger, Mats; Dahl-Sørensen, Rasmus; Brochmann, Nana; Nielsen, Karsten; Thiele, Jürgen; Jensen, Morten K.; Weis Bjerrum, Ole; Kruse, Torben A.; Hasselbalch, Hans Carl

    2016-01-01

    Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of “ET” patients. PMID:27579896

  13. A Signature Style

    ERIC Educational Resources Information Center

    Smiles, Robin V.

    2005-01-01

    This article discusses Dr. Amalia Amaki and her approach to art as her signature style by turning everyday items into fine art. Amaki is an assistant professor of art, art history, and Black American studies at the University of Delaware. She loves taking unexpected an object and redefining it in the context of art--like a button, a fan, a faded…

  14. Diagnosing Musculoskeletal Tumours

    PubMed Central

    Carter, Simon R.; Spooner, David; Sneath, Rodney S.

    2001-01-01

    In 1993 we became aware of a worrying increase in apparent errors in the histopathological diagnosis of musculoskeletal tumours in our Unit. As a result all cases seen over the past 8 years were reviewed by an independent panel. Of the 1996 cases reviewed there was an error in 87. In 54 cases (2.7%) this had led to some significant change in the active management of the patient. The main areas where errors arose were in those very cases where clinical and radiological features were not helpful in confirming or refuting the diagnosis. The incidence of errors rose with the passage of time, possibly related to a deterioration in the pathologist’s health. The error rate in diagnosing bone tumours in previously published series ranges from 9 to 40%. To ensure as accurate a rate of diagnosis as possible multidisciplinary working and regular audit are essential. PMID:18521309

  15. Diagnosable structured logic array

    NASA Technical Reports Server (NTRS)

    Whitaker, Sterling (Inventor); Miles, Lowell (Inventor); Gambles, Jody (Inventor); Maki, Gary K. (Inventor)

    2009-01-01

    A diagnosable structured logic array and associated process is provided. A base cell structure is provided comprising a logic unit comprising a plurality of input nodes, a plurality of selection nodes, and an output node, a plurality of switches coupled to the selection nodes, where the switches comprises a plurality of input lines, a selection line and an output line, a memory cell coupled to the output node, and a test address bus and a program control bus coupled to the plurality of input lines and the selection line of the plurality of switches. A state on each of the plurality of input nodes is verifiably loaded and read from the memory cell. A trusted memory block is provided. The associated process is provided for testing and verifying a plurality of truth table inputs of the logic unit.

  16. The effects of extrinsic motivation on signature authorship opinions in forensic signature blind trials.

    PubMed

    Dewhurst, Tahnee N; Found, Bryan; Ballantyne, Kaye N; Rogers, Doug

    2014-03-01

    Expertise studies in forensic handwriting examination involve comparisons of Forensic Handwriting Examiners' (FHEs) opinions with lay-persons on blind tests. All published studies of this type have reported real and demonstrable skill differences between the specialist and lay groups. However, critics have proposed that any difference shown may be indicative of a lack of motivation on the part of lay participants, rather than a real difference in skill. It has been suggested that qualified FHEs would be inherently more motivated to succeed in blinded validation trials, as their professional reputations could be at risk, should they perform poorly on the task provided. Furthermore, critics suggest that lay-persons would be unlikely to be highly motivated to succeed, as they would have no fear of negative consequences should they perform badly. In an effort to investigate this concern, a blind signature trial was designed and administered to forty lay-persons. Participants were required to compare known (exemplar) signatures of an individual to questioned signatures and asked to express an opinion regarding whether the writer of the known signatures wrote each of the questioned signatures. The questioned signatures comprised a mixture of genuine, disguised and simulated signatures. The forty participants were divided into two separate groupings. Group 'A' were requested to complete the trial as directed and were advised that for each correct answer they would be financially rewarded, for each incorrect answer they would be financially penalized, and for each inconclusive opinion they would receive neither penalty nor reward. Group 'B' was requested to complete the trial as directed, with no mention of financial recompense or penalty. The results of this study do not support the proposition that motivation rather than skill difference is the source of the statistical difference in opinions between individuals' results in blinded signature proficiency trials.

  17. Diagnosing mucopolysaccharidosis IVA.

    PubMed

    Wood, Timothy C; Harvey, Katie; Beck, Michael; Burin, Maira Graeff; Chien, Yin-Hsiu; Church, Heather J; D'Almeida, Vânia; van Diggelen, Otto P; Fietz, Michael; Giugliani, Roberto; Harmatz, Paul; Hawley, Sara M; Hwu, Wuh-Liang; Ketteridge, David; Lukacs, Zoltan; Miller, Nicole; Pasquali, Marzia; Schenone, Andrea; Thompson, Jerry N; Tylee, Karen; Yu, Chunli; Hendriksz, Christian J

    2013-03-01

    Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.

  18. Diagnosing oceanic nutrient deficiency

    NASA Astrophysics Data System (ADS)

    Moore, C. Mark

    2016-11-01

    The supply of a range of nutrient elements to surface waters is an important driver of oceanic production and the subsequent linked cycling of the nutrients and carbon. Relative deficiencies of different nutrients with respect to biological requirements, within both surface and internal water masses, can be both a key indicator and driver of the potential for these nutrients to become limiting for the production of new organic material in the upper ocean. The availability of high-quality, full-depth and global-scale datasets on the concentrations of a wide range of both macro- and micro-nutrients produced through the international GEOTRACES programme provides the potential for estimation of multi-element deficiencies at unprecedented scales. Resultant coherent large-scale patterns in diagnosed deficiency can be linked to the interacting physical-chemical-biological processes which drive upper ocean nutrient biogeochemistry. Calculations of ranked deficiencies across multiple elements further highlight important remaining uncertainties in the stoichiometric plasticity of nutrient ratios within oceanic microbial systems and caveats with regards to linkages to upper ocean nutrient limitation. This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

  19. Diagnosing pulmonary embolism

    PubMed Central

    Riedel, M

    2004-01-01

    Objective testing for pulmonary embolism is necessary, because clinical assessment alone is unreliable and the consequences of misdiagnosis are serious. No single test has ideal properties (100% sensitivity and specificity, no risk, low cost). Pulmonary angiography is regarded as the final arbiter but is ill suited for diagnosing a disease present in only a third of patients in whom it is suspected. Some tests are good for confirmation and some for exclusion of embolism; others are able to do both but are often non-diagnostic. For optimal efficiency, choice of the initial test should be guided by clinical assessment of the likelihood of embolism and by patient characteristics that may influence test accuracy. Standardised clinical estimates can be used to give a pre-test probability to assess, after appropriate objective testing, the post-test probability of embolism. Multidetector computed tomography can replace both scintigraphy and angiography for the exclusion and diagnosis of this disease and should now be considered the central imaging investigation in suspected pulmonary embolism. PMID:15192162

  20. Wake Signature Detection

    NASA Astrophysics Data System (ADS)

    Spedding, Geoffrey R.

    2014-01-01

    An accumulated body of quantitative evidence shows that bluff-body wakes in stably stratified environments have an unusual degree of coherence and organization, so characteristic geometries such as arrays of alternating-signed vortices have very long lifetimes, as measured in units of buoyancy timescales, or in the downstream distance scaled by a body length. The combination of pattern geometry and persistence renders the detection of these wakes possible in principle. It now appears that identifiable signatures can be found from many disparate sources: Islands, fish, and plankton all have been noted to generate features that can be detected by climate modelers, hopeful navigators in open oceans, or hungry predators. The various types of wakes are reviewed with notes on why their signatures are important and to whom. A general theory of wake pattern formation is lacking and would have to span many orders of magnitude in Reynolds number.

  1. SMAWT Signature Test

    DTIC Science & Technology

    1974-10-01

    were generally inversely proportional to the size assesments of the flash and smoke . Table 26 shows the percent of change in average judgments of...Average Time of Gunner’s View Obscuration by Smoke During Firings From the Wood Line .. .. ..... ..... ...... ..... .. 18 7. Average Obscuration Times...of Gunner’s View Obscuration by Smoke - Grass Line 19 8. Normalized Comparisons of the Relative Grades Assigned to Systems Signature Components

  2. Knowledge Signatures for Information Integration

    SciTech Connect

    Thomson, Judi; Cowell, Andrew J.; Paulson, Patrick R.; Butner, R. Scott; Whiting, Mark A.

    2003-10-25

    This paper introduces the notion of a knowledge signature: a concise, ontologically-driven representation of the semantic characteristics of data. Knowledge signatures provide programmatic access to data semantics while allowing comparisons to be made across different types of data such as text, images or video, enabling efficient, automated information integration. Through observation, which determines the degree of association between data and ontological concepts, and refinement, which uses the axioms and structure of the domain ontology to place the signature more accurately within the context of the domain, knowledge signatures can be created. A comparison of such signatures for two different pieces of data results in a measure of their semantic separation. This paper discusses the definition of knowledge signatures along with the design and prototype implementation of a knowledge signature generator.

  3. Diagnosable systems for intermittent faults

    NASA Technical Reports Server (NTRS)

    Mallela, S.; Masson, G. M.

    1978-01-01

    The fault diagnosis capabilities of systems composed of interconnected units capable of testing each other are studied for the case of systems with intermittent faults. A central role is played by the concept of t(i)-fault diagnosability. A system is said to be t(i)-fault diagnosable when it is such that if no more than t(i) units are intermittently faulty then a fault-free unit will never be diagnosed as faulty and the diagnosis at any time is at worst incomplete. Necessary and sufficient conditions for t(i)-fault diagnosability are proved, and bounds for t(i) are established. The conditions are in general more restrictive than those for permanent-fault diagnosability. For intermittent faults there is only one testing strategy (repetitive testing), and consequently only one type of intermittent-fault diagnosable system.

  4. Transcriptome analysis and molecular signature of human retinal pigment epithelium

    PubMed Central

    Strunnikova, N.V.; Maminishkis, A.; Barb, J.J.; Wang, F.; Zhi, C.; Sergeev, Y.; Chen, W.; Edwards, A.O.; Stambolian, D.; Abecasis, G.; Swaroop, A.; Munson, P.J.; Miller, S.S.

    2010-01-01

    Retinal pigment epithelium (RPE) is a polarized cell layer critical for photoreceptor function and survival. The unique physiology and relationship to the photoreceptors make the RPE a critical determinant of human vision. Therefore, we performed a global expression profiling of native and cultured human fetal and adult RPE and determined a set of highly expressed ‘signature’ genes by comparing the observed RPE gene profiles to the Novartis expression database (SymAtlas: http://wombat.gnf.org/index.html) of 78 tissues. Using stringent selection criteria of at least 10-fold higher expression in three distinct preparations, we identified 154 RPE signature genes, which were validated by qRT-PCR analysis in RPE and in an independent set of 11 tissues. Several of the highly expressed signature genes encode proteins involved in visual cycle, melanogenesis and cell adhesion and Gene ontology analysis enabled the assignment of RPE signature genes to epithelial channels and transporters (ClCN4, BEST1, SLCA20) or matrix remodeling (TIMP3, COL8A2). Fifteen RPE signature genes were associated with known ophthalmic diseases, and 25 others were mapped to regions of disease loci. An evaluation of the RPE signature genes in a recently completed AMD genomewide association (GWA) data set revealed that TIMP3, GRAMD3, PITPNA and CHRNA3 signature genes may have potential roles in AMD pathogenesis and deserve further examination. We propose that RPE signature genes are excellent candidates for retinal diseases and for physiological investigations (e.g. dopachrome tautomerase in melanogenesis). The RPE signature gene set should allow the validation of RPE-like cells derived from human embryonic or induced pluripotent stem cells for cell-based therapies of degenerative retinal diseases. PMID:20360305

  5. The probative character of Forensic Handwriting Examiners' identification and elimination opinions on questioned signatures.

    PubMed

    Found, Bryan; Rogers, Doug

    2008-06-10

    This 5-year study investigated the character of Forensic Handwriting Examiners' (FHEs) authorship opinions on questioned signatures through the medium of blind validation trials. Twenty-nine thousand eight hundred and eleven authorship opinions were expressed by FHEs on trial kits comprising randomized questioned genuine signatures (written by the specimen writer), disguised signatures (written by the specimen writer) and simulated signatures (not written by the specimen writer). Results showed that, as a group, FHEs were significantly more confident at identifying writers' genuine signatures than identifying writers' disguised signatures or eliminating specimen writers from having authored simulated signatures. It is proposed that the difference in FHE confidence arises from the difficulty they have in deciding which alternative authorship explanation accounts for perceived combinations of similar and dissimilar features between specimen and questioned signatures.

  6. Signatures of nonthermal melting

    PubMed Central

    Zier, Tobias; Zijlstra, Eeuwe S.; Kalitsov, Alan; Theodonis, Ioannis; Garcia, Martin E.

    2015-01-01

    Intense ultrashort laser pulses can melt crystals in less than a picosecond but, in spite of over thirty years of active research, for many materials it is not known to what extent thermal and nonthermal microscopic processes cause this ultrafast phenomenon. Here, we perform ab-initio molecular-dynamics simulations of silicon on a laser-excited potential-energy surface, exclusively revealing nonthermal signatures of laser-induced melting. From our simulated atomic trajectories, we compute the decay of five structure factors and the time-dependent structure function. We demonstrate how these quantities provide criteria to distinguish predominantly nonthermal from thermal melting. PMID:26798822

  7. Signature CERN-URSS

    SciTech Connect

    2006-01-24

    Le DG W.Jentschke souhaite la bienvenue à l'assemblée et aux invités pour la signature du protocole entre le Cern et l'URSS qui est un événement important. C'est en 1955 que 55 visiteurs soviétiques ont visité le Cern pour la première fois. Le premier DG au Cern, F.Bloch, et Mons.Amaldi sont aussi présents. Tandis que le discours anglais de W.Jentschke est traduit en russe, le discours russe de Mons.Morozov est traduit en anglais.

  8. How Is Aplastic Anemia Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Aplastic Anemia Diagnosed? Your doctor will diagnose aplastic anemia based on your medical and family histories, a ... your primary care doctor thinks you have aplastic anemia, he or she may refer you to a ...

  9. Neuroblastoma in Children: Just Diagnosed Information

    MedlinePlus

    ... Other Press Room Employment Feedback Contact Select Page Neuroblastoma in Children – Just Diagnosed Home > Cancer Resources > Types ... Diagnosed Just Diagnosed In Treatment After Treatment Diagnosing Neuroblastoma Depending on the location of the tumor and ...

  10. Signatures of the Martian rotation parameters in the Doppler and range observables

    NASA Astrophysics Data System (ADS)

    Yseboodt, Marie; Dehant, Véronique; Péters, Marie-Julie; Folkner, William M.

    2016-10-01

    Because of Mars rotation, the position of a lander on Mars' surface is affected by different motions: the nutations, the precession, the length-of-day variations and the polar motion.We derive first-order expressions of the signature of these different rotation parameters in a Doppler observable between a lander and the Earth. These expressions are function of the diurnal rotation of Mars, the lander position (its latitude and its longitude), the planet radius and the amplitude of the rotation parameter. The nutation signature is proportional to the Earth declination with respect to Mars.For an equatorial lander, the largest signatures in the Doppler observable are for the length-of-day variations, precession rate and rigid nutations. The polar motion and the liquid core signature have a much smaller amplitude.All the signatures, with the exception of the polar motion, decrease as the lander gets closer to the pole, while the polar motion signature decreases if the lander is closer to the equator.Similarly, we also derive expressions for the signatures of the rotation parameters in the lander-Earth range observable.These expressions are useful in order to find when these signatures are maximal during one day or on a longer timescale, therefore to identify the times during a geodesy mission where the signatures can be maximized.Numerical values for these signatures are given for the future InSight and ExoMars landers.

  11. Twin signal signature sensing: Application to shorted winding monitoring, detection and localization

    SciTech Connect

    Streifel, R.J.; Marks, R.J.; El-Sharkawi, A.E.; Kerszenbaum, I.

    1995-12-31

    Using twin signal sensing we propose a method to monitor, detect and localize shorts in power system devices with windings: including rotors, transformers and motors. There has, to date, been no effective way to do so. The most obvious approach, time domain reflectometry, fails due to the reactive coupling of the windings. Twin signal signature sensing of shorts results from identical signals being simultaneously injected in both sides of the windings. The reflected signals are measured and the difference amplified to produce the signature signal. The signature signal characterizes the current state of the windings. When winding shorts are present, the electrical characteristics of the device will be different and thus the signature signal will also change. The changes in the signature signal can be monitored to detect shorted windings. While a device is in operation, the signature signals can be monitored and the development of winding shorts can be diagnosed through the process of novelty detection. After a device is cleaned or otherwise known to be functioning correctly (no winding shorts), signature signals can be collected which represent the healthy device. If a sufficient number of signals can be collected, the signal space representing healthy windings can be characterized. A detection surface can be placed around the healthy signature signals to provide a partition of the signal space into two regions: healthy and faulty. Any signature signal which is not within the healthy signature partition will indicate a faulted device.

