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Gene Set (gene + set)
Selected AbstractsIdentification of differentially expressed genes in psoriasis using expression profiling approachesEXPERIMENTAL DERMATOLOGY, Issue 9 2005K. Itoh Abstract:, To identify differentially expressed genes which play causal roles in pathogenesis and maintenance for psoriasis, we used BodyMapping and introduced amplified fragment length polymorphism approaches. From the BodyMap database, we selected 2007 genes which specifically expressed in epithelial tissues. Among 2007 genes, we surveyed genes which differentially expressed in involved or uninvolved psoriatic lesional skin samples compared with atopic dermatitis, mycosis fungoides, and normal skin samples. As a result of surveying 2007 genes, 241 genes were differentially expressed only in involved psoriatic skin but not in the other samples. Hierarchical cluster analysis of gene expression profiles showed that 13 independent psoriatic-involved skin samples clustered tightly together, reflecting highly similar expression profiles. Using the same 2007 gene set, we examined gene expression levels in five serial lesions from distal uninvolved psoriatic skin to involved psoriatic plaque. We identified seven genes such as alpha-1-microglobulin/bikunin precursor, calnexin, claudin 1, leucine zipper down-regulated in cancer 1, tyrosinase-related protein 1, Yes-associated protein 1, and unc-13-like protein (Coleonyx elegans) which show high-expression levels only in uninvolved psoriatic lesions. These seven genes, which were reported to be related to apoptosis or antiproliferation, might have causal roles in pathophysiology in psoriasis. [source] The gene expression signature of genomic instability in breast cancer is an independent predictor of clinical outcome,INTERNATIONAL JOURNAL OF CANCER, Issue 7 2009Jens K. Habermann Abstract Recently, expression profiling of breast carcinomas has revealed gene signatures that predict clinical outcome, and discerned prognostically relevant breast cancer subtypes. Measurement of the degree of genomic instability provides a very similar stratification of prognostic groups. We therefore hypothesized that these features are linked. We used gene expression profiling of 48 breast cancer specimens that profoundly differed in their degree of genomic instability and identified a set of 12 genes that defines the 2 groups. The biological and prognostic significance of this gene set was established through survival prediction in published datasets from patients with breast cancer. Of note, the gene expression signatures that define specific prognostic subtypes in other breast cancer datasets, such as luminal A and B, basal, normal-like, and ERBB2+, and prognostic signatures including MammaPrint® and Oncotype DX, predicted genomic instability in our samples. This remarkable congruence suggests a biological interdependence of poor-prognosis gene signatures, breast cancer subtypes, genomic instability, and clinical outcome. © 2008 Wiley-Liss, Inc. [source] Molecular profiling of platinum resistant ovarian cancer,INTERNATIONAL JOURNAL OF CANCER, Issue 8 2006Jozien Helleman Abstract The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n = 5) and the responders (n = 19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68,1.09) and a specificity of 59% (95% CI: 0.47,0.71)(OR = 0.09, p = 0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p < 0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies. © 2005 Wiley-Liss, Inc. [source] Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/NrfAGING CELL, Issue 5 2009Riva P. Oliveira Summary Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress,response conditions. Under nonstressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1- dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses. [source] Human Variation in Alcohol Response Is Influenced by Variation in Neuronal Signaling GenesALCOHOLISM, Issue 5 2010Geoff Joslyn Background:, Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. Methods:, A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. Results:, The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. Conclusions:, These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects. [source] Chemokine RANTES Promoter Polymorphisms in Allergic Rhinitis,THE LARYNGOSCOPE, Issue 4 2004Jeong Joong Kim PhD Abstract Objectives/Hypothesis RANTES is one of the most widely studied of the chemokines linked to allergic diseases. Two polymorphisms of the RANTES promoter region (,403 G/A and ,28 C/G) have been found. The authors investigated whether these RANTES promoter polymorphisms were associated with allergic rhinitis. Study Design Case-control study. Methods Blood samples