  12. Advanced spectral signature discrimination algorithm

    NASA Astrophysics Data System (ADS)

    Chakravarty, Sumit; Cao, Wenjie; Samat, Alim

    2013-05-01

    This paper presents a novel approach to the task of hyperspectral signature analysis. Hyperspectral signature analysis has been studied a lot in literature and there has been a lot of different algorithms developed which endeavors to discriminate between hyperspectral signatures. There are many approaches for performing the task of hyperspectral signature analysis. Binary coding approaches like SPAM and SFBC use basic statistical thresholding operations to binarize a signature which are then compared using Hamming distance. This framework has been extended to techniques like SDFC wherein a set of primate structures are used to characterize local variations in a signature together with the overall statistical measures like mean. As we see such structures harness only local variations and do not exploit any covariation of spectrally distinct parts of the signature. The approach of this research is to harvest such information by the use of a technique similar to circular convolution. In the approach we consider the signature as cyclic by appending the two ends of it. We then create two copies of the spectral signature. These three signatures can be placed next to each other like the rotating discs of a combination lock. We then find local structures at different circular shifts between the three cyclic spectral signatures. Texture features like in SDFC can be used to study the local structural variation for each circular shift. We can then create different measure by creating histogram from the shifts and thereafter using different techniques for information extraction from the histograms. Depending on the technique used different variant of the proposed algorithm are obtained. Experiments using the proposed technique show the viability of the proposed methods and their performances as compared to current binary signature coding techniques.

  13. Multimodal signature modeling of humans

    NASA Astrophysics Data System (ADS)

    Cathcart, J. Michael; Kocher, Brian; Prussing, Keith; Lane, Sarah; Thomas, Alan

    2010-04-01

    Georgia Tech been investigating method for the detection of covert personnel in traditionally difficult environments (e.g., urban, caves). This program focuses on a detailed phenomenological analysis of human physiology and signatures with the subsequent identification and characterization of potential observables. Both aspects are needed to support the development of personnel detection and tracking algorithms. The difficult nature of these personnel-related problems dictates a multimodal sensing approach. Human signature data of sufficient and accurate quality and quantity do not exist, thus the development of an accurate signature model for a human is needed. This model should also simulate various human activities to allow motion-based observables to be exploited. This paper will describe a multimodal signature modeling approach that incorporates human physiological aspects, thermoregulation, and dynamics into the signature calculation. This approach permits both passive and active signatures to be modeled. The focus of the current effort involved the computation of signatures in urban environments. This paper will discuss the development of a human motion model for use in simulating both electro-optical signatures and radar-based signatures. Video sequences of humans in a simulated urban environment will also be presented; results using these sequences for personnel tracking will be presented.

  14. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.

    PubMed

    Hu, Shimin; Xu-Monette, Zijun Y; Tzankov, Alexander; Green, Tina; Wu, Lin; Balasubramanyam, Aarthi; Liu, Wei-min; Visco, Carlo; Li, Yong; Miranda, Roberto N; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Choi, William W L; Zhao, Xiaoying; van Krieken, J Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Zhou, Fan; Slack, Graham W; Gascoyne, Randy D; Tu, Meifeng; Variakojis, Daina; Chen, Weina; Go, Ronald S; Piris, Miguel A; Møller, Michael B; Medeiros, L Jeffrey; Young, Ken H

    2013-05-16

    Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

  15. Signature CERN-URSS

    ScienceCinema

    None

    2016-07-12

    Le DG W.Jentschke souhaite la bienvenue à l'assemblée et aux invités pour la signature du protocole entre le Cern et l'URSS qui est un événement important. C'est en 1955 que 55 visiteurs soviétiques ont visité le Cern pour la première fois. Le premier DG au Cern, F.Bloch, et Mons.Amaldi sont aussi présents. Tandis que le discours anglais de W.Jentschke est traduit en russe, le discours russe de Mons.Morozov est traduit en anglais.

  16. Signatures of aging revisited

    SciTech Connect

    Drell, S.; Jeanloz, R.; Cornwall, J.; Dyson, F.; Eardley, D.

    1998-03-18

    This study is a follow-on to the review made by JASON during its 1997 Summer Study of what is known about the aging of critical constituents, particularly the high explosives, metals (Pu, U), and polymers in the enduring stockpile. The JASON report (JSR-97-320) that summarized the findings was based on briefings by the three weapons labs (LANL, LLNL, SNL). They presented excellent technical analyses covering a broad range of scientific and engineering problems pertaining to determining signatures of aging. But the report also noted: `Missing, however, from the briefings and the written documents made available to us by the labs and DOE, was evidence of an adequately sharp focus and high priorities on a number of essential near-term needs of maintaining weapons in the stockpile.

  17. Landsat Signature Development Program

    NASA Technical Reports Server (NTRS)

    Hall, R. N.; Mcguire, K. G.; Bland, R. A.

    1976-01-01

    The Landsat Signature Development Program, LSDP, is designed to produce an unsupervised classification of a scene from a Landsat tape. This classification is based on the clustering tendencies of the multispectral scanner data processed from the scene. The program will generate a character map that, by identifying each of the general classes of surface features extracted from the scene data with a specific line printer symbol, indicates the approximate locations and distributions of these general classes within the scene. Also provided with the character map are a number of tables each of which describes either some aspect of the spectral properties of the resultant classes, some inter-class relationship, the incidence of picture elements assigned to the various classes in the character map classification of the scene, or some significant intermediate stage in the development of the final classes.

  18. Multisensors signature prediction workbench

    NASA Astrophysics Data System (ADS)

    Latger, Jean; Cathala, Thierry

    2015-10-01

    Guidance of weapon systems relies on sensors to analyze targets signature. Defense weapon systems also need to detect then identify threats also using sensors. The sensors performance is very dependent on conditions e.g. time of day, atmospheric propagation, background ... Visible camera are very efficient for diurnal fine weather conditions, long wave infrared sensors for night vision, radar systems very efficient for seeing through atmosphere and/or foliage ... Besides, multi sensors systems, combining several collocated sensors with associated algorithms of fusion, provide better efficiency (typically for Enhanced Vision Systems). But these sophisticated systems are all the more difficult to conceive, assess and qualify. In that frame, multi sensors simulation is highly required. This paper focuses on multi sensors simulation tools. A first part makes a state of the Art of such simulation workbenches with a special focus on SE-Workbench. SEWorkbench is described with regards to infrared/EO sensors, millimeter waves sensors, active EO sensors and GNSS sensors. Then a general overview of simulation of targets and backgrounds signature objectives is presented, depending on the type of simulation required (parametric studies, open loop simulation, closed loop simulation, hybridization of SW simulation and HW ...). After the objective review, the paper presents some basic requirements for simulation implementation such as the deterministic behavior of simulation, mandatory to repeat it many times for parametric studies... Several technical topics are then discussed, such as the rendering technique (ray tracing vs. rasterization), the implementation (CPU vs. GP GPU) and the tradeoff between physical accuracy and performance of computation. Examples of results using SE-Workbench are showed and commented.

  19. Signatures of dark matter

    NASA Astrophysics Data System (ADS)

    Baltz, Edward Anthony

    It is well known that most of the mass in the universe remains unobserved save for its gravitational effect on luminous matter. The nature of this ``dark matter'' remains a mystery. From measurements of the primordial deuterium abundance, the theory of big bang nucleosynthesis predicts that there are not enough baryons to account for the amount of dark matter observed, thus the missing mass must take an exotic form. Several promising candidates have been proposed. In this work I will describe my research along two main lines of inquiry into the dark matter puzzle. The first possibility is that the dark matter is exotic massive particles, such as those predicted by supersymmetric extensions to the standard model of particle physics. Such particles are generically called WIMPs, for weakly interacting massive particles. Focusing on the so-called neutralino in supersymmetric models, I discuss the possible signatures of such particles, including their direct detection via nuclear recoil experiments and their indirect detection via annihilations in the halos of galaxies, producing high energy antiprotons, positrons and gamma rays. I also discuss signatures of the possible slow decays of such particles. The second possibility is that there is a population of black holes formed in the early universe. Any dark objects in galactic halos, black holes included, are called MACHOs, for massive compact halo objects. Such objects can be detected by their gravitational microlensing effects. Several possibilities for sources of baryonic dark matter are also interesting for gravitational microlensing. These include brown dwarf stars and old, cool white dwarf stars. I discuss the theory of gravitational microlensing, focusing on the technique of pixel microlensing. I make predictions for several planned microlensing experiments with ground based and space based telescopes. Furthermore, I discuss binary lenses in the context of pixel microlensing. Finally, I develop a new technique for

  20. Signatures of AGN feedback

    NASA Astrophysics Data System (ADS)

    Wylezalek, D.; Zakamska, N.

    2016-06-01

    Feedback from active galactic nuclei (AGN) is widely considered to be the main driver in regulating the growth of massive galaxies. It operates by either heating or driving the gas that would otherwise be available for star formation out of the galaxy, preventing further increase in stellar mass. Observational proof for this scenario has, however, been hard to come by. We have assembled a large sample of 133 radio-quiet type-2 and red AGN at 0.1signatures are hosted in galaxies that are more `quenched' considering their stellar mass than galaxies with weaker outflow signatures. This correlation is only seen in AGN host galaxies with SFR >100 M_{⊙} yr^{-1} where presumably the coupling of the AGN-driven wind to the gas is strongest. This observation is consistent with the AGN having a net suppression, or `negative' impact, through feedback on the galaxies' star formation history.

  1. How Is Stomach Cancer Diagnosed?

    MedlinePlus

    ... Cancer Early Detection, Diagnosis, and Staging How Is Stomach Cancer Diagnosed? Stomach cancers are usually found when ... Ask Your Doctor About Stomach Cancer? More In Stomach Cancer About Stomach Cancer Causes, Risk Factors, and ...

  2. How Is Childhood Leukemia Diagnosed?

    MedlinePlus

    ... Early Detection, Diagnosis, and Types How Is Childhood Leukemia Diagnosed? Most of the signs and symptoms of ... enlarged spleen or liver. Tests to look for leukemia in children If the doctor thinks your child ...

  3. How Is Pulmonary Embolism Diagnosed?

    MedlinePlus

    ... Doctors can use computed tomography (to-MOG-rah-fee) scans, or CT scans, to look for blood ... Pulmonary Angiography Pulmonary angiography (an-jee-OG-rah-fee) is another test used to diagnose PE. This ...

  4. How Is Atrial Fibrillation Diagnosed?

    MedlinePlus

    ... event monitor for weeks or until symptoms occur. Stress Test Some heart problems are easier to diagnose ... heart is working hard and beating fast. During stress testing , you exercise to make your heart work ...

  5. How Are Wilms Tumors Diagnosed?

    MedlinePlus

    ... Tumor Early Detection, Diagnosis, and Staging How Are Wilms Tumors Diagnosed? Wilms tumors are usually found when a ... Your Child’s Doctor About Wilms Tumor? More In Wilms Tumor About Wilms Tumor Causes, Risk Factors, and Prevention ...

  6. Multiplexed detection of fungal nucleic acid signatures.

    PubMed

    Diaz, Mara R; Dunbar, Sherry A; Jacobson, James W

    2008-04-01

    Diagnoses of opportunistic mycotic infections constitute an increasing clinical problem. Conventional diagnostic tests are time consuming and lack specificity and sensitivity for accurate and timely prognoses. This unit provides a comprehensive description of a fungal detection method that combines nucleic acid signatures with flow cytometry. The multiplexed assay, which uses xMAP technology, consists of unique fluorescent microspheres covalently bound to species-specific fungal oligonucleotide probes. In the presence of the complementary target sequence, the probe hybridizes to its biotinylated target. Quantification of the reaction is based on the fluorescence signal of the reporter molecule that binds to the biotin moieties of the target. The assay can be expanded to include other microorganisms and has the capability to simultaneously test 100 different fungal probes per tube/well. The speed, flexibility in design, and high-throughput capability makes this assay an attractive diagnostic tool for fungal infections and other related maladies.

  7. Index of Spectrum Signature Data

    DTIC Science & Technology

    1985-05-01

    Frederick Research Corporation. Alexandria. VA 163 AN/APG-030 Radar Receiver Heasureaents Electromagnetic Coapatibilitv Analysis Center, US Navv Marine ... Electromagnetic Compatibility Characteristics of the W 86 Gun Fire Control Svstem. Naval HEapons Lab, Dahlgren, VA 501 Partial Spectrum Signature...ECAC-I-IO-(SS) DEPARTMENT OF DEFENSE Electromagnetic Compatibility Analysis Center Annapolis, Maryland 21402 INDEX OF SPECTRUM SIGNATURE DATA

  8. Cell short circuit, preshort signature

    NASA Technical Reports Server (NTRS)

    Lurie, C.

    1980-01-01

    Short-circuit events observed in ground test simulations of DSCS-3 battery in-orbit operations are analyzed. Voltage signatures appearing in the data preceding the short-circuit event are evaluated. The ground test simulation is briefly described along with performance during reconditioning discharges. Results suggest that a characteristic signature develops prior to a shorting event.

  9. Determination of minimal transcriptional signatures of compounds for target prediction

    PubMed Central

    2012-01-01

    The identification of molecular target and mechanism of action of compounds is a key hurdle in drug discovery. Multiplexed techniques for bead-based expression profiling allow the measurement of transcriptional signatures of compound-treated cells in high-throughput mode. Such profiles can be used to gain insight into compounds' mode of action and the protein targets they are modulating. Through the proxy of target prediction from such gene signatures we explored important aspects of the use of transcriptional profiles to capture biological variability of perturbed cellular assays. We found that signatures derived from expression data and signatures derived from biological interaction networks performed equally well, and we showed that gene signatures can be optimised using a genetic algorithm. Gene signatures of approximately 128 genes seemed to be most generic, capturing a maximum of the perturbation inflicted on cells through compound treatment. Moreover, we found evidence for oxidative phosphorylation to be one of the most general ways to capture compound perturbation. PMID:22574917

  10. Prognostic value of a 92-probe signature in breast cancer.

    PubMed

    Akter, Salima; Choi, Tae Gyu; Nguyen, Minh Nam; Matondo, Abel; Kim, Jin-Hwan; Jo, Yong Hwa; Jo, Ara; Shahid, Muhammad; Jun, Dae Young; Yoo, Ji Youn; Nguyen, Ngoc Ngo Yen; Seo, Seong-Wook; Ali, Liaquat; Lee, Ju-Seog; Yoon, Kyung-Sik; Choe, Wonchae; Kang, Insug; Ha, Joohun; Kim, Jayoung; Kim, Sung Soo

    2015-06-20

    Clinical applications of gene expression signatures in breast cancer prognosis still remain limited due to poor predictive strength of single training datasets and appropriate invariable platforms. We proposed a gene expression signature by reducing baseline differences and analyzing common probes among three recent Affymetrix U133 plus 2 microarray data sets. Using a newly developed supervised method, a 92-probe signature found in this study was associated with overall survival. It was robustly validated in four independent data sets and then repeated on three subgroups by incorporating 17 breast cancer microarray datasets. The signature was an independent predictor of patients' survival in univariate analysis [(HR) 1.927, 95% CI (1.237-3.002); p < 0.01] as well as multivariate analysis after adjustment of clinical variables [(HR) 7.125, 95% CI (2.462-20.618); p < 0.001]. Consistent predictive performance was found in different multivariate models in increased patient population (p = 0.002). The survival signature predicted a late metastatic feature through 5-year disease free survival (p = 0.006). We identified subtypes within the lymph node positive (p < 0.001) and ER positive (p = 0.01) patients that best reflected the invasive breast cancer biology. In conclusion using the Common Probe Approach, we present a novel prognostic signature as a predictor in breast cancer late recurrences.

  11. Compound signature detection on LINCS L1000 big data

    PubMed Central

    Liu, Chenglin; Su, Jing; Yang, Fei; Wei, Kun; Ma, Jinwen; Zhou, Xiaobo

    2015-01-01

    The Library of Integrated Network-based Cellular Signatures (LINCS) L1000 big data provide gene expression profiles induced by over 10,000 compounds, shRNAs, and kinase inhibitors using the L1000 platform. We developed csNMF, a systematic compound signature discovery pipeline covering from raw L1000 data processing to drug screening and mechanism generation. The csNMF pipeline demonstrated better performance than the original L1000 pipeline. The discovered compound signatures of breast cancer were consistent with the LINCS KINOMEscan data and were clinically relevant. The csNMF pipeline provided a novel and complete tool to expedite signature-based drug discovery leveraging the LINCS L1000 resources. PMID:25609570

  12. Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature.