for genetic analysis were obtained from 151 individuals with allergic rhinitis and from 278 healthy individuals without atopic disease. Polymerase chain reaction,based assays for detection of the ,403 G/A and ,28 C/G polymorphisms of the RANTES gene were used for genotyping. Results The frequencies of both the RANTES ,403A and ,28G alleles were significantly higher in patients with allergic rhinitis than in control subjects (P < .05 for both). Conclusion The study results indicated that the ,403 and ,28 alleles in the RANTES promoter region belong to the predictor gene set for allergic rhinitis and could be used in genomic analysis. [source] Identification of a novel cis -acting element conferring sulfur deficiency response in Arabidopsis rootsTHE PLANT JOURNAL, Issue 3 2005Akiko Maruyama-Nakashita Summary SULTR1;1 high-affinity sulfate transporter is highly regulated in the epidermis and cortex of Arabidopsis roots responding to sulfur deficiency (,S). We identified a novel cis -acting element involved in the ,S-inducible expression of sulfur-responsive genes in Arabidopsis. The promoter region of SULTR1;1 was dissected for deletion and gain-of-function analysis using luciferase (LUC) reporter gene in transgenic Arabidopsis. The 16-bp sulfur-responsive element (SURE) from ,2777 to ,2762 of SULTR1;1 promoter was sufficient and necessary for the ,S-responsive expression, which was reversed when supplied with cysteine and glutathione (GSH). The SURE sequence contained an auxin response factor (ARF) binding sequence (GAGACA). However, SURE was not responsive to naphthalene acetic acid, indicating its specific function in the sulfur response. The base substitution analysis indicated the significance of a 5-bp sequence (GAGAC) within the conserved ARF binding site as a core element for the ,S response. Microarray analysis of early ,S response in Arabidopsis roots indicated the presence of SURE core sequences in the promoter regions of ,S-inducible genes on a full genome GeneChip array. It is suggested that SURE core sequences may commonly regulate the expression of a gene set required for adaptation to the ,S environment. [source] High-Dimensional Cox Models: The Choice of Penalty as Part of the Model Building ProcessBIOMETRICAL JOURNAL, Issue 1 2010Axel Benner Abstract The Cox proportional hazards regression model is the most popular approach to model covariate information for survival times. In this context, the development of high-dimensional models where the number of covariates is much larger than the number of observations ( ) is an ongoing challenge. A practicable approach is to use ridge penalized Cox regression in such situations. Beside focussing on finding the best prediction rule, one is often interested in determining a subset of covariates that are the most important ones for prognosis. This could be a gene set in the biostatistical analysis of microarray data. Covariate selection can then, for example, be done by L1 -penalized Cox regression using the lasso (Tibshirani (1997). Statistics in Medicine16, 385,395). Several approaches beyond the lasso, that incorporate covariate selection, have been developed in recent years. This includes modifications of the lasso as well as nonconvex variants such as smoothly clipped absolute deviation (SCAD) (Fan and Li (2001). Journal of the American Statistical Association96, 1348,1360; Fan and Li (2002). The Annals of Statistics30, 74,99). The purpose of this article is to implement them practically into the model building process when analyzing high-dimensional data with the Cox proportional hazards model. To evaluate penalized regression models beyond the lasso, we included SCAD variants and the adaptive lasso (Zou (2006). Journal of the American Statistical Association101, 1418,1429). We compare them with "standard" applications such as ridge regression, the lasso, and the elastic net. Predictive accuracy, features of variable selection, and estimation bias will be studied to assess the practical use of these methods. We observed that the performance of SCAD and adaptive lasso is highly dependent on nontrivial preselection procedures. A practical solution to this problem does not yet exist. Since there is high risk of missing relevant covariates when using SCAD or adaptive lasso applied after an inappropriate initial selection step, we recommend to stay with lasso or the elastic net in actual data applications. But with respect to the promising results for truly sparse models, we see some advantage of SCAD and adaptive lasso, if better preselection procedures would be available. This requires further methodological research. [source] Computational identification of altered metabolism using gene expression and metabolic pathwaysBIOTECHNOLOGY & BIOENGINEERING, Issue 4 2009Hojung Nam Abstract Understanding altered metabolism is an important issue because altered metabolism is often revealed as a cause or an effect in pathogenesis. It has also been shown to be an important factor in the manipulation of an organism's metabolism in metabolic engineering. Unfortunately, it is not yet possible to measure the concentration levels of all metabolites in the genome-wide scale of a metabolic network; consequently, a method that infers the alteration of metabolism is beneficial. The present study proposes a computational method that identifies genome-wide altered metabolism by analyzing functional units of KEGG pathways. As control of a metabolic pathway is accomplished by altering the activity of at least one rate-determining step enzyme, not all gene expressions of enzymes in the pathway demonstrate significant changes even if the pathway is altered. Therefore, we measure the alteration levels of a metabolic pathway by selectively observing expression levels of significantly changed genes in a pathway. The proposed method was applied to two strains of Saccharomyces cerevisiae gene expression profiles measured in very high-gravity (VHG) fermentation. The method identified altered metabolic pathways whose properties are related to ethanol and osmotic stress responses which had been known to be observed in VHG fermentation because of the high sugar concentration in growth media and high ethanol concentration in fermentation products. With the identified altered pathways, the proposed method achieved best accuracy and sensitivity rates for the Red Star (RS) strain compared to other three related studies (gene-set enrichment analysis (GSEA), significance analysis of microarray to gene set (SAM-GS), reporter metabolite), and for the CEN.PK 113-7D (CEN) strain, the proposed method and the GSEA method showed comparably similar performances. Biotechnol. Bioeng. 2009;103: 835,843. © 2009 Wiley Periodicals, Inc. [source] Dynamics of genome evolution in facultative symbionts of aphidsENVIRONMENTAL MICROBIOLOGY, Issue 8 2010Patrick H. Degnan Summary Aphids are sap-feeding insects that host a range of bacterial endosymbionts including the obligate, nutritional mutualist Buchnera plus several bacteria that are not required for host survival. Among the latter, ,Candidatus Regiella insecticola' and ,Candidatus Hamiltonella defensa' are found in pea aphids and other hosts and have been shown to protect aphids from natural enemies. We have sequenced almost the entire genome of R. insecticola (2.07 Mbp) and compared it with the recently published genome of H. defensa (2.11 Mbp). Despite being sister species the two genomes are highly rearranged and the genomes only have ,55% of genes in common. The functions encoded by the shared genes imply that the bacteria have similar metabolic capabilities, including only two essential amino acid biosynthetic pathways and active uptake mechanisms for the remaining eight, and similar capacities for host cell toxicity and invasion (type 3 secretion systems and RTX toxins). These observations, combined with high sequence divergence of orthologues, strongly suggest an ancient divergence after establishment of a symbiotic lifestyle. The divergence in gene sets and in genome architecture implies a history of rampant recombination and gene inactivation and the ongoing integration of mobile DNA (insertion sequence elements, prophage and plasmids). [source] Chromosomal antioxidant genes have metal ion-specific roles as determinants of bacterial metal toleranceENVIRONMENTAL MICROBIOLOGY, Issue 10 2009Joe J. Harrison Summary Microbiological metal toxicity involves redox reactions between metal species and cellular molecules, and therefore, we hypothesized that antioxidant systems might be chromosomal determinants affecting the susceptibility of bacteria to metal toxicity. Here, survival was quantified in metal ion-exposed planktonic cultures of several Escherichia coli strains, each bearing a mutation in a gene important for redox homeostasis. This characterized ,250 gene,metal combinations and identified that sodA, sodB, gor, trxA, gshA, grxA and marR have distinct roles in safeguarding or sensitizing cells to different toxic metal ions (Cr2O72,, Co2+, Cu2+, Ag+, Zn2+, AsO2,, SeO32, or TeO32,). To shed light on these observations, fluorescent sensors for reactive oxygen species (ROS) and reduced thiol (RSH) quantification were used to ascertain that different metal ions exert oxidative toxicity through disparate modes-of-action. These oxidative mechanisms of metal toxicity were categorized as involving ROS and thiol-disulfide chemistry together (AsO2,, SeO32,), ROS predominantly (Cu2+, Cr2O72,) or thiol-disulfide