    PubMed

    Tomioka, N; Oba, S; Ohira, M; Misra, A; Fridlyand, J; Ishii, S; Nakamura, Y; Isogai, E; Hirata, T; Yoshida, Y; Todo, S; Kaneko, Y; Albertson, D G; Pinkel, D; Feuerstein, B G; Nakagawara, A

    2008-01-17

    Human neuroblastoma remains enigmatic because it often shows spontaneous regression and aggressive growth. The prognosis of advanced stage of sporadic neuroblastomas is still poor. Here, we investigated whether genomic and molecular signatures could categorize new therapeutic risk groups in primary neuroblastomas. We conducted microarray-based comparative genomic hybridization (array-CGH) with a DNA chip carrying 2464 BAC clones to examine genomic aberrations of 236 neuroblastomas and used in-house cDNA microarrays for gene-expression profiling. Array-CGH demonstrated three major genomic groups of chromosomal aberrations: silent (GGS), partial gains and/or losses (GGP) and whole gains and/or losses (GGW), which well corresponded with the patterns of chromosome 17 abnormalities. They were further classified into subgroups with different outcomes. In 112 sporadic neuroblastomas, MYCN amplification was frequent in GGS (22%) and GGP (53%) and caused serious outcomes in patients. Sporadic tumors with a single copy of MYCN showed the 5-year cumulative survival rates of 89% in GGS, 53% in GGP and 85% in GGW. Molecular signatures also segregated patients into the favorable and unfavorable prognosis groups (P=0.001). Both univariate and multivariate analyses revealed that genomic and molecular signatures were mutually independent, powerful prognostic indicators. Thus, combined genomic and molecular signatures may categorize novel risk groups and confer new clues for allowing tailored or even individualized medicine to patients with neuroblastoma.

  13. Signatures of AGN feedback

    NASA Astrophysics Data System (ADS)

    Wylezalek, Dominika; Zakamska, Nadia L.; MaNGA-GMOS Team

    2017-01-01

    Feedback from actively accreting SMBHs (Active Galactic Nuclei, AGN) is now widely considered to be the main driver in regulating the growth of massive galaxies. Observational proof for this scenario has, however, been hard to come by. Many attempts at finding a conclusive observational proof that AGN may be able to quench star formation and regulate the host galaxies' growth have shown that this problem is highly complex.I will present results from several projects that focus on understanding the power, reach and impact of feedback processes exerted by AGN. I will describe recent efforts in our group of relating feedback signatures to the specific star formation rate in their host galaxies, where our results are consistent with the AGN having a `negative' impact through feedback on the galaxies' star formation history (Wylezalek+2016a,b). Furthermore, I will show that powerful AGN-driven winds can be easily hidden and not be apparent in the integrated spectrum of the galaxy. This implies that large IFU surveys, such as the SDSS-IV MaNGA survey, might uncover many previously unknown AGN and outflows that are potentially very relevant for understanding the role of AGN in galaxy evolution (Wylezalek+2016c)!

  14. Statistical clumped isotope signatures

    PubMed Central

    Röckmann, T.; Popa, M. E.; Krol, M. C.; Hofmann, M. E. G.

    2016-01-01

    High precision measurements of molecules containing more than one heavy isotope may provide novel constraints on element cycles in nature. These so-called clumped isotope signatures are reported relative to the random (stochastic) distribution of heavy isotopes over all available isotopocules of a molecule, which is the conventional reference. When multiple indistinguishable atoms of the same element are present in a molecule, this reference is calculated from the bulk (≈average) isotopic composition of the involved atoms. We show here that this referencing convention leads to apparent negative clumped isotope anomalies (anti-clumping) when the indistinguishable atoms originate from isotopically different populations. Such statistical clumped isotope anomalies must occur in any system where two or more indistinguishable atoms of the same element, but with different isotopic composition, combine in a molecule. The size of the anti-clumping signal is closely related to the difference of the initial isotope ratios of the indistinguishable atoms that have combined. Therefore, a measured statistical clumped isotope anomaly, relative to an expected (e.g. thermodynamical) clumped isotope composition, may allow assessment of the heterogeneity of the isotopic pools of atoms that are the substrate for formation of molecules. PMID:27535168

  15. Challenges in diagnosing hepatic encephalopathy.

    PubMed

    Weissenborn, K

    2015-02-01

    The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction.

  16. Thyroid hemangiomas diagnosed on sonography.

    PubMed

    Park, Sung Hee; Kim, Soo Jin; Jung, Hyun Kyung

    2014-04-01

    Primary thyroid hemangiomas are extremely rare, and only a few cases have been previously reported. Primary hemangiomas are developmental anomalies resulting from the inability of the angioblastic mesenchyme to form canals. Thyroid hemangiomas are generally considered difficult to diagnose preoperatively because of their low incidence and nonspecific imaging findings. Here we report 2 cases of thyroid hemangiomas that were diagnosed correctly on preoperative sonography. Our cases showed similar sonographic findings, such as well-circumscribed hypoechoic lesions with internal channel-like linear lines, and bloody content was aspirated during fine-needle aspirations. Our report shows that thyroid hemangiomas can be diagnosed correctly by sonography with or without confirmation of bloody content in the lesions by fine-needle aspiration.

  17. Diagnosing and Treating Hantavirus Pulmonary Syndrome (HPS)

    MedlinePlus

    ... CDC.gov . Hantavirus Share Compartir Diagnosing and Treating Hantavirus Pulmonary Syndrome (HPS) Diagnosing HPS Diagnosing HPS in ... of patients that develop HPS from New World Hantaviruses recover completely. No chronic infection has been detected ...

  18. Intrusion detection using secure signatures

    DOEpatents

    Nelson, Trent Darnel; Haile, Jedediah

    2014-09-30

    A method and device for intrusion detection using secure signatures comprising capturing network data. A search hash value, value employing at least one one-way function, is generated from the captured network data using a first hash function. The presence of a search hash value match in a secure signature table comprising search hash values and an encrypted rule is determined. After determining a search hash value match, a decryption key is generated from the captured network data using a second hash function, a hash function different form the first hash function. One or more of the encrypted rules of the secure signatures table having a hash value equal to the generated search hash value are then decrypted using the generated decryption key. The one or more decrypted secure signature rules are then processed for a match and one or more user notifications are deployed if a match is identified.

  19. Retail applications of signature verification

    NASA Astrophysics Data System (ADS)

    Zimmerman, Thomas G.; Russell, Gregory F.; Heilper, Andre; Smith, Barton A.; Hu, Jianying; Markman, Dmitry; Graham, Jon E.; Drews, Clemens

    2004-08-01

    The dramatic rise in identity theft, the ever pressing need to provide convenience in checkout services to attract and retain loyal customers, and the growing use of multi-function signature captures devices in the retail sector provides favorable conditions for the deployment of dynamic signature verification (DSV) in retail settings. We report on the development of a DSV system to meet the needs of the retail sector. We currently have a database of approximately 10,000 signatures collected from 600 subjects and forgers. Previous work at IBM on DSV has been merged and extended to achieve robust performance on pen position data available from commercial point of sale hardware, achieving equal error rates on skilled forgeries and authentic signatures of 1.5% to 4%.

  20. Ballastic signature identification systems study

    NASA Technical Reports Server (NTRS)

    Reich, A.; Hine, T. L.

    1976-01-01

    The results are described of an attempt to establish a uniform procedure for documenting (recording) expended bullet signatures as effortlessly as possible and to build a comprehensive library of these signatures in a form that will permit the automated comparison of a new suspect bullet with the prestored library. The ultimate objective is to achieve a standardized format that will permit nationwide interaction between police departments, crime laboratories, and other interested law enforcement agencies.

  1. Express

    Integrated Risk Information System (IRIS)

    Express ; CASRN 101200 - 48 - 0 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinogenic Effect

  2. How Is Fanconi Anemia Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Fanconi Anemia Diagnosed? People who have Fanconi anemia (FA) are born with the disorder. They may ... questions about: Any personal or family history of anemia Any surgeries you’ve had related to the ...

  3. System diagnosability using triplet assertion

    SciTech Connect

    Lombardi, F.

    1982-01-01

    A new technique for system diagnosability is presented. It is based on a triplet assertion strategy to overcome the asymmetric invalidation and the requirement of a central test controller. The basic characteristics of the triplet assertion are generalized to higher networks. The application of this technique to parallel processing is outlined. 24 references.

  4. Delineating transcriptional networks of prognostic gene signatures refines treatment recommendations for lymph node-negative breast cancer patients.

    PubMed

    Lanigan, Fiona; Brien, Gerard L; Fan, Yue; Madden, Stephen F; Jerman, Emilia; Maratha, Ashwini; Aloraifi, Fatima; Hokamp, Karsten; Dunne, Eiseart J; Lohan, Amanda J; Flanagan, Louise; Garbe, James C; Stampfer, Martha R; Fridberg, Marie; Jirstrom, Karin; Quinn, Cecily M; Loftus, Brendan; Gallagher, William M; Geraghty, James; Bracken, Adrian P

    2015-09-01

    The majority of women diagnosed with lymph node-negative breast cancer are unnecessarily treated with damaging chemotherapeutics after surgical resection. This highlights the importance of understanding and more accurately predicting patient prognosis. In the present study, we define the transcriptional networks regulating well-established prognostic gene expression signatures. We find that the same set of transcriptional regulators consistently lie upstream of both 'prognosis' and 'proliferation' gene signatures, suggesting that a central transcriptional network underpins a shared phenotype within these signatures. Strikingly, the master transcriptional regulators within this network predict recurrence risk for lymph node-negative breast cancer better than currently used multigene prognostic assays, particularly in estrogen receptor-positive patients. Simultaneous examination of p16(INK4A) expression, which predicts tumours that have bypassed cellular senescence, revealed that intermediate levels of p16(INK4A) correlate with an intact pRB pathway and improved survival. A combination of these master transcriptional regulators and p16(INK4A), termed the OncoMasTR score, stratifies tumours based on their proliferative and senescence capacity, facilitating a clearer delineation of lymph node-negative breast cancer patients at high risk of recurrence, and thus requiring chemotherapy. Furthermore, OncoMasTR accurately classifies over 60% of patients as 'low risk', an improvement on existing prognostic assays, which has the potential to reduce overtreatment in early-stage patients. Taken together, the present study provides new insights into the transcriptional regulation of cellular proliferation in breast cancer and provides an opportunity to enhance and streamline methods of predicting breast cancer prognosis.

  5. Quantum messages with signatures forgeable in arbitrated quantum signature schemes

    NASA Astrophysics Data System (ADS)

    Kim, Taewan; Choi, Jeong Woon; Jho, Nam-Su; Lee, Soojoon

    2015-02-01

    Even though a method to perfectly sign quantum messages has not been known, the arbitrated quantum signature scheme has been considered as one of the good candidates. However, its forgery problem has been an obstacle to the scheme becoming a successful method. In this paper, we consider one situation, which is slightly different from the forgery problem, that we use to check whether at least one quantum message with signature can be forged in a given scheme, although all the messages cannot be forged. If there are only a finite number of forgeable quantum messages in the scheme, then the scheme can be secured against the forgery attack by not sending forgeable quantum messages, and so our situation does not directly imply that we check whether the scheme is secure against the attack. However, if users run a given scheme without any consideration of forgeable quantum messages, then a sender might transmit such forgeable messages to a receiver and in such a case an attacker can forge the messages if the attacker knows them. Thus it is important and necessary to look into forgeable quantum messages. We show here that there always exists such a forgeable quantum message-signature pair for every known scheme with quantum encryption and rotation, and numerically show that there are no forgeable quantum message-signature pairs that exist in an arbitrated quantum signature scheme.

  6. Simulating realistic predator signatures in quantitative fatty acid signature analysis

    USGS Publications Warehouse

    Bromaghin, Jeffrey F.

    2015-01-01

    Diet estimation is an important field within quantitative ecology, providing critical insights into many aspects of ecology and community dynamics. Quantitative fatty acid signature analysis (QFASA) is a prominent method of diet estimation, particularly for marine mammal and bird species. Investigators using QFASA commonly use computer simulation to evaluate statistical characteristics of diet estimators for the populations they study. Similar computer simulations have been used to explore and compare the performance of different variations of the original QFASA diet estimator. In both cases, computer simulations involve bootstrap sampling prey signature data to construct pseudo-predator signatures with known properties. However, bootstrap sample sizes have been selected arbitrarily and pseudo-predator signatures therefore may not have realistic properties. I develop an algorithm to objectively establish bootstrap sample sizes that generates pseudo-predator signatures with realistic properties, thereby enhancing the utility of computer simulation for assessing QFASA estimator performance. The algorithm also appears to be computationally efficient, resulting in bootstrap sample sizes that are smaller than those commonly used. I illustrate the algorithm with an example using data from Chukchi Sea polar bears (Ursus maritimus) and their marine mammal prey. The concepts underlying the approach may have value in other areas of quantitative ecology in which bootstrap samples are post-processed prior to their use.

  7. Tamoxifen therapy benefit predictive signature coupled with prognostic signature of post-operative recurrent risk for early stage ER+ breast cancer.

    PubMed

    Cai, Hao; Li, Xiangyu; Li, Jing; Ao, Lu; Yan, Haidan; Tong, Mengsha; Guan, Qingzhou; Li, Mengyao; Guo, Zheng

    2015-12-29

    Two types of prognostic signatures for predicting recurrent risk of ER+ breast cancer patients have been developed: one type for patients accepting surgery only and another type for patients receiving post-operative tamoxifen therapy. However, the first type of signature cannot distinguish high-risk patients who cannot benefit from tamoxifen therapy, while the second type of signature cannot identify patients who will be at low risk of recurrence even if they accept surgery only. In this study, we proposed to develop two coupled signatures to solve these problems based on within-sample relative expression orderings (REOs) of gene pairs. Firstly, we identified a prognostic signature of post-operative recurrent risk using 544 samples of ER+ breast cancer patients accepting surgery only. Then, applying this drug-free signature to 840 samples of patients receiving post-operative tamoxifen therapy, we recognized 553 samples of patients who would have been at high risk of recurrence if they had accepted surgery only and used these samples to develop a tamoxifen therapy benefit predictive signature. The two coupled signatures were validated in independent data. The signatures developed in this study are robust against experimental batch effects and applicable at the individual levels, which can facilitate the clinical decision of tamoxifen therapy.

  8. Tamoxifen therapy benefit predictive signature coupled with prognostic signature of post-operative recurrent risk for early stage ER+ breast cancer

    PubMed Central

    Cai, Hao; Li, Xiangyu; Li, Jing; Ao, Lu; Yan, Haidan; Tong, Mengsha; Guan, Qingzhou; Li, Mengyao; Guo, Zheng

    2015-01-01

    Two types of prognostic signatures for predicting recurrent risk of ER+ breast cancer patients have been developed: one type for patients accepting surgery only and another type for patients receiving post-operative tamoxifen therapy. However, the first type of signature cannot distinguish high-risk patients who cannot benefit from tamoxifen therapy, while the second type of signature cannot identify patients who will be at low risk of recurrence even if they accept surgery only. In this study, we proposed to develop two coupled signatures to solve these problems based on within-sample relative expression orderings (REOs) of gene pairs. Firstly, we identified a prognostic signature of post-operative recurrent risk using 544 samples of ER+ breast cancer patients accepting surgery only. Then, applying this drug-free signature to 840 samples of patients receiving post-operative tamoxifen therapy, we recognized 553 samples of patients who would have been at high risk of recurrence if they had accepted surgery only and used these samples to develop a tamoxifen therapy benefit predictive signature. The two coupled signatures were validated in independent data. The signatures developed in this study are robust against experimental batch effects and applicable at the individual levels, which can facilitate the clinical decision of tamoxifen therapy. PMID:26527319

  9. Zhong TAA signature — EDRN Public Portal

    Cancer.gov

    The TAA signature is a diagnostic array of five markers capable of distinguishing patients with non-small cell lung cancer (NSCLC) from normal control subjects. The diagnostic array was developed by enriching and screening phage-expressed tumor-associated proteins, and using these in a fluorescent protein microarray to identify and measure multiple non-small cell lung cancer-associated antibodies and show how simultaneous measurements can be combined into a single diagnostic assay. Although the identity of the phage-expressed proteins is not critical for use in a diagnostic assay, the sequences were compared with the GenBank database to obtain possible identity. The five proteins in the final diagnostic array are GAGE7, BAC clone RP11-499F19, SEC15L2, PMS2P7 (PMS2L15), and EEF1A.

  10. Signature molecular descriptor : advanced applications.

    SciTech Connect

    Visco, Donald Patrick, Jr.

    2010-04-01

    In this work we report on the development of the Signature Molecular Descriptor (or Signature) for use in the solution of inverse design problems as well as in highthroughput screening applications. The ultimate goal of using Signature is to identify novel and non-intuitive chemical structures with optimal predicted properties for a given application. We demonstrate this in three studies: green solvent design, glucocorticoid receptor ligand design and the design of inhibitors for Factor XIa. In many areas of engineering, compounds are designed and/or modified in incremental ways which rely upon heuristics or institutional knowledge. Often multiple experiments are performed and the optimal compound is identified in this brute-force fashion. Perhaps a traditional chemical scaffold is identified and movement of a substituent group around a ring constitutes the whole of the design process. Also notably, a chemical being evaluated in one area might demonstrate properties very attractive in another area and serendipity was the mechanism for solution. In contrast to such approaches, computer-aided molecular design (CAMD) looks to encompass both experimental and heuristic-based knowledge into a strategy that will design a molecule on a computer to meet a given target. Depending on the algorithm employed, the molecule which is designed might be quite novel (re: no CAS registration number) and/or non-intuitive relative to what is known about the problem at hand. While CAMD is a fairly recent strategy (dating to the early 1980s), it contains a variety of bottlenecks and limitations which have prevented the technique from garnering more attention in the academic, governmental and industrial institutions. A main reason for this is how the molecules are described in the computer. This step can control how models are developed for the properties of interest on a given problem as well as how to go from an output of the algorithm to an actual chemical structure. This report

  11. Beam-beam deflection and signature curves for elliptic beams

    SciTech Connect

    Ziemann, V.

    1990-10-22

    In this note we will present closed expressions for the beam-beam deflection angle for arbitrary elliptic beams including tilt. From these expressions signature curves, i.e., systematic deviations from the round beam deflection curve due to ellipticity or tilt are derived. In the course of the presentation we will prove that it is generally impossible to infer individual beam sizes from beam-beam deflection scans. 3 refs., 2 figs.

  12. Proteomic Signatures of Thymomas

    PubMed Central

    Shilo, Konstantin; Hitchcock, Charles L.; Freitas, Michael A.

    2016-01-01

    Based on the histological features and outcome, the current WHO classification separates thymomas into A, AB, B1, B2 and B3 subtypes. It is hypothesized that the type A thymomas are derived from the thymic medulla while the type B thymomas are derived from the cortex. Due to occasional histological overlap between the tumor subtypes creating difficulties in their separation, the aim of this study was to provide their proteomic characterization and identify potential immunohistochemical markers aiding in tissue diagnosis. Pair-wise comparison of neoplastic and normal thymus by liquid chromatography tandem mass spectrometry (LC-MS/MS) of formalin fixed paraffin embedded tissue revealed 61 proteins differentially expressed in thymomas compared to normal tissue. Hierarchical clustering showed distinct segregation of subtypes AB, B1 and B2 from that of A and B3. Most notably, desmoyokin, a protein that is encoded by the AHNAK gene, was associated with type A thymomas and medulla of normal thymus, by LC-MS/MS and immunohistochemistry. In this global proteomic characterization of the thymoma, several proteins unique to different thymic compartments and thymoma subtypes were identified. Among differentially expressed proteins, desmoyokin is a marker specific for thymic medulla and is potentially promising immunohistochemical marker in separation of type A and B3 thymomas. PMID:27832160

  13. Signature Visualization of Software Binaries

    SciTech Connect

    Panas, T

    2008-07-01

    In this paper we present work on the visualization of software binaries. In particular, we utilize ROSE, an open source compiler infrastructure, to pre-process software binaries, and we apply a landscape metaphor to visualize the signature of each binary (malware). We define the signature of a binary as a metric-based layout of the functions contained in the binary. In our initial experiment, we visualize the signatures of a series of computer worms that all originate from the same line. These visualizations are useful for a number of reasons. First, the images reveal how the archetype has evolved over a series of versions of one worm. Second, one can see the distinct changes between version. This allows the viewer to form conclusions about the development cycle of a particular worm.

  14. Graph Analytics for Signature Discovery

    SciTech Connect

    Hogan, Emilie A.; Johnson, John R.; Halappanavar, Mahantesh; Lo, Chaomei

    2013-06-01

    Within large amounts of seemingly unstructured data it can be diffcult to find signatures of events. In our work we transform unstructured data into a graph representation. By doing this we expose underlying structure in the data and can take advantage of existing graph analytics capabilities, as well as develop new capabilities. Currently we focus on applications in cybersecurity and communication domains. Within cybersecurity we aim to find signatures for perpetrators using the pass-the-hash attack, and in communications we look for emails or phone calls going up or down a chain of command. In both of these areas, and in many others, the signature we look for is a path with certain temporal properties. In this paper we discuss our methodology for finding these temporal paths within large graphs.

  15. Measurement of sniper infrared signatures

    NASA Astrophysics Data System (ADS)

    Kastek, M.; Dulski, R.; Trzaskawka, P.; Bieszczad, G.

    2009-09-01

    The paper presents some practical aspects of sniper IR signature measurements. Description of particular signatures for sniper and background in typical scenarios has been presented. We take into consideration sniper activities in open area as well as in urban environment. The measurements were made at field test ground. High precision laboratory measurements were also performed. Several infrared cameras were used during measurements to cover all measurement assumptions. Some of the cameras are measurement class devices with high accuracy and speed. The others are microbolometer cameras with FPA detector similar to those used in real commercial counter-sniper systems. The registration was made in SWIR and LWIR spectral bands simultaneously. An ultra fast visual camera was also used for visible spectra registration. Exemplary sniper IR signatures for typical situation were presented.

  16. Peripheral blood monocyte gene expression profile clinically stratifies patients with recent-onset type 1 diabetes.

    PubMed

    Irvine, Katharine M; Gallego, Patricia; An, Xiaoyu; Best, Shannon E; Thomas, Gethin; Wells, Christine; Harris, Mark; Cotterill, Andrew; Thomas, Ranjeny

    2012-05-01

    Novel biomarkers of disease progression after type 1 diabetes onset are needed. We profiled peripheral blood (PB) monocyte gene expression in six healthy subjects and 16 children with type 1 diabetes diagnosed ∼3 months previously and analyzed clinical features from diagnosis to 1 year. Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy control subjects, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose-adjusted HbA(1c) levels during the first year, compared with patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g., induction of HIF1A, DDIT3, DDIT4, and GRP78). Quantitative PCR (qPCR) of a 9-gene panel correlated with glycemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. A PB gene expression signature correlates with glycemic control in the first year after diabetes diagnosis and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and postonset and systemic stresses as contributors to innate immune function in type 1 diabetes.

  17. Spectral signatures of Earth's climate variability as observed from space and diagnosed from reanalyses

    NASA Astrophysics Data System (ADS)

    Brindley, Helen; Bantges, Richard; Russell, Jacqueline; Murray, Jonathan; Harries, John

    2015-04-01

    Measurements of the Earth's spectrally resolved outgoing longwave radiation have the intrinsic information content and link to the overall energy budget that implies that they are ideal candidates to monitor the climate and detect and attribute change. Theoretical studies have shown how distinct longwave spectral signals from different climate forcing and feedback mechanisms may be derived and appear to combine with a high degree of linearity. However, an open, important question which has not yet been fully addressed concerns the exact level of short-term variability seen in observed longwave spectra. We investigate this here by exploiting the emerging radiance record available from the Infrared Atmospheric Sounding Interferometer (IASI) on the Metop-A satellite. We use five years of IASI data to assess the level of interannual variability seen in all-sky spectra at different spatial scales. Maximum variability is seen at the smallest scales investigated (10° zonal means) at northern and southern high latitudes across the centre of the 15 μm CO2 band. As spatial scale increases, the overall magnitude of interannual variability reduces across the spectrum and the spectral shape of the variability changes. We show that the interannual variability manifested across the IASI spectra is less than 0.17 K in brightness temperature in the all-sky global annual mean, collapsing to a value of less than 0.05 K in the atmospheric window, a spectral region whose variability is dominated by fluctuations in surface and cloud properties. Spectrally integrating the IASI measurements to create pseudo broadband and window channels indicates a variation about the mean that is higher for the broadband than the window channel at the global and quasi-global scale and over the Southern Hemisphere. These findings are in agreement with observations from CERES Terra over the same period and imply that at the largest spatial scales, over the period considered here, fluctuations in mid-upper tropospheric temperatures and water vapour, and not cloud or surface temperature, play the dominant role in determining the level of interannual variability in all-sky outgoing longwave radiation. This pattern of behavior is not seen in spectra simulated using reanalysis fields that have been sub-sampled to match the Metop-A satellite track. Possible reasons for this discrepancy will be discussed in this paper.

  18. Textural signatures for wetland vegetation

    NASA Technical Reports Server (NTRS)

    Whitman, R. I.; Marcellus, K. L.

    1973-01-01

    This investigation indicates that unique textural signatures do exist for specific wetland communities at certain times in the growing season. When photographs with the proper resolution are obtained, the textural features can identify the spectral features of the vegetation community seen with lower resolution mapping data. The development of a matrix of optimum textural signatures is the goal of this research. Seasonal variations of spectral and textural features are particularly important when performing a vegetations analysis of fresh water marshes. This matrix will aid in flight planning, since expected seasonal variations and resolution requirements can be established prior to a given flight mission.

  19. Ballistic Signature Identification System Study

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The first phase of a research project directed toward development of a high speed automatic process to be used to match gun barrel signatures imparted to fired bullets was documented. An optical projection technique has been devised to produce and photograph a planar image of the entire signature, and the phototransparency produced is subjected to analysis using digital Fourier transform techniques. The success of this approach appears to be limited primarily by the accuracy of the photographic step since no significant processing limitations have been encountered.

  20. Diagnosability issues in multiprocessor systems

    SciTech Connect

    Raghavan, V.

    1989-01-01

    In a seminal paper on fault diagnosis, Preparata, Metze, and Chien introduced a graph-theoretical model. Barsi, Grandoni, and Maestrini relaxed some constraints in this model to create a different model for fault diagnosis. Both these models have become the subject of intense research in the past two decades. A major open problem for these models is the question of sequential t-diagnosability-Given an arbitrary system of units and that there are no more than t faulty units in it, can we always identify at least one faulty unit The author shows that this problem is co-NP complete in both models. Recent research has shown that there are polynomial time algorithms to find the maximum number of faulty units a system can withstand and still identify all of them from a single collection of test results. He presents improved algorithms to solve this problem in both models. Using the letters n,m, and {tau} to denote the number of units, the number of tests, and the maximum number of faulty units respectively, our results can be summarized as follows: in the model of Barsi, Grandoni, and Maestrini, the algorithm has a time complexity of O(n{tau}{sup 2}/log{tau}) improving on the currently known O(n{tau}{sup 2}); in the model of Preparata, Metze, and Chien, the algorithm has a complexity of O(n{tau}{sup 2.5}) improving on the currently known O(mn{sup 1.5}). He also presents related results in the latter model, which suggest the possibility of reducing the complexity even further. Finally, he develops a general scheme for characterizing diagnosable systems. Using this scheme, he solves the open problem of characterizing t/s and sequentially t-diagnosable systems. The characterizations are then used to rederive some known results.

  1. Improved method of signature extraction

    NASA Technical Reports Server (NTRS)

    Christianson, D.; Gordon, M.; Kistler, R.; Kriegler, F. J.; Lampert, S.; Marshall, R. E.; Mclaughlin, R.; Smith, V.

    1977-01-01

    System promises capability of rapidly processing large amounts of data generated by currently available and planned multispectral sensors, such as those utilized on aircraft and spacecraft. Techniques developed for system, greatly decrease operator time required for signature extraction from multispectral data base.

  2. Topological Signatures for Population Admixture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Topological Signatures for Population AdmixtureDeniz Yorukoglu1, Filippo Utro1, David Kuhn2, Saugata Basu3 and Laxmi Parida1* Abstract Background: As populations with multi-linear transmission (i.e., mixing of genetic material from two parents, say) evolve over generations, the genetic transmission...

  3. MK 66 Rocket Signature Reduction

    DTIC Science & Technology

    1982-04-01

    Indian Head, Maryland. ’The objec- tive of the study was to reduce the visible signature of the rocket motor. The rocket motor used for demonstration tests...15 6. Actual Emmiissions . . . . . . ........... . 16 7. Human Eye Adjusted Emmissions ..................... .. 16 8. Cross...altered. Additives are commonly used in gun propellants for elimination of muzzle flash. Their use in tactical rockets has been very limited, and

  4. Disaster relief through composite signatures

    NASA Astrophysics Data System (ADS)

    Hawley, Chadwick T.; Hyde, Brian; Carpenter, Tom; Nichols, Steve

    2012-06-01

    A composite signature is a group of signatures that are related in such a way to more completely or further define a target or operational endeavor at a higher fidelity. This paper builds on previous work developing innovative composite signatures associated with civil disasters, including physical, chemical and pattern/behavioral. For the composite signature approach to be successful it requires effective data fusion and visualization. This plays a key role in both preparedness and the response and recovery which are critical to saving lives. Visualization tools enhance the overall understanding of the crisis by pulling together and analyzing the data, and providing a clear and complete analysis of the information to the organizations/agencies dependant on it for a successful operation. An example of this, Freedom Web, is an easy-to-use data visualization and collaboration solution for use in homeland security, emergency preparedness, situational awareness, and event management. The solution provides a nationwide common operating picture for all levels of government through a web based, map interface. The tool was designed to be utilized by non-geospatial experts and is easily tailored to the specific needs of the users. Consisting of standard COTS and open source databases and a web server, users can view, edit, share, and highlight information easily and quickly through a standard internet browser.

  5. Connecting genes, coexpression modules, and molecular signatures to environmental stress phenotypes in plants

    PubMed Central

    Weston, David J; Gunter, Lee E; Rogers, Alistair; Wullschleger, Stan D

    2008-01-01

    Background One of the eminent opportunities afforded by modern genomic technologies is the potential to provide a mechanistic understanding of the processes by which genetic change translates to phenotypic variation and the resultant appearance of distinct physiological traits. Indeed much progress has been made in this area, particularly in biomedicine where functional genomic information can be used to determine the physiological state (e.g., diagnosis) and predict phenotypic outcome (e.g., patient survival). Ecology currently lacks an analogous approach where genomic information can be used to diagnose the presence of a given physiological state (e.g., stress response) and then predict likely phenotypic outcomes (e.g., stress duration and tolerance, fitness). Results Here, we demonstrate that a compendium of genomic signatures can be used to classify the plant abiotic stress phenotype in Arabidopsis according to the architecture of the transcriptome, and then be linked with gene coexpression network analysis to determine the underlying genes governing the phenotypic response. Using this approach, we confirm the existence of known stress responsive pathways and marker genes, report a common abiotic stress responsive transcriptome and relate phenotypic classification to stress duration. Conclusion Linking genomic signatures to gene coexpression analysis provides a unique method of relating an observed plant phenotype to changes in gene expression that underlie that phenotype. Such information is critical to current and future investigations in plant biology and, in particular, to evolutionary ecology, where a mechanistic understanding of adaptive physiological responses to abiotic stress can provide researchers with a tool of great predictive value in understanding species and population level adaptation to climate change. PMID:18248680

  6. How Is Acute Lymphocytic Leukemia Diagnosed?

    MedlinePlus

    ... Adults Early Detection, Diagnosis, and Types How Is Acute Lymphocytic Leukemia Diagnosed? Certain signs and symptoms can suggest that ... described below. Tests used to diagnose and classify ALL If your doctor thinks you have leukemia, he ...

  7. How Is Heart Valve Disease Diagnosed?

    MedlinePlus

    ... page from the NHLBI on Twitter. How Is Heart Valve Disease Diagnosed? Your primary care doctor may detect a heart murmur or other signs of heart valve disease. However, a cardiologist usually will diagnose the condition. ...

  8. How Is Deep Vein Thrombosis Diagnosed?

    MedlinePlus

    ... Vein Thrombosis Diagnosed? Your doctor will diagnose deep vein thrombosis (DVT) based on your medical history, a physical exam, and test results. He or she will identify your risk factors and rule out other causes of your symptoms. ...

  9. How Is a Heart Attack Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is a Heart Attack Diagnosed? Your doctor will diagnose a heart attack ... This Content: NEXT >> Featured Video What is a heart attack? 05/22/2014 Describes how a heart attack ...

  10. How Are Obesity and Overweight Diagnosed?

    MedlinePlus

    ... Information Clinical Trials Resources and Publications How are obesity & overweight diagnosed? Skip sharing on social media links ... and Blood Institute. (2012). How are overweight and obesity diagnosed? Retrieved August 8, 2012, from http://www. ...

  11. Testing the generalizability of the ISO model for nursing diagnoses.

    PubMed

    Harris, Marcelline; Kim, Hyeoneui; Rhudy, Lori; Savova, Guergana; Chute, Christopher

    2003-01-01

    The purpose of this study was to explore whether the ISO reference terminology model for nursing diagnoses could be generalized to the MDS data set that, like nursing terminologies standardizes expressions of the concepts within and relevant to the domain of nursing practice. We first constructed paraphrased expressions of the rubrics from the data set. Next we dissected those expressions into the reference model domains of focus and judgment, recorded any qualifiers required for either domain, and semantic links required to represent associative relations. Our findings demonstrate that the ISO model for nursing diagnoses is generalizable to the MDS data set, however expansions to the model are required if the model is to be used to represent objects rather than terms.

  12. Block truncation signature coding for hyperspectral analysis

    NASA Astrophysics Data System (ADS)

    Chakravarty, Sumit; Chang, Chein-I.

    2008-08-01

    This paper introduces a new signature coding which is designed based on the well-known Block Truncation Coding (BTC). It comprises of bit-maps of the signature blocks generated by different threshold criteria. Two new BTC-based algorithms are developed for signature coding, to be called Block Truncation Signature Coding (BTSC) and 2-level BTSC (2BTSC). In order to compare the developed BTC based algorithms with current binary signature coding schemes such as Spectral Program Analysis Manager (SPAM) developed by Mazer et al. and Spectral Feature-based Binary Coding (SFBC) by Qian et al., three different thresholding functions, local block mean, local block gradient, local block correlation are derived to improve the BTSC performance where the combined bit-maps generated by these thresholds can provide better spectral signature characterization. Experimental results reveal that the new BTC-based signature coding performs more effectively in characterizing spectral variations than currently available binary signature coding methods.