chemistry predominantly (Ag+, Co2+, Zn2+, TeO32,). Corresponding to this, promoter- luxCDABE fusions showed that toxic doses of different metal ions up- or downregulate the transcription of gene sets marking distinct pathways of cellular oxidative stress. Altogether, our findings suggest that different metal ions are lethal to cells through discrete pathways of oxidative biochemistry, and moreover, indicate that chromosomally encoded antioxidant systems may have metal ion-specific physiological roles as determinants of bacterial metal tolerance. [source] Two independent gene signatures in pediatric t(4;11) acute lymphoblastic leukemia patientsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2009Luca Trentin Abstract Objective:, Gene expression profiles become increasingly more important for diagnostic procedures, allowing clinical predictions including treatment response and outcome. However, the establishment of specific and robust gene signatures from microarray data sets requires the analysis of large numbers of patients and the application of complex biostatistical algorithms. Especially in case of rare diseases and due to these constrains, diagnostic centers with limited access to patients or bioinformatic resources are excluded from implementing these new technologies. Method:, In our study we sought to overcome these limitations and for proof of principle, we analyzed the rare t(4;11) leukemia disease entity. First, gene expression data of each t(4;11) leukemia patient were normalized by pairwise subtraction against normal bone marrow (n = 3) to identify significantly deregulated gene sets for each patient. Result:, A ,core signature' of 186 commonly deregulated genes present in each investigated t(4;11) leukemia patient was defined. Linking the obtained gene sets to four biological discriminators (HOXA gene expression, age at diagnosis, fusion gene transcripts and chromosomal breakpoints) divided patients into two distinct subgroups: the first one comprised infant patients with low HOXA genes expression and the MLL breakpoints within introns 11/12. The second one comprised non-infant patients with high HOXA expression and MLL breakpoints within introns 9/10. Conclusion:, A yet homogeneous leukemia entity was further subdivided, based on distinct genetic properties. This approach provided a simplified way to obtain robust and disease-specific gene signatures even in smaller cohorts. [source] Heterogeneity of gene expression profiles in head and neck cancerHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 12 2007Jimmy Pramana MD Abstract Background. Results of gene expression profiling studies from different institutes often lack consistency. This could be due to the use of different microarray platforms and protocols, or to intratumoral heterogeneity in mRNA expression. The aim of our study was to quantify intratumoral heterogeneity in head and neck cancer. Methods. Forty-four fresh frozen biopsies were taken from 22 patients, 2 per tumor. RNA was extracted, tested for quality, amplified, labeled, and hybridized to a 35k oligoarray. Results. Unsupervised clustering analyses using all genes, the most variable genes, or random gene sets showed that 80% to 90% of biopsy pairs clustered together. A within-pair-between-pair scatter ratio analysis showed that the similarity between matching pairs was significantly greater than that between random pairs (p <.00001). Conclusions. Two biopsies from the same tumor show far greater similarity in gene expression than biopsies from different tumors, supporting the use of 1 biopsy for expression profiling. © 2007 Wiley Periodicals, Inc. Head Neck 2007 [source] Molecular Basis of the Anaerobic Response in PlantsIUBMB LIFE, Issue 2 2001Rudy Dolferus The response of plants to flooding is complex and involves the induction of specific gene sets. A multidisciplinary approach by several research teams has led to a reasonably good understanding of the low oxygen response, and many of the genes and proteins that are involved are known. But the factors that are critical in determining tolerance or intolerance remain unknown. Microarray technology offers renewed hope to unravel the complex changes in gene expression occurring in plants upon low oxygen treatment and what mechanisms are involved in the response. [source] Pathway analysis of dilated cardiomyopathy using global proteomic profiling and enrichment mapsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 6 2010Ruth Isserlin Abstract Global protein expression profiling can potentially uncover perturbations associated with common forms of heart disease. We have used shotgun MS/MS to monitor the state of biological systems in cardiac tissue correlating with disease onset, cardiac insufficiency and progression to heart failure in a time-course mouse model of dilated cardiomyopathy. However, interpreting the functional significance of the hundreds of differentially expressed proteins has been challenging. Here, we utilize improved enrichment statistical methods and an extensive collection of functionally related gene sets, gaining a more comprehensive understanding of the progressive alterations associated with functional decline in dilated cardiomyopathy. We visualize the enrichment results as an Enrichment Map, where significant gene sets are grouped based on annotation similarity. This approach vastly simplifies the interpretation of the large number of enriched gene sets found. For pathways of specific interest, such as Apoptosis and the MAPK (mitogen-activated protein kinase) cascade, we performed a more detailed analysis of the underlying signaling network, including experimental validation of expression patterns. [source] Seed after-ripening is a discrete developmental pathway associated with specific gene networks in ArabidopsisTHE PLANT JOURNAL, Issue 2 2008Esther Carrera Summary After-ripening (AR) is a time and environment regulated process occurring in the dry seed, which determines the germination potential of seeds. Both metabolism and perception of the phytohormone abscisic acid (ABA) are important in the initiation and maintenance of dormancy. However, molecular mechanisms that regulate the capacity for dormancy or germination through AR are unknown. To understand the relationship between ABA and AR, we analysed genome expression in Arabidopsis thaliana mutants defective in seed ABA synthesis (aba1-1) or perception (abi1-1). Even though imbibed mutant seeds showed no dormancy, they exhibited changes in global gene expression resulting from dry AR that were comparable with changes occurring in wild-type (WT) seeds. Core gene sets were identified that were positively or negatively regulated by dry seed storage. Each set included a gene encoding repression or activation of ABA function (LPP2 and ABA1, respectively), thereby suggesting a mechanism through which dry AR may modulate subsequent germination potential in WT seeds. Application of exogenous ABA to after-ripened WT seeds did not reimpose characteristics of freshly harvested seeds on imbibed seed gene expression patterns. It was shown that secondary dormancy states reinstate AR status-specific gene expression patterns. A model is presented that separates the action of ABA in seed dormancy from AR and dry storage regulated gene expression. These results have major implications for the study of genetic mechanisms altered in seeds as a result of crop domestication into agriculture, and for seed behaviour during dormancy cycling in natural ecosystems. [source] Abiotic stress and plant responses from the whole vine to the genesAUSTRALIAN JOURNAL OF GRAPE AND WINE RESEARCH, Issue 2010G.R. CRAMER Abstract Drought, salinity and extreme temperatures significantly limit the distribution of grapes around the world. In this review, the literature of grape responses to abiotic stress with particular reference to whole plant and molecular responses observed in recent studies is discussed. A number of short-term and long-term studies on grapevine shoots and berries have been conducted using a systems biology approach. Transcripts, proteins and metabolites were profiled. Water deficit, salinity and chilling altered the steady-state abundance of a large number of transcripts. Common responses to these stresses included changes in hormone metabolism, particularly abscisic acid (ABA), photosynthesis, growth, transcription, protein synthesis, signalling and cellular defences. Some of the transcriptional changes induced by stress were confirmed by proteomic and metabolomic analyses. More than 2000 genes were identified whose transcript abundance was altered by both water deficit and ABA. Different gene sets were used to map molecular pathways regulated by ABA, water deficit, salinity and chilling in grapevine. This work supports the hypothesis that ABA is a central regulator of abiotic stress tolerance mechanisms. ABA affects signalling pathways that trigger important molecular activities involving metabolism, transcription, protein synthesis, and cellular defence and also regulates important physiological responses such as stomatal conductance, photoprotection and growth. Systems biology approaches are providing more comprehensive understanding of the complex plant responses to abiotic stress. The molecular sets generated from mapping the ABA-inducible stress responses provide numerous targets for genetic and cultural manipulation for improved plant protection and grape quality. [source] | ||||||||||||||||