  13. Epigenetic signatures of invasive status in populations of marine invertebrates

    PubMed Central

    Ardura, Alba; Zaiko, Anastasija; Morán, Paloma; Planes, Serge; Garcia-Vazquez, Eva

    2017-01-01

    Epigenetics, as a DNA signature that affects gene expression and enables rapid reaction of an organism to environmental changes, is likely involved in the process of biological invasions. DNA methylation is an epigenetic mechanism common to plants and animals for regulating gene expression. In this study we show, for the first time in any marine species, significant reduction of global methylation levels during the expansive phase of a pygmy mussel (Xenostrobus securis) recent invasion in Europe (two-year old), while in older introductions such epigenetic signature of invasion was progressively reduced. Decreased methylation was interpreted as a rapid way of increasing phenotypic plasticity that would help invasive populations to thrive. This epigenetic signature of early invasion was stronger than the expected environmental signature of environmental stress in younger populations sampled from ports, otherwise detected in a much older population (>90 year old) of the also invasive tubeworm Ficopomatus enigmaticus established in similar locations. Higher epigenetic than genetic diversity found in X. securis was confirmed from F. enigmaticus samples. As reported for introduced plants and vertebrates, epigenetic variation could compensate for relatively lower genetic variation caused by founder effects. These phenomena were compared with epigenetic mechanisms involved in metastasis, as parallel processes of community (biological invasion) and organism (cancer) invasions. PMID:28205577

  14. Epigenetic signatures of invasive status in populations of marine invertebrates

    NASA Astrophysics Data System (ADS)

    Ardura, Alba; Zaiko, Anastasija; Morán, Paloma; Planes, Serge; Garcia-Vazquez, Eva

    2017-02-01

    Epigenetics, as a DNA signature that affects gene expression and enables rapid reaction of an organism to environmental changes, is likely involved in the process of biological invasions. DNA methylation is an epigenetic mechanism common to plants and animals for regulating gene expression. In this study we show, for the first time in any marine species, significant reduction of global methylation levels during the expansive phase of a pygmy mussel (Xenostrobus securis) recent invasion in Europe (two-year old), while in older introductions such epigenetic signature of invasion was progressively reduced. Decreased methylation was interpreted as a rapid way of increasing phenotypic plasticity that would help invasive populations to thrive. This epigenetic signature of early invasion was stronger than the expected environmental signature of environmental stress in younger populations sampled from ports, otherwise detected in a much older population (>90 year old) of the also invasive tubeworm Ficopomatus enigmaticus established in similar locations. Higher epigenetic than genetic diversity found in X. securis was confirmed from F. enigmaticus samples. As reported for introduced plants and vertebrates, epigenetic variation could compensate for relatively lower genetic variation caused by founder effects. These phenomena were compared with epigenetic mechanisms involved in metastasis, as parallel processes of community (biological invasion) and organism (cancer) invasions.

  15. Partially Blind Signatures Based on Quantum Cryptography

    NASA Astrophysics Data System (ADS)

    Cai, Xiao-Qiu; Niu, Hui-Fang

    2012-12-01

    In a partially blind signature scheme, the signer explicitly includes pre-agreed common information in the blind signature, which can improve the availability and performance. We present a new partially blind signature scheme based on fundamental properties of quantum mechanics. In addition, we analyze the security of this scheme, and show it is not possible to forge valid partially blind signatures. Moreover, the comparisons between this scheme and those based on public-key cryptography are also discussed.

  16. Methods of diagnosing alagille syndrome

    DOEpatents

    Li, Linheng; Hood, Leroy; Krantz, Ian D.; Spinner, Nancy B.

    2004-03-09

    The present invention provides an isolated polypeptide exhibiting substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the polypeptide does not have the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. The invention further provides an isolated nucleic acid molecule containing a nucleotide sequence encoding substantially the same amino acid sequence as JAGGED, or an active fragment thereof, provided that the nucleotide sequence does not encode the amino acid sequence of SEQ ID NO:5 or SEQ ID NO:6. Also provided herein is a method of inhibiting differentiation of hematopoietic progenitor cells by contacting the progenitor cells with an isolated JAGGED polypeptide, or active fragment thereof. The invention additionally provides a method of diagnosing Alagille Syndrome in an individual. The method consists of detecting an Alagille Syndrome disease-associated mutation linked to a JAGGED locus.

  17. 48 CFR 4.102 - Contractor's signature.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Contractor's signature. 4... ADMINISTRATIVE MATTERS Contract Execution 4.102 Contractor's signature. (a) Individuals. A contract with an... be signed by that individual, and the signature shall be followed by the individual's typed,...

  18. Identification of characteristic molecular signature for volatile organic compounds in peripheral blood of rat

    SciTech Connect

    Kim, Jeong Kyu; Jung, Kwang Hwa; Noh, Ji Heon; Eun, Jung Woo; Bae, Hyun Jin; Xie, Hong Jian; Jang, Ja-June; Ryu, Jae Chun; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

    2011-01-15

    In a previous report we demonstrated that the transcriptomic response of liver tissue was specific to toxicants, and a characteristic molecular signature could be used as an early prognostic biomarker in rats. It is necessary to determine the transcriptomic response to toxicants in peripheral blood for application to the human system. Volatile organic compounds (VOCs) comprise a major group of pollutants which significantly affect the chemistry of the atmosphere and human health. In this study we identified and validated the specific molecular signatures of toxicants in rat whole blood as early predictors of environmental toxicants. VOCs (dichloromethane, ethylbenzene, and trichloroethylene) were administered to 11-week-old SD male rats after 48 h of exposure, peripheral whole blood was subjected to expression profiling analysis. Unsupervised gene expression analysis resulted in a characteristic molecular signature for each toxicant, and supervised analysis identified 1,217 outlier genes as distinct molecular signatures discerning VOC exposure from healthy controls. Further analysis of multi-classification suggested 337 genes as early detective molecular markers for three VOCs with 100% accuracy. A large-scale gene expression analysis of a different VOC exposure animal model suggested that characteristic expression profiles exist in blood cells and multi-classification of this VOC-specific molecular signature can discriminate each toxicant at an early exposure time. This blood expression signature can thus be used as discernable surrogate marker for detection of biological responses to VOC exposure in an environment.

  19. Immune signatures of protective spleen memory CD8 T cells

    PubMed Central

    Brinza, Lilia; Djebali, Sophia; Tomkowiak, Martine; Mafille, Julien; Loiseau, Céline; Jouve, Pierre-Emmanuel; de Bernard, Simon; Buffat, Laurent; Lina, Bruno; Ottmann, Michèle; Rosa-Calatrava, Manuel; Schicklin, Stéphane; Bonnefoy, Nathalie; Lauvau, Grégoire; Grau, Morgan; Wencker, Mélanie; Arpin, Christophe; Walzer, Thierry; Leverrier, Yann; Marvel, Jacqueline

    2016-01-01

    Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy. PMID:27883012

  20. Metabolomics of Human Cerebrospinal Fluid Identifies Signatures of Malignant Glioma*

    PubMed Central

    Locasale, Jason W.; Melman, Tamar; Song, Susan; Yang, Xuemei; Swanson, Kenneth D.; Cantley, Lewis C.; Wong, Eric T.; Asara, John M.

    2012-01-01

    Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases. PMID:22240505

  1. Signatures of topological Josephson junctions

    NASA Astrophysics Data System (ADS)

    Peng, Yang; Pientka, Falko; Berg, Erez; Oreg, Yuval; von Oppen, Felix

    2016-08-01

    Quasiparticle poisoning and diabatic transitions may significantly narrow the window for the experimental observation of the 4 π -periodic dc Josephson effect predicted for topological Josephson junctions. Here, we show that switching-current measurements provide accessible and robust signatures for topological superconductivity which persist in the presence of quasiparticle poisoning processes. Such measurements provide access to the phase-dependent subgap spectrum and Josephson currents of the topological junction when incorporating it into an asymmetric SQUID together with a conventional Josephson junction with large critical current. We also argue that pump-probe experiments with multiple current pulses can be used to measure the quasiparticle poisoning rates of the topological junction. The proposed signatures are particularly robust, even in the presence of Zeeman fields and spin-orbit coupling, when focusing on short Josephson junctions. Finally, we also consider microwave excitations of short topological Josephson junctions which may complement switching-current measurements.

  2. Polarization signatures of airborne particulates

    NASA Astrophysics Data System (ADS)

    Raman, Prashant; Fuller, Kirk A.; Gregory, Don A.

    2013-07-01

    Exploratory research has been conducted with the aim of completely determining the polarization signatures of selected particulates as a function of wavelength. This may lead to a better understanding of the interaction between electromagnetic radiation and such materials, perhaps leading to the point detection of bio-aerosols present in the atmosphere. To this end, a polarimeter capable of measuring the complete Mueller matrix of highly scattering samples in transmission and reflection (with good spectral resolution from 300 to 1100 nm) has been developed. The polarization properties of Bacillus subtilis (surrogate for anthrax spore) are compared to ambient particulate matter species such as pollen, dust, and soot. Differentiating features in the polarization signatures of these samples have been identified, thus demonstrating the potential applicability of this technique for the detection of bio-aerosol in the ambient atmosphere.

  3. Signatures of a shadow biosphere.

    PubMed

    Davies, Paul C W; Benner, Steven A; Cleland, Carol E; Lineweaver, Charles H; McKay, Christopher P; Wolfe-Simon, Felisa

    2009-03-01

    Astrobiologists are aware that extraterrestrial life might differ from known life, and considerable thought has been given to possible signatures associated with weird forms of life on other planets. So far, however, very little attention has been paid to the possibility that our own planet might also host communities of weird life. If life arises readily in Earth-like conditions, as many astrobiologists contend, then it may well have formed many times on Earth itself, which raises the question whether one or more shadow biospheres have existed in the past or still exist today. In this paper, we discuss possible signatures of weird life and outline some simple strategies for seeking evidence of a shadow biosphere.

  4. Autophagy-related prognostic signature for breast cancer.

    PubMed

    Gu, Yunyan; Li, Pengfei; Peng, Fuduan; Zhang, Mengmeng; Zhang, Yuanyuan; Liang, Haihai; Zhao, Wenyuan; Qi, Lishuang; Wang, Hongwei; Wang, Chenguang; Guo, Zheng

    2016-03-01

    Autophagy is a process that degrades intracellular constituents, such as long-lived or damaged proteins and organelles, to buffer metabolic stress under starvation conditions. Deregulation of autophagy is involved in the progression of cancer. However, the predictive value of autophagy for breast cancer prognosis remains unclear. First, based on gene expression profiling, we found that autophagy genes were implicated in breast cancer. Then, using the Cox proportional hazard regression model, we detected autophagy prognostic signature for breast cancer in a training dataset. We identified a set of eight autophagy genes (BCL2, BIRC5, EIF4EBP1, ERO1L, FOS, GAPDH, ITPR1 and VEGFA) that were significantly associated with overall survival in breast cancer. The eight autophagy genes were assigned as a autophagy-related prognostic signature for breast cancer. Based on the autophagy-related signature, the training dataset GSE21653 could be classified into high-risk and low-risk subgroups with significantly different survival times (HR = 2.72, 95% CI = (1.91, 3.87); P = 1.37 × 10(-5)). Inactivation of autophagy was associated with shortened survival of breast cancer patients. The prognostic value of the autophagy-related signature was confirmed in the testing dataset GSE3494 (HR = 2.12, 95% CI = (1.48, 3.03); P = 1.65 × 10(-3)) and GSE7390 (HR = 1.76, 95% CI = (1.22, 2.54); P = 9.95 × 10(-4)). Further analysis revealed that the prognostic value of the autophagy signature was independent of known clinical prognostic factors, including age, tumor size, grade, estrogen receptor status, progesterone receptor status, ERBB2 status, lymph node status and TP53 mutation status. Finally, we demonstrated that the autophagy signature could also predict distant metastasis-free survival for breast cancer.

  5. Nonlinear analysis of dynamic signature

    NASA Astrophysics Data System (ADS)

    Rashidi, S.; Fallah, A.; Towhidkhah, F.

    2013-12-01

    Signature is a long trained motor skill resulting in well combination of segments like strokes and loops. It is a physical manifestation of complex motor processes. The problem, generally stated, is that how relative simplicity in behavior emerges from considerable complexity of perception-action system that produces behavior within an infinitely variable biomechanical and environmental context. To solve this problem, we present evidences which indicate that motor control dynamic in signing process is a chaotic process. This chaotic dynamic may explain a richer array of time series behavior in motor skill of signature. Nonlinear analysis is a powerful approach and suitable tool which seeks for characterizing dynamical systems through concepts such as fractal dimension and Lyapunov exponent. As a result, they can be analyzed in both horizontal and vertical for time series of position and velocity. We observed from the results that noninteger values for the correlation dimension indicates low dimensional deterministic dynamics. This result could be confirmed by using surrogate data tests. We have also used time series to calculate the largest Lyapunov exponent and obtain a positive value. These results constitute significant evidence that signature data are outcome of chaos in a nonlinear dynamical system of motor control.

  6. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia

    PubMed Central

    Vener, Tatiana I.; Raponi, Mitch; Ritchie, Ellen K.; Smith, B. Douglas; Gore, Steven D.; Morris, Lawrence E.; Feldman, Eric J.; Greer, Jacqueline M.; Malek, Sami; Carraway, Hetty E.; Ironside, Valerie; Galkin, Steven; Levis, Mark J.; McDevitt, Michael A.; Roboz, Gail R.; Gocke, Christopher D.; Derecho, Carlo; Palma, John; Wang, Yixin; Kaufmann, Scott H.; Wright, John J.; Garret-Mayer, Elizabeth

    2012-01-01

    Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771. PMID:22001391

  7. Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia.

    PubMed

    Karp, Judith E; Vener, Tatiana I; Raponi, Mitch; Ritchie, Ellen K; Smith, B Douglas; Gore, Steven D; Morris, Lawrence E; Feldman, Eric J; Greer, Jacqueline M; Malek, Sami; Carraway, Hetty E; Ironside, Valerie; Galkin, Steven; Levis, Mark J; McDevitt, Michael A; Roboz, Gail R; Gocke, Christopher D; Derecho, Carlo; Palma, John; Wang, Yixin; Kaufmann, Scott H; Wright, John J; Garret-Mayer, Elizabeth

    2012-01-05

    Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.

  8. [Differential diagnoses of West syndrome].

    PubMed

    Fejerman, Natalio

    2013-09-06

    This study describes the clinical and electroencephalographic characteristics of epileptic spasms, and more especially those that occur during the first two years of life (infantile spasms). West syndrome has been clearly defined as the association between infantile spasms with an electroencephalographic pattern of hypsarrhythmia. Although intellectual deficit appears in almost all cases in which infantile spasms are not controlled with medication, this is a developmental aspect of the condition and not a manifestation that must necessarily be present in order to define the syndrome. The analysis of the interictal and ictal electroencephalogram readings, together with the clinical characteristics of the spasms and the neurological examination of patients, provides some orientation as regards the causations. Despite the spectrum that the title of this work focuses on, the study does not cover the treatment of early infants with West syndrome. Emphasis is placed on the differential diagnoses of West syndrome with other epileptic syndromes that manifest in the first two years of life, and more especially with a series of abnormal non-epileptic motor phenomena that occur in early infants. All these last non-epileptic disorders are displayed in a table, but benign myoclonus of early infancy or Fejerman syndrome is given as a paradigmatic example for the differential diagnosis. The primordial aim is to prevent neurologically healthy early infants from receiving antiepileptic drugs and even adrenocorticotropic hormone or corticoids due to a mistaken diagnosis.

  9. [Left pulmonary agenesis diagnosed late].

    PubMed

    Deleanu, Oana; Pătraşcu, Natalia; Nebunoiu, Ana-Maria; Vintilă, V; Ulmeanu, Ruxandra; Mihălţan, F D

    2010-01-01

    We present the case of a 51 years old female-patient, with severe dextroscoliosis, having like unique symptom progressive dyspnea. The blood samples reveals polycythemia, the radiological exam shows the opacification of 2/3 of the left thorax, the absence of the lung structure in the other 1/3, the deviation of the mediastinum, and dextroscoliosis; the computed tomography reveals the absence of the left lung artery and the left airways, compensatory hyperinflation of the right lung and dilatation of the trunk and right pulmonary artery; the bronchoscopy does not visualize the carina or the left main bronchus, typical for pulmonary agenesis. Echocardiography confirmed the absence of left pulmonary artery and shows mild pulmonary hypertension (systolic pressure in the pulmonary artery of 33 mmHg) with dilatation of the right cavities, but good cinetics. We face a case of pulmonary agenesis lately diagnosed, with modest functional cardiologic implications, limited therapeutic options and good survival, justified by the late appearance of the pulmonary hypertension of low severity and without worsening in time.

  10. A gene transcription signature of obesity in breast cancer.

    PubMed

    Creighton, Chad J; Sada, Yvonne H; Zhang, Yiqun; Tsimelzon, Anna; Wong, Helen; Dave, Bhuvanesh; Landis, Melissa D; Bear, Harry D; Rodriguez, Angel; Chang, Jenny C

    2012-04-01

    Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of 103 tumors for which the patients' body mass index (BMI) was ascertained. Sample profiles were stratified according to patients' obesity phenotype defined as normal (BMI < 25), overweight (BMI 25-29.9), or obese (BMI ≥ 30). Widespread gene expression alterations were evident in breast tumors from obese patients as compared to other tumors, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. In multiple public expression data sets of breast cancers (representing > 1,500 patients), manifestation of the obesity signature patterns correlated with manifestation of a gene signature for IGF signaling and (to a lesser extent) with lower levels of estrogen receptor. In one patient cohort, manifestation of the obesity signature correlated with shorter time to metastases. A number of small molecules either induced or suppressed the obesity-associated transcriptional program in vitro; estrogens alpha-estradiol, levonorgestrel, and hexestrol induced the program, while several anti-parkinsonian agents targeting neurotransmitter receptor pathways repressed the program. Obesity in breast cancer patients appears to impact the gene expression patterns of the tumor (perhaps as a result of altered body chemistry). These results warrant further investigation of obesity-associated modifiers of breast cancer risk and disease outcome.

  11. Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment.

    PubMed

    Perl, Andras

    2010-02-01

    Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T and B cells in SLE. In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes, enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells. MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common T and B cell biomarkers and targets for treatment in SLE.

  12. Stromal-Based Signatures for the Classification of Gastric Cancer.

    PubMed

    Uhlik, Mark T; Liu, Jiangang; Falcon, Beverly L; Iyer, Seema; Stewart, Julie; Celikkaya, Hilal; O'Mahony, Marguerita; Sevinsky, Christopher; Lowes, Christina; Douglass, Larry; Jeffries, Cynthia; Bodenmiller, Diane; Chintharlapalli, Sudhakar; Fischl, Anthony; Gerald, Damien; Xue, Qi; Lee, Jee-Yun; Santamaria-Pang, Alberto; Al-Kofahi, Yousef; Sui, Yunxia; Desai, Keyur; Doman, Thompson; Aggarwal, Amit; Carter, Julia H; Pytowski, Bronislaw; Jaminet, Shou-Ching; Ginty, Fiona; Nasir, Aejaz; Nagy, Janice A; Dvorak, Harold F; Benjamin, Laura E

    2016-05-01

    Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.

  13. Development of Asset Fault Signatures for Prognostic and Health Management in the Nuclear Industry

    SciTech Connect

    Vivek Agarwal; Nancy J. Lybeck; Randall Bickford; Richard Rusaw

    2014-06-01

    Proactive online monitoring in the nuclear industry is being explored using the Electric Power Research Institute’s Fleet-Wide Prognostic and Health Management (FW-PHM) Suite software. The FW-PHM Suite is a set of web-based diagnostic and prognostic tools and databases that serves as an integrated health monitoring architecture. The FW-PHM Suite has four main modules: Diagnostic Advisor, Asset Fault Signature (AFS) Database, Remaining Useful Life Advisor, and Remaining Useful Life Database. This paper focuses on development of asset fault signatures to assess the health status of generator step-up generators and emergency diesel generators in nuclear power plants. Asset fault signatures describe the distinctive features based on technical examinations that can be used to detect a specific fault type. At the most basic level, fault signatures are comprised of an asset type, a fault type, and a set of one or more fault features (symptoms) that are indicative of the specified fault. The AFS Database is populated with asset fault signatures via a content development exercise that is based on the results of intensive technical research and on the knowledge and experience of technical experts. The developed fault signatures capture this knowledge and implement it in a standardized approach, thereby streamlining the diagnostic and prognostic process. This will support the automation of proactive online monitoring techniques in nuclear power plants to diagnose incipient faults, perform proactive maintenance, and estimate the remaining useful life of assets.

  14. Prognostic Value of microRNA Signature in Patients with Gastric Cancers

    PubMed Central

    Liu, Hai-Ting; Wang, Ya-Wen; Xing, Ai-Yan; Shi, Duan-Bo; Zhang, Hui-; Guo, Xiang-Yu; Xu, Jing-; Gao, Peng

    2017-01-01

    The occurrence of lymph node metastases (LNM) after endoscopic submucosal dissection (ESD) in patients with gastric cancer (GC) leads to poor prognosis. However, few biomarkers are available to predict LNM in GC patients. Thus, we measured expression of 6 cancer-related miRNAs using real-time RT-PCR in 102 GC samples that were randomized into a training set and a testing set (each, 51 cases). Using logistic regression, we identified 4-miRNA (miR-27b, miR-128, miR-100 and miR-214) signatures for predicting LNM in GC patients. Patients with high-risk scores for the 4-miRNA signature tended to have higher LNM than those with low-risk scores. Meanwhile, the ROC curve of the 4-miRNA signature was better for predicting LNM in GC patients. In addition, Cox regression analysis indicated that a 2-miRNA signature (miR-27b and miR-214) or a miR-214/N stage signature was predictive of survival for GC patients. This work describes a previously unrecognized 4-miRNA signature involved in LNM and a 2-miRNA signature or miR-214/N stage signature related to GC patients’ survival. PMID:28202938

  15. L1000CDS2: LINCS L1000 characteristic direction signatures search engine

    PubMed Central

    Duan, Qiaonan; Reid, St Patrick; Clark, Neil R; Wang, Zichen; Fernandez, Nicolas F; Rouillard, Andrew D; Readhead, Ben; Tritsch, Sarah R; Hodos, Rachel; Hafner, Marc; Niepel, Mario; Sorger, Peter K; Dudley, Joel T; Bavari, Sina; Panchal, Rekha G; Ma’ayan, Avi

    2017-01-01

    The library of integrated network-based cellular signatures (LINCS) L1000 data set currently comprises of over a million gene expression profiles of chemically perturbed human cell lines. Through unique several intrinsic and extrinsic benchmarking schemes, we demonstrate that processing the L1000 data with the characteristic direction (CD) method significantly improves signal to noise compared with the MODZ method currently used to compute L1000 signatures. The CD processed L1000 signatures are served through a state-of-the-art web-based search engine application called L1000CDS2. The L1000CDS2 search engine provides prioritization of thousands of small-molecule signatures, and their pairwise combinations, predicted to either mimic or reverse an input gene expression signature using two methods. The L1000CDS2 search engine also predicts drug targets for all the small molecules profiled by the L1000 assay that we processed. Targets are predicted by computing the cosine similarity between the L1000 small-molecule signatures and a large collection of signatures extracted from the gene expression omnibus (GEO) for single-gene perturbations in mammalian cells. We applied L1000CDS2 to prioritize small molecules that are predicted to reverse expression in 670 disease signatures also extracted from GEO, and prioritized small molecules that can mimic expression of 22 endogenous ligand signatures profiled by the L1000 assay. As a case study, to further demonstrate the utility of L1000CDS2, we collected expression signatures from human cells infected with Ebola virus at 30, 60 and 120 min. Querying these signatures with L1000CDS2 we identified kenpaullone, a GSK3B/CDK2 inhibitor that we show, in subsequent experiments, has a dose-dependent efficacy in inhibiting Ebola infection in vitro without causing cellular toxicity in human cell lines. In summary, the L1000CDS2 tool can be applied in many biological and biomedical settings, while improving the extraction of knowledge

  16. Novel approaches in diagnosing tuberculosis

    NASA Astrophysics Data System (ADS)

    Kolk, Arend H. J.; Dang, Ngoc A.; Kuijper, Sjoukje; Gibson, Tim; Anthony, Richard; Claassens, Mareli M.; Kaal, Erwin; Janssen, Hans-Gerd

    2011-06-01

    The WHO declared tuberculosis (TB) a global emergency. An estimated 8-9 million new cases occur each year with 2-3 million deaths. Currently, TB is diagnosed mostly by chest-X ray and staining of the mycobacteria in sputum with a detection limit of 1x104 bacteria /ml. There is an urgent need for better diagnostic tools for TB especially for developing countries. We have validated the electronic nose from TD Technology for the detection of Mycobacterium tuberculosis by headspace analysis of 284 sputum samples from TB patients. We used linear discriminant function analysis resulting in a sensitivity of 75% a specificity of 67% and an accuracy of 69%. Further research is still required to improve the results by choosing more selective sensors and sampling techniques. We used a fast gas chromatography- mass spectrometry method (GC-MS). The automated procedure is based on the injection of sputum samples which are methylated inside the GC injector using thermally assisted hydrolysis and methylation (THM-GC-MS). Hexacosanoic acid in combination with tuberculostearic acid was found to be specific for the presence of M. tuberculosis. The detection limit was similar to microscopy. We found no false positives, all microscopy and culture positive samples were also found positive with the THM-GC-MS method. The detection of ribosomal RNA from the infecting organism offers great potential since rRNA molecules outnumber chromosomal DNA by a factor 1000. It thus may possible to detect the organism without amplification of the nucleic acids (NA). We used a capture and a tagged detector probe for the direct detection of M. tuberculosis in sputum. So far the detection limit is 1x106 bacteria / ml. Currently we are testing a Lab-On-A-Chip Interferometer detection system.

  17. Are Pediatricians Diagnosing Obese Children?

    PubMed Central

    Thomas, Katharine; Urrego, Fernando

    2017-01-01

    Background: Pediatric obesity is the most prevalent nutritional disorder in American children. The detrimental social, psychological, and physiological effects of obesity call for pediatricians to address this health concern. The literature demonstrates that clinicians are underreporting the diagnosis of obesity in the pediatric setting. The primary purpose of this study was to determine if pediatricians at one pediatrics clinic in the Ochsner Health System are documenting the presence of an overweight or obese body mass index (BMI) as a diagnosis in the medical record. A secondary purpose of this study was to determine the demographics of all pediatric patients in the Ochsner Health System to be used for program development. Methods: A retrospective medical record review was conducted. Records from April 1, 2012 to April 1, 2016, were reviewed for the presence of the diagnosis of BMI classified as obese or overweight. Results: We analyzed a total of 175,066 records in this study. Of these records, 1.32% documented a diagnosis of obesity, and 0.5% documented a BMI score indicating overweight. The percentages of patient visits that met the Centers for Disease Control and Prevention criteria to be classified as obese or overweight were 28.66% and 30.41%, respectively. The majority of our pediatric patients were male (51.76%), white (43.31%), and 5-12 years old (43.80%). Conclusion: This study demonstrates that pediatricians at Ochsner Health Center for Children are not diagnosing patients who have unhealthy BMI scores as overweight or obese. Interventions are needed to increase the identification of children who may benefit from receiving resources that encourage a healthy lifestyle and optimal weight maintenance. PMID:28331453

  18. Newly Diagnosed Acute Promyelocytic Leukemia

    PubMed Central

    Avvisati, Giuseppe

    2011-01-01

    Acute promyelocytic leukemia (APL) represents a medical emergency with a high rate of early mortality. As a consequence, as soon as the diagnosis is suspected based upon cytologic criteria, it is necessary to start all- trans retinoic acid (ATRA) treatment without delay. For patients with newly diagnosed APL, induction therapy with ATRA plus anthracycline based chemotherapy is recommended. At present the combination of arsenic trioxide plus ATRA should be considered for patients who are not candidates for anthracycline-based therapy. For pediatric and adult patients with APL aged < 60 years who achieve a CR with induction, I recommend 3 intensive courses of consolidation chemotherapy associated to ATRA, targeted on the basis of the risk group at diagnosis. In patients treated with a very intensive consolidation chemotherapy maintenance treatment can be omitted. However If a maintenance treatment has to be adopted I suggest the use of intermittent ATRA for 15 days every 3 months for a period of 2 years, rather than ATRA associated to chemotherapy. Moreover, taking into account the medical literature, a reduced dosage of ATRA ( 25 mg/m2) in pediatric patients and a consolidation chemotherapy of reduced intensity in elderly patients is recommended. Furthermore, in order to maximize survival, careful attention should be reserved to the coagulopathy and to the appearance of the differentiation syndrome. Finally, PCR for the PML/RARA fusion gene on a bone marrow specimen every three months for two years, and then every six months for additional three years are needed during the follow-up. PMID:22220261

  19. Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers

    PubMed Central

    Wang, I-Ming; Zhang, Bin; Yang, Xia; Zhu, Jun; Stepaniants, Serguei; Zhang, Chunsheng; Meng, Qingying; Peters, Mette; He, Yudong; Ni, Chester; Slipetz, Deborah; Crackower, Michael A; Houshyar, Hani; Tan, Christopher M; Asante-Appiah, Ernest; O'Neill, Gary; Jane Luo, Mingjuan; Thieringer, Rolf; Yuan, Jeffrey; Chiu, Chi-Sung; Yee Lum, Pek; Lamb, John; Boie, Yves; Wilkinson, Hilary A; Schadt, Eric E; Dai, Hongyue; Roberts, Christopher

    2012-01-01

    Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases. PMID:22806142

  20. Reactive oxygen species–associated molecular signature predicts survival in patients with sepsis

    PubMed Central

    Zhou, Tong; Wang, Ting; Slepian, Marvin J.; Garcia, Joe G. N.; Hecker, Louise

    2016-01-01

    Abstract Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)–associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies. PMID:27252846

  1. Search for signatures in miRNAs associated with cancer

    PubMed Central

    Kothandan, Ram; Biswas, Sumit

    2013-01-01

    Since the first discovery in the early 1990's, the predicted and validated population of microRNAs (miRNAs or miRs) has grown significantly. These small (~22 nucleotides long) regulators of gene expression have been implicated and associated with several genes in the cancer pathway as well. Globally, the identification and verification of microRNAs as biomarkers for cancer cell types has been the area of thrust for most miRNA biologists. However, there has been a noticeable vacuum when it comes to identifying a common signature or trademark that could be used to demarcate a miR to be associated with the development or suppression of cancer. To answer these queries, we report an in silico study involving the identification of global signatures in experimentally validated microRNAs which have been associated with cancer. This study has thrown light on the presence of significant common signatures, viz., - sequential and hybridization, which may distinguish a miR to be associated with cancer. Based on our analysis, we suggest the utility of such signatures in the design and development of algorithms for prediction of miRs involved in the cancer pathway. PMID:23861569

  2. Gene expression profile correlates with T cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy

    PubMed Central

    Prins, Robert M.; Soto, Horacio; Konkankit, Vera; Odesa, Sylvia K.; Eskin, Ascia; Yong, William H.; Nelson, Stanley F.; Liau, Linda M.

    2010-01-01

    Purpose To assess the feasibility, safety, and toxicity of autologous tumor lysate-pulsed dendritic cell (DC) vaccination and toll-like receptor (TLR) agonists in patients with newly diagnosed and recurrent glioblastoma. Clinical and immune responses were monitored and correlated with tumor gene expression profiles. Experimental Design Twenty-three patients with glioblastoma (WHO grade IV) were enrolled in this dose-escalation study and received three biweekly injections of glioma lysate-pulsed DCs followed by booster vaccinations with either imiquimod or poly-ICLC adjuvant every three months until tumor progression. Gene expression profiling, IHC, FACS, and cytokine bead arrays were performed on patient tumors and PBMC. Results DC vaccinations are safe and not associated with any dose-limiting toxicity. The median overall survival from the time of initial surgical diagnosis of glioblastoma was 31.4 months, with a one-, two-, and three-year survival rate of 91%, 55% and 47%, respectively. Patients whose tumors had mesenchymal gene expression signatures exhibited increased survival following DC vaccination compared to historical controls of the same genetic subtype. Tumor samples with a mesenchymal gene expression signature had a higher number of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) compared with glioblastomas of other gene expression signatures (p = 0.006). Conclusion Autologous tumor lysate-pulsed DC vaccination in conjunction with TLR agonists is safe as adjuvant therapy in newly diagnosed and recurrent glioblastoma patients. Our results suggest that the mesenchymal gene expression profile may identify an immunogenic subgroup of glioblastoma that may be more responsive to immune-based therapies. PMID:21135147

  3. A Molecular Signature of Proteinuria in Glomerulonephritis

    PubMed Central

    Reich, Heather N.; Tritchler, David; Cattran, Daniel C.; Eichinger, Felix; Boucherot, Anissa; Henger, Anna; Berthier, Celine C.; Nair, Viji; Cohen, Clemens D.

    2010-01-01

    Proteinuria is the most important predictor of outcome in glomerulonephritis and experimental data suggest that the tubular cell response to proteinuria is an important determinant of progressive fibrosis in the kidney. However, it is unclear whether proteinuria is a marker of disease severity or has a direct effect on tubular cells in the kidneys of patients with glomerulonephritis. Accordingly we studied an in vitro model of proteinuria, and identified 231 “albumin-regulated genes” differentially expressed by primary human kidney tubular epithelial cells exposed to albumin. We translated these findings to human disease by studying mRNA levels of these genes in the tubulo-interstitial compartment of kidney biopsies from patients with IgA nephropathy using microarrays. Biopsies from patients with IgAN (n = 25) could be distinguished from those of control subjects (n = 6) based solely upon the expression of these 231 “albumin-regulated genes.” The expression of an 11-transcript subset related to the degree of proteinuria, and this 11-mRNA subset was also sufficient to distinguish biopsies of subjects with IgAN from control biopsies. We tested if these findings could be extrapolated to other proteinuric diseases beyond IgAN and found that all forms of primary glomerulonephritis (n = 33) can be distinguished from controls (n = 21) based solely on the expression levels of these 11 genes derived from our in vitro proteinuria model. Pathway analysis suggests common regulatory elements shared by these 11 transcripts. In conclusion, we have identified an albumin-regulated 11-gene signature shared between all forms of primary glomerulonephritis. Our findings support the hypothesis that albuminuria may directly promote injury in the tubulo-interstitial compartment of the kidney in patients with glomerulonephritis. PMID:20976140

  4. Infrared signatures for remote sensing

    SciTech Connect

    McDowell, R.S.; Sharpe, S.W.; Kelly, J.F.

    1994-04-01

    PNL`s capabilities for infrared and near-infrared spectroscopy include tunable-diode-laser (TDL) systems covering 300--3,000 cm{sup {minus}1} at <10-MHz bandwidth; a Bruker Fourier-transform infrared (FTIR) spectrometer for the near- to far-infrared at 50-MHz resolution; and a stable line-tunable, 12-w cw CO{sub 2} laser. PNL also has a beam expansion source with a 12-cm slit, which provides a 3-m effective path for gases at {approximately}10 K, giving a Doppler width of typically 10 MHz; and long-path static gas cells (to 100 m). In applying this equipment to signatures work, the authors emphasize the importance of high spectral resolution for detecting and identifying atmospheric interferences; for identifying the optimum analytical frequencies; for deriving, by spectroscopic analysis, the molecular parameters needed for modeling; and for obtaining data on species and/or bands that are not in existing databases. As an example of such spectroscopy, the authors have assigned and analyzed the C-Cl stretching region of CCl{sub 4} at 770--800 cm{sup {minus}1}. This is an important potential signature species whose IR absorption has remained puzzling because of the natural isotopic mix, extensive hot-band structure, and a Fermi resonance involving a nearby combination band. Instrument development projects include the IR sniffer, a small high-sensitivity, high-discrimination (Doppler-limited) device for fence-line or downwind monitoring that is effective even in regions of atmospheric absorption; preliminary work has achieved sensitivities at the low-ppb level. Other work covers trace species detection with TDLs, and FM-modulated CO{sub 2} laser LIDAR. The authors are planning a field experiment to interrogate the Hanford tank farm for signature species from Rattlesnake Mountain, a standoff of ca. 15 km, to be accompanied by simultaneous ground-truthing at the tanks.

  5. Signature of anisotropic bubble collisions

    SciTech Connect

    Salem, Michael P.

    2010-09-15

    Our universe may have formed via bubble nucleation in an eternally inflating background. Furthermore, the background may have a compact dimension--the modulus of which tunnels out of a metastable minimum during bubble nucleation--which subsequently grows to become one of our three large spatial dimensions. When in this scenario our bubble universe collides with other ones like it, the collision geometry is constrained by the reduced symmetry of the tunneling instanton. While the regions affected by such bubble collisions still appear (to leading order) as disks in an observer's sky, the centers of these disks all lie on a single great circle, providing a distinct signature of anisotropic bubble nucleation.

  6. Spectroscopic signature for ferroelectric ice

    NASA Astrophysics Data System (ADS)

    Wójcik, Marek J.; Gług, Maciej; Boczar, Marek; Boda, Łukasz

    2014-09-01

    Various forms of ice exist within our galaxy. Particularly intriguing type of ice - ‘ferroelectric ice' was discovered experimentally and is stable in temperatures below 72 K. This form of ice can generate enormous electric fields and can play an important role in planetary formation. In this letter we present Car-Parrinello simulation of infrared spectra of ferroelectric ice and compare them with spectra of hexagonal ice. Librational region of the spectra can be treated as spectroscopic signature of ice XI and can be of help to identify ferroelectric ice in the Universe.

  7. Satellite signatures in SLR observations

    NASA Technical Reports Server (NTRS)

    Appleby, G. M.

    1993-01-01

    We examine the evidence for the detection of satellite-dependent signatures in the laser range observations obtained by the UK single-photon Satellite Laser Ranging (SLR) System models of the expected observation distributions from Ajisai and Lageos are developed from the published satellite spread functions and from the characteristics of the SLR System and compared with the observations. The effects of varying return strengths are discussed using the models and by experimental observations of Ajisai, during which a range of return levels from single to multiple photons is achieved. The implications of these results for system-dependent center for mass corrections are discussed.

  8. Observational Signatures of Magnetic Reconnection

    NASA Technical Reports Server (NTRS)

    Savage, Sabrina

    2014-01-01

    Magnetic reconnection is often referred to as the primary source of energy release during solar flares. Directly observing reconnection occurring in the solar atmosphere, however, is not trivial considering that the scale size of the diffusion region is magnitudes smaller than the observational capabilities of current instrumentation, and coronal magnetic field measurements are not currently sufficient to capture the process. Therefore, predicting and studying observationally feasible signatures of the precursors and consequences of reconnection is necessary for guiding and verifying the simulations that dominate our understanding. I will present a set of such observations, particularly in connection with long-duration solar events, and compare them with recent simulations and theoretical predictions.

  9. Gut microbiota signatures of longevity.

    PubMed

    Kong, Fanli; Hua, Yutong; Zeng, Bo; Ning, Ruihong; Li, Ying; Zhao, Jiangchao

    2016-09-26

    An aging global population poses substantial challenges to society [1]. Centenarians are a model for healthy aging because they have reached the extreme limit of life by escaping, surviving, or delaying chronic diseases [2]. The genetics of centenarians have been extensively examined [3], but less is known about their gut microbiotas. Recently, Biagi et al.[4] characterized the gut microbiota in Italian centenarians and semi-supercentenarians. Here, we compare the gut microbiota of Chinese long-living people with younger age groups, and with the results from the Italian population [4], to identify gut-microbial signatures of healthy aging.

  10. Quantum broadcasting multiple blind signature with constant size

    NASA Astrophysics Data System (ADS)

    Xiao, Min; Li, Zhenli

    2016-09-01

    Using quantum homomorphic signature in quantum network, we propose a quantum broadcasting multiple blind signature scheme. Different from classical signature and current quantum signature schemes, the multi-signature proposed in our scheme is not generated by simply putting the individual signatures together, but by aggregating the individual signatures based on homomorphic property. Therefore, the size of the multi-signature is constant. Furthermore, based on a wide range of investigation for the security of existing quantum signature protocols, our protocol is designed to resist possible forgery attacks against signature and message from the various attack sources and disavowal attacks from participants.

  11. Molecular signatures of lung cancer: defining new diagnostic and therapeutic paradigms.

    PubMed

    Balko, Justin M; Arteaga, Carlos L

    2012-02-01

    Molecular profiling holds great promise for improving our ability to diagnose, prognosticate, and select individualized treatments for lung cancer patients. However, using multidimensional data and novel technologies to derive these profiles is limited by our ability to employ the assay in a clinical scenario where it can impact the course of disease. Although many molecular signatures have been reported in lung cancer, as of yet, few have been sufficiently validated for widespread clinical use. Recently, several novel signatures have been reported, which address critical aspects of patient care and/or demonstrate improved efforts for appropriate clinical validation. Here, we present our opinion on the current state of the field of molecular signatures in lung cancer.

  12. Visual signatures in video visualization.

    PubMed

    Chen, Min; Botchen, Ralf P; Hashim, Rudy R; Weiskopf, Daniel; Ertl, Thomas; Thornton, Ian M

    2006-01-01

    Video visualization is a computation process that extracts meaningful information from original video data sets and conveys the extracted information to users in appropriate visual representations. This paper presents a broad treatment of the subject, following a typical research pipeline involving concept formulation, system development, a path-finding user study, and a field trial with real application data. In particular, we have conducted a fundamental study on the visualization of motion events in videos. We have, for the first time, deployed flow visualization techniques in video visualization. We have compared the effectiveness of different abstract visual representations of videos. We have conducted a user study to examine whether users are able to learn to recognize visual signatures of motions, and to assist in the evaluation of different visualization techniques. We have applied our understanding and the developed techniques to a set of application video clips. Our study has demonstrated that video visualization is both technically feasible and cost-effective. It has provided the first set of evidence confirming that ordinary users can be accustomed to the visual features depicted in video visualizations, and can learn to recognize visual signatures of a variety of motion events.

  13. Cloning and detecting signature microRNAs from mammalian cells.

    PubMed

    Sun, Guihua; Li, Haitang; Rossi, John J

    2007-01-01

    MicroRNAs (miRNAs) are about 19- to 24-nucleotides long noncoding regulatory small RNAs that could silence target gene expression through base pairing to the complementary sequences in the 3' untranslated region (3'UTR) of targeted genes. They are evolutionally conserved and play an important regulatory role in embryogenesis, cell differentiation, and proliferation. They are also involved in pathogenesis and progression of some human diseases. There are about 1000 human miRNAs predicted today, and it is estimated that they could target about 30% of all human transcripts. Profiling the miRNAs that are expressed in the experimental cells became an important issue as different cells express different signature miRNAs or express the same miRNAs at different level. Small RNA cloning is a reliable way to characterize those tissue- or cell-specific signature miRNAs. This chapter describes a relatively nonlaborious polyadenylation-mediated complementary DNA (cDNA) cloning method that will identify most of the small RNAs expressed in the cells of interest. This procedure can also be used to verify bioinformatic predictions of miRNAs/small interfering RNAs (siRNAs) as well as to identify new miRNAs/siRNAs.

  14. Secure Obfuscation for Encrypted Group Signatures

    PubMed Central

    Fan, Hongfei; Liu, Qin

    2015-01-01

    In recent years, group signature techniques are widely used in constructing privacy-preserving security schemes for various information systems. However, conventional techniques keep the schemes secure only in normal black-box attack contexts. In other words, these schemes suppose that (the implementation of) the group signature generation algorithm is running in a platform that is perfectly protected from various intrusions and attacks. As a complementary to existing studies, how to generate group signatures securely in a more austere security context, such as a white-box attack context, is studied in this paper. We use obfuscation as an approach to acquire a higher level of security. Concretely, we introduce a special group signature functionality-an encrypted group signature, and then provide an obfuscator for the proposed functionality. A series of new security notions for both the functionality and its obfuscator has been introduced. The most important one is the average-case secure virtual black-box property w.r.t. dependent oracles and restricted dependent oracles which captures the requirement of protecting the output of the proposed obfuscator against collision attacks from group members. The security notions fit for many other specialized obfuscators, such as obfuscators for identity-based signatures, threshold signatures and key-insulated signatures. Finally, the correctness and security of the proposed obfuscator have been proven. Thereby, the obfuscated encrypted group signature functionality can be applied to variants of privacy-preserving security schemes and enhance the security level of these schemes. PMID:26167686

  15. Input apparatus for dynamic signature verification systems

    DOEpatents

    EerNisse, Errol P.; Land, Cecil E.; Snelling, Jay B.

    1978-01-01

    The disclosure relates to signature verification input apparatus comprising a writing instrument and platen containing piezoelectric transducers which generate signals in response to writing pressures.

  16. A cis-Regulatory Signature for Chordate Anterior Neuroectodermal Genes

    PubMed Central

    Christiaen, Lionel; Joly, Jean-Stéphane

    2010-01-01

    One of the striking findings of comparative developmental genetics was that expression patterns of core transcription factors are extraordinarily conserved in bilaterians. However, it remains unclear whether cis-regulatory elements of their target genes also exhibit common signatures associated with conserved embryonic fields. To address this question, we focused on genes that are active in the anterior neuroectoderm and non-neural ectoderm of the ascidian Ciona intestinalis. Following the dissection of a prototypic anterior placodal enhancer, we searched all genomic conserved non-coding elements for duplicated motifs around genes showing anterior neuroectodermal expression. Strikingly, we identified an over-represented pentamer motif corresponding to the binding site of the homeodomain protein OTX, which plays a pivotal role in the anterior development of all bilaterian species. Using an in vivo reporter gene assay, we observed that 10 of 23 candidate cis-regulatory elements containing duplicated OTX motifs are active in the anterior neuroectoderm, thus showing that this cis-regulatory signature is predictive of neuroectodermal enhancers. These results show that a common cis-regulatory signature corresponding to K50-Paired homeodomain transcription factors is found in non-coding sequences flanking anterior neuroectodermal genes in chordate embryos. Thus, field-specific selector genes impose architectural constraints in the form of combinations of short tags on their target enhancers. This could account for the strong evolutionary conservation of the regulatory elements controlling field-specific selector genes responsible for body plan formation. PMID:20419150

  17. Critical thinking and accuracy of nurses' diagnoses.

    PubMed

    Lunney, Margaret

    2003-01-01

    Interpretations of patient data are complex and diverse, contributing to a risk of low accuracy nursing diagnoses. This risk is confirmed in research findings that accuracy of nurses' diagnoses varied widely from high to low. Highly accurate diagnoses are essential, however, to guide nursing interventions for the achievement of positive health outcomes. Development of critical thinking abilities is likely to improve accuracy of nurses' diagnoses. New views of critical thinking serve as a basis for critical thinking in nursing. Seven cognitive skills and ten habits of mind are identified as dimensions of critical thinking for use in the diagnostic process. Application of the cognitive skills of critical thinking illustrates the importance of using critical thinking for accuracy of nurses' diagnoses. Ten strategies are proposed for self-development of critical thinking abilities.

  18. Characterization of key transcription factors as molecular signatures of HPV-positive and HPV-negative oral cancers.

    PubMed

    Verma, Gaurav; Vishnoi, Kanchan; Tyagi, Abhishek; Jadli, Mohit; Singh, Tejveer; Goel, Ankit; Sharma, Ankita; Agarwal, Kiran; Prasad, Subhash Chandra; Pandey, Durgatosh; Sharma, Shashi; Mehrotra, Ravi; Singh, Sukh Mahendra; Bharti, Alok Chandra

    2017-03-01

    Prior studies established constitutively active AP-1, NF-κB, and STAT3 signaling in oral cancer. Differential expression/activation of specific members of these transcription factors has been documented in HPV-positive oral lesions that respond better to therapy. We performed a comprehensive analysis of differentially expressed, transcriptionally active members of these pivotal signaling mediators to develop specific signatures of HPV-positive and HPV-negative oral lesions by immunohistochemical method that is applicable in low-resource settings. We examined a total of 31 prospective and 30 formalin-fixed, paraffin-embedded tissues from treatment-naïve, histopathologically and clinically confirmed cases diagnosed as oral or oropharyngeal squamous cell carcinoma (OSCC/OPSCC). Following determination of their HPV status by GP5 + /GP6 +  PCR, the sequential sections of the tissues were evaluated for expression of JunB, JunD, c-Fos, p50, p65, STAT3, and pSTAT3(Y705), along with two key regulatory proteins pEGFR and p16 by IHC. Independent analysis of JunB and p65 showed direct correlation with HPV positivity, whereas STAT3 and pSTAT3 were inversely correlated. A combined analysis of transcription factors revealed a more restrictive combination, characterized by the presence of AP-1 and NF-κB lacking involvement of STAT3 that strongly correlated with HPV-positive tumors. Presence of STAT3/pSTAT3 with NF-κB irrespective of the presence or absence of AP-1 members was present in HPV-negative lesions. Expression of pSTAT3 strongly correlated with all the AP-1/NF-κB members (except JunD), its upstream activator pEGFR(Y)(1092) , and HPV infection-related negative regulator p16. Overall, we show a simple combination of AP-1, NF-κB, and STAT3 members' expression that may serve as molecular signature of HPV-positive lesions or more broadly the tumors that show better prognosis.

  19. The defining DNA methylation signature of Floating-Harbor Syndrome.

    PubMed

    Hood, Rebecca L; Schenkel, Laila C; Nikkel, Sarah M; Ainsworth, Peter J; Pare, Guillaume; Boycott, Kym M; Bulman, Dennis E; Sadikovic, Bekim

    2016-12-09

    Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.

  20. Microfluidic platform for the quantitative analysis of leukocyte migration signatures.

    PubMed

    Boneschansker, Leo; Yan, Jun; Wong, Elisabeth; Briscoe, David M; Irimia, Daniel

    2014-09-03

    Leukocyte migration into tissues is characteristic of inflammation. It is usually measured in vitro as the average displacement of populations of cells towards a chemokine gradient, not acknowledging other patterns of cell migration. Here, we designed and validated a microfluidic migration platform to simultaneously analyse four qualitative migration patterns: chemoattraction, -repulsion, -kinesis and -inhibition, using single-cell quantitative metrics of direction, speed, persistence and fraction of cells responding. We find that established chemokines, complement component 5a and IL-8 induce chemoattraction and repulsion in equal proportions, resulting in the dispersal of cells. These migration signatures are characterized by high persistence and speed and are independent of the chemokine dose or receptor expression. Furthermore, we find that twice as many T lymphocytes migrate away than towards stromal cell-derived factor 1 and their directional migration patterns are not persistent. Overall, our platform helps discover migratory signature responses and uncovers an avenue for precise characterization of leukocyte migration and therapeutic modulators.

  1. MICROFLUIDIC PLATFORM FOR THE QUANTITATIVE ANALYSIS OF LEUKOCYTE MIGRATION SIGNATURES

    PubMed Central

    Wong, Elisabeth; Briscoe, David M.; Irimia, Daniel

    2014-01-01

    Leukocyte migration into tissues is characteristic of inflammation. It is usually measured in vitro as the average displacement of populations of cells towards a chemokine gradient, not acknowledging other patterns of cell migration. Here, we designed and validated a microfluidic migration platform to simultaneously analyze four qualitative migration patterns: chemo-attraction, -repulsion, -kinesis and -inhibition, using single-cell quantitative metrics of direction, speed, persistence, and fraction of cells responding. We find that established chemokines C5a and IL-8 induce chemoattraction and repulsion in equal proportions, resulting in the dispersal of cells. These migration signatures are characterized by high persistence and speed and are independent of the chemokine dose or receptor expression. Furthermore, we find that twice as many T-lymphocytes migrate away than towards SDF-1 and their directional migration patterns are not persistent. Overall, our platform characterizes migratory signature responses and uncovers an avenue for precise characterization of leukocyte migration and therapeutic modulators. PMID:25183261

  2. Signature spectrale des grains interstellaires.

    NASA Astrophysics Data System (ADS)

    Léger, A.

    Notre connaissance de la nature des grains interstellaires reposait sur un nombre très restreint de signatures spectrales dans la courbe d'extinction du milieu interstellaire. Une information considérable est contenue dans les 40 bandes interstellaires diffuses dans le visible, mais reste inexploitée. L'interprétation récente des cinq bandes IR en émission, en terme de molécules d'hydrocarbures aromatiques polycycliques, est développée. Elle permet l'utilisation d'une information spectroscopique comparable, à elle seule, à ce sur quoi était basée jusqu'alors notre connaissance de la matière interstellaire condensée. Différentes implications de cette mise en évidence sont proposées.

  3. Irma multisensor predictive signature model

    NASA Astrophysics Data System (ADS)

    Watson, John S.; Flynn, David S.; Wellfare, Michael R.; Richards, Mike; Prestwood, Lee

    1995-06-01

    The Irma synthetic signature model was one of the first high resolution synthetic infrared (IR) target and background signature models to be developed for tactical air-to-surface weapon scenarios. Originally developed in 1980 by the Armament Directorate of the Air Force Wright Laboratory (WL/MN), the Irma model was used exclusively to generate IR scenes for smart weapons research and development. In 1988, a number of significant upgrades to Irma were initiated including the addition of a laser channel. This two channel version, Irma 3.0, was released to the user community in 1990. In 1992, an improved scene generator was incorporated into the Irma model which supported correlated frame-to-frame imagery. This and other improvements were released in Irma 2.2. Recently, Irma 3.2, a passive IR/millimeter wave (MMW) code, was completed. Currently, upgrades are underway to include an active MMW channel. Designated Irma 4.0, this code will serve as a cornerstone of sensor fusion research in the laboratory from 6.1 concept development to 6.3 technology demonstration programs for precision guided munitions. Several significant milestones have been reached in this development process and are demonstrated. The Irma 4.0 software design has been developed and interim results are available. Irma is being developed to facilitate multi-sensor smart weapons research and development. It is currently in distribution to over 80 agencies within the U.S. Air Force, U.S. Army, U.S. Navy, ARPA, NASA, Department of Transportation, academia, and industry.

  4. The Pedagogic Signature of the Teaching Profession

    ERIC Educational Resources Information Center

    Kiel, Ewald; Lerche, Thomas; Kollmannsberger, Markus; Oubaid, Viktor; Weiss, Sabine

    2016-01-01

    Lee S. Shulman deplores that the field of education as a profession does not have a pedagogic signature, which he characterizes as a synthesis of cognitive, practical and moral apprenticeship. In this context, the following study has three goals: 1) In the first theoretical part, the basic problems of constructing a pedagogic signature are…

  5. 21 CFR 11.50 - Signature manifestations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ELECTRONIC RECORDS; ELECTRONIC SIGNATURES Electronic Records § 11.50 Signature manifestations. (a) Signed electronic... the same controls as for electronic records and shall be included as part of any human readable...

  6. 48 CFR 4.102 - Contractor's signature.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Contractor's signature. 4.102 Section 4.102 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION GENERAL ADMINISTRATIVE MATTERS Contract Execution 4.102 Contractor's signature. (a) Individuals. A contract with...

  7. A Real Quantum Designated Verifier Signature Scheme

    NASA Astrophysics Data System (ADS)

    Shi, Wei-Min; Zhou, Yi-Hua; Yang, Yu-Guang

    2015-09-01

    The effectiveness of most quantum signature schemes reported in the literature can be verified by a designated person, however, those quantum signature schemes aren't the real traditional designated verifier signature schemes, because the designated person hasn't the capability to efficiently simulate a signature which is indistinguishable from a signer, which cannot satisfy the requirements in some special environments such as E-voting, call for tenders and software licensing. For solving this problem, a real quantum designated verifier signature scheme is proposed in this paper. According to the property of unitary transformation and quantum one-way function, only a verifier designated by a signer can verify the "validity of a signature" and the designated verifier cannot prove to a third party that the signature was produced by the signer or by himself through a transcript simulation algorithm. Moreover, the quantum key distribution and quantum encryption algorithm guarantee the unconditional security of this scheme. Analysis results show that this new scheme satisfies the main security requirements of designated verifier signature scheme and the major attack strategies.

  8. Does Social Work Have a Signature Pedagogy?

    ERIC Educational Resources Information Center

    Earls Larrison, Tara; Korr, Wynne S.

    2013-01-01

    This article contributes to discourse on signature pedagogy by reconceptualizing how our pedagogies are understood and defined for social work education. We critique the view that field education is social work's signature pedagogy and consider what pedagogies are distinct about the teaching and learning of social work. Using Shulman's…

  9. 5 CFR 850.106 - Electronic signatures.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... to any provisions prescribed by the Director under § 850.104— (1) An electronic communication may be... signature of an electronic communication may be deemed to satisfy any statutory or regulatory requirement... section, an electronic signature is a method of signing an electronic communication, including...

  10. Defining the chromatin signature of inducible genes in T cells

    PubMed Central

    2009-01-01

    Background Specific chromatin characteristics, especially the modification status of the core histone proteins, are associated with active and inactive genes. There is growing evidence that genes that respond to environmental or developmental signals may possess distinct chromatin marks. Using a T cell model and both genome-wide and gene-focused approaches, we examined the chromatin characteristics of genes that respond to T cell activation. Results To facilitate comparison of genes with similar basal expression levels, we used expression-profiling data to bin genes according to their basal expression levels. We found that inducible genes in the lower basal expression bins, especially rapidly induced primary response genes, were more likely than their non-responsive counterparts to display the histone modifications of active genes, have RNA polymerase II (Pol II) at their promoters and show evidence of ongoing basal elongation. There was little or no evidence for the presence of active chromatin marks in the absence of promoter Pol II on these inducible genes. In addition, we identified a subgroup of genes with active promoter chromatin marks and promoter Pol II but no evidence of elongation. Following T cell activation, we find little evidence for a major shift in the active chromatin signature around inducible gene promoters but many genes recruit more Pol II and show increased evidence of elongation. Conclusions These results suggest that the majority of inducible genes are primed for activation by having an active chromatin signature and promoter Pol II with or without ongoing elongation. PMID:19807913

  11. Fleet-Wide Prognostic and Health Management Suite: Asset Fault Signature Database

    SciTech Connect

    Vivek Agarwal; Nancy J. Lybeck; Randall Bickford; Richard Rusaw

    2015-06-01

    Proactive online monitoring in the nuclear industry is being explored using the Electric Power Research Institute’s Fleet-Wide Prognostic and Health Management (FW-PHM) Suite software. The FW-PHM Suite is a set of web-based diagnostic and prognostic tools and databases that serves as an integrated health monitoring architecture. The FW-PHM Suite has four main modules: (1) Diagnostic Advisor, (2) Asset Fault Signature (AFS) Database, (3) Remaining Useful Life Advisor, and (4) Remaining Useful Life Database. The paper focuses on the AFS Database of the FW-PHM Suite, which is used to catalog asset fault signatures. A fault signature is a structured representation of the information that an expert would use to first detect and then verify the occurrence of a specific type of fault. The fault signatures developed to assess the health status of generator step-up transformers are described in the paper. The developed fault signatures capture this knowledge and implement it in a standardized approach, thereby streamlining the diagnostic and prognostic process. This will support the automation of proactive online monitoring techniques in nuclear power plants to diagnose incipient faults, perform proactive maintenance, and estimate the remaining useful life of assets.

  12. Signatures of mutational processes in human cancer

    PubMed Central

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Aparicio, Samuel A.J.R.; Behjati, Sam; Biankin, Andrew V.; Bignell, Graham R.; Bolli, Niccolo; Borg, Ake; Børresen-Dale, Anne-Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam P.; Caldas, Carlos; Davies, Helen R.; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn Erla; Foekens, John A.; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imielinsk, Marcin; Jäger, Natalie; Jones, David T.W.; Jones, David; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R.; López-Otín, Carlos; Martin, Sancha; Munshi, Nikhil C.; Nakamura, Hiromi; Northcott, Paul A.; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V.; Puente, Xose S.; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L.; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N.; Span, Paul N.; Teague, Jon W.; Totoki, Yasushi; Tutt, Andrew N.J.; Valdés-Mas, Rafael; van Buuren, Marit M.; van ’t Veer, Laura; Vincent-Salomon, Anne; Waddell, Nicola; Yates, Lucy R.; Zucman-Rossi, Jessica; Futreal, P. Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M.; Siebert, Reiner; Campo, Elías; Shibata, Tatsuhiro; Pfister, Stefan M.; Campbell, Peter J.; Stratton, Michael R.

    2013-01-01

    All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy. PMID:23945592

  13. Real time gamma-ray signature identifier

    DOEpatents

    Rowland, Mark [Alamo, CA; Gosnell, Tom B [Moraga, CA; Ham, Cheryl [Livermore, CA; Perkins, Dwight [Livermore, CA; Wong, James [Dublin, CA

    2012-05-15

    A real time gamma-ray signature/source identification method and system using principal components analysis (PCA) for transforming and substantially reducing one or more comprehensive spectral libraries of nuclear materials types and configurations into a corresponding concise representation/signature(s) representing and indexing each individual predetermined spectrum in principal component (PC) space, wherein an unknown gamma-ray signature may be compared against the representative signature to find a match or at least characterize the unknown signature from among all the entries in the library with a single regression or simple projection into the PC space, so as to substantially reduce processing time and computing resources and enable real-time characterization and/or identification.

  14. Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

    PubMed Central

    Greening, David W.; Ji, Hong; Chen, Maoshan; Robinson, Bruce W. S.; Dick, Ian M.; Creaney, Jenette; Simpson, Richard J.

    2016-01-01

    Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets. PMID:27605433

  15. Using fractal analysis of thermal signatures for thyroid disease evaluation

    NASA Astrophysics Data System (ADS)

    Gavriloaia, Gheorghe; Sofron, Emil; Gavriloaia, Mariuca-Roxana; Ghemigean, Adina-Mariana

    2010-11-01

    The skin is the largest organ of the body and it protects against heat, light, injury and infection. Skin temperature is an important parameter for diagnosing diseases. Thermal analysis is non-invasive, painless, and relatively inexpensive, showing a great potential research. Since the thyroid regulates metabolic rate it is intimately connected to body temperature, more than, any modification of its function generates a specific thermal image on the neck skin. The shapes of thermal signatures are often irregular in size and shape. Euclidean geometry is not able to evaluate their shape for different thyroid diseases, and fractal geometry is used in this paper. Different thyroid diseases generate different shapes, and their complexity are evaluated by specific mathematical approaches, fractal analysis, in order to the evaluate selfsimilarity and lacunarity. Two kinds of thyroid diseases, hyperthyroidism and papillary cancer are analyzed in this paper. The results are encouraging and show the ability to continue research for thermal signature to be used in early diagnosis of thyroid diseases.

  16. Gene Expression Profiles in Peripheral Blood Mononuclear Cells Can Distinguish Patients with Non-Small-Cell Lung Cancer from Patients with Non-Malignant Lung Disease

    PubMed Central

    Showe, Michael K.; Vachani, Anil; Kossenkov, Andrew V.; Yousef, Malik; Nichols, Calen; Nikonova, Elena V.; Chang, Celia; Kucharczuk, John; Tran, Bao; Wakeam, Elliot; Yie, Ting An; Speicher, David; Rom, William N.; Albelda, Steven

    2009-01-01

    Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small-cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell (PBMC) samples including 137 patients with NSCLC tumors and 91 patient controls with non-malignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC-gene signature in 18 NSCLCs taken pre-surgery, with matched samples from 2-5 months post-surgery, showed that in 78% of cases, the signature was reduced post-surgery and disappeared entirely in 33%. Our results demonstrate the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations. PMID:19951989

  17. Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test

    PubMed Central

    Zuiker, Rob G.J.A.; Tribouley, Catherine; Diamant, Zuzana; Boot, J. Diderik; Cohen, Adam F.; Van Dyck, K.; De Lepeleire, I.; Rivas, Veronica M.; Malkov, Vladislav A.; Burggraaf, Jacobus; Ruddy, Marcella K.

    2016-01-01

    Background Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly

  18. A multiple redundant genetic switch locks in the transcriptional signature of T regulatory cells

    PubMed Central

    Fu, Wenxian; Ergun, Ayla; Lu, Ting; Hill, Jonathan A.; Haxhinasto, Sokol; Fassett, Marlys S.; Gazit, Roi; Adoro, Stanley; Glimcher, Laurie; Chan, Susan; Kastner, Philippe; Rossi, Derrick; Collins, James J.; Mathis, Diane; Benoist, Christophe

    2013-01-01

    The transcription factor FoxP3 partakes dominantly in the specification and function of FoxP3+CD4+ T regulatory cells (Tregs), but is neither strictly necessary nor sufficient to determine the characteristic Treg signature. Computational network inference and experimental testing assessed the contribution of other transcription factors (TF). Enforced expression of Helios or Xbp1 elicited specific signatures, but Eos, Irf4, Satb1, Lef1 and Gata1 elicited exactly the same outcome, synergizing with FoxP3 to activate most of the Treg signature, including key TFs, and enhancing FoxP3 occupancy at its genomic targets. Conversely, the Treg signature was robust to inactivation of any single cofactor. A redundant genetic switch thus locks-in the Treg phenotype, a model which accounts for several aspects of Treg physiology, differentiation and stability. PMID:22961053

  19. Dynamic characteristics of signatures: effects of writer style on genuine and simulated signatures.

    PubMed

    Mohammed, Linton; Found, Bryan; Caligiuri, Michael; Rogers, Doug

    2015-01-01

    The aims of this study were to determine if computer-measured dynamic features (duration, size, velocity, jerk, and pen pressure) differ between genuine and simulated signatures. Sixty subjects (3 equal groups of 3 signature styles) each provided 10 naturally written (genuine) signatures. Each of these subjects then provided 15 simulations of each of three model signatures. The genuine (N = 600) and simulated (N = 2700) signatures were collected using a digitizing tablet. MovAlyzeR(®) software was used to estimate kinematic parameters for each pen stroke. Stroke duration, velocity, and pen pressure were found to discriminate between genuine and simulated signatures regardless of the simulator's own style of signature or the style of signature being simulated. However, there was a significant interaction between style and condition for size and jerk (a measure of smoothness). The results of this study, based on quantitative analysis and dynamic handwriting features, indicate that the style of the simulator's own signature and the style of signature being simulated can impact the characteristics of handwriting movements for simulations. Writer style characteristics might therefore need to be taken into consideration as potentially significant when evaluating signature features with a view to forming opinions regarding authenticity.

  20. Seasons on Venus - cloud cover signatures

    NASA Astrophysics Data System (ADS)

    Limaye, Sanjay; Markiewicz, Wojciech; Krauss, Robert

    2015-04-01

    With the smallest obliquity and orbital eccentricity of any planet around the Sun, Venus is not generally expected to show any seasonal variations in its atmosphere. Careful analysis of the global images obtained by the Venus Monitoring Camera (VMC) on board European Space Agency's Venus Express orbiter from 12 June 2006 orbit 24) till 15 September 2014 (orbit 3043) reveal short term variations and a detectable periodic variation in the normalized intensity (reflectance) as well as in unit optical depth at a fixed local time at low latitudes as well as at high latitudes. VMC ultraviolet images were brightness normalized using Minnaert Law and the brightness at the sub-solar meridian at different latitudes in the southern hemisphere. The unit optical dept was inferred by precision location of the limb location in images acquired during the apoapsis portion of the orbit at range greater than ~ 30,000 km from Venus center. The temporal changes of the unit optical depth was monitored at fixed solar zenith angles and latitude. The seasonal signature is more pronounced at high latitudes compared to low latitudes. The data suggest that the variations in insolation due to heliocentric range and the small obliquity are responsible for the periodic changes in the Venus cloud cover. Concurrent changes in the cloud changes are also observed at other three wavelengths (550, 950 and 1050 nm) at which VMC obtained images, but the number of images at these wavelengths is much smaller. A secular decrease in the image brightness is observed over the life of the Venus Express mission, most likely due to the degradation of the some of the optical/sensor elements.

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