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  • 1
    Online Resource
    Online Resource
    Clustered Genomic Alterations in Chromosome 7p Dictate Outcomes and Targeted Treatment Responses of Lung Adenocarcinoma With EGFR -Activating Mutations
    American Society of Clinical Oncology (ASCO) ; 2011
    In:  Journal of Clinical Oncology Vol. 29, No. 25 ( 2011-09-01), p. 3435-3442
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 29, No. 25 ( 2011-09-01), p. 3435-3442
    Abstract: Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been proven more effective for patients with lung adenocarcinoma with EGFR-activating mutation rather than wild type, the former group still includes approximately 30% nonresponders. The molecular basis of this substantial response heterogeneity is unknown. Our purpose was to seek molecular aberrations contributing to disease progression at the genome-wide level and identify the prognostic signature unique to patients with EGFR-activating mutation. Patients and Methods We first investigated the molecular differences between tumors with EGFR-activating mutation and wild-type tumors by conducting high-density array comparative genomic hybridization on a collection of 138 adenocarcinoma tissues. We then used an independent group of 114 patients to validate the clinical relevance of copy-number alterations (CNAs) in predicting overall and disease-free survival. Finally, focusing on 23 patients with EGFR mutation receiving EGFR-TKI treatment, we investigated the association between CNAs and response to EGFR-TKIs. Results We identified chromosome regions with differential CNAs between tumors with EGFR-activating mutation and wild-type tumors and found the aberration sites to cluster highly on chromosome 7p. A cluster of six representative chromosome 7p genes predicted overall and disease-free survival for patients with EGFR-activating mutation but not for those with wild type. Importantly, simultaneous presence of more genes with increased CNAs in this cluster correlated with less favorable response to EGFR-TKIs in patients with EGFR-activating mutation. Conclusion Our results shed light on why responses to EGFR-TKIs are heterogeneous among patients with EGFR-activating mutation. They may lead to better patient management in this population.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2011.35.3979
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2011
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Trait-trait dynamic interaction: 2D-trait eQTL mapping for genetic variation study
    Springer Science and Business Media LLC ; 2008
    In:  BMC Genomics Vol. 9, No. 1 ( 2008-12)
    Details
    In: BMC Genomics, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2008-12)
    Abstract: Many studies have shown that the abundance level of gene expression is heritable. Analogous to the traditional genetic study, most researchers treat the expression of one gene as a quantitative trait and map it to expression quantitative trait loci (eQTL). This is 1D-trait mapping. 1D-trait mapping ignores the trait-trait interaction completely, which is a major shortcoming. Results To overcome this limitation, we study the expression of a pair of genes and treat the variation in their co-expression pattern as a two dimensional quantitative trait. We develop a method to find gene pairs, whose co-expression patterns, including both signs and strengths, are mediated by genetic variations and map these 2D-traits to the corresponding genetic loci. We report several applications by combining 1D-trait mapping with 2D-trait mapping, including the contribution of genetic variations to the perturbations in the regulatory mechanisms of yeast metabolic pathways. Conclusion Our approach of 2D-trait mapping provides a novel and effective way to connect the genetic variation with higher order biological modules via gene expression profiles.
    Type of Medium: Online Resource
    ISSN: 1471-2164
    URL: Article
    DOI: 10.1186/1471-2164-9-242
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2041499-7
    SSG: 12
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  • 3
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    Online Resource
    R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 20 ( 2015-07-10), p. 2303-2310
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 20 ( 2015-07-10), p. 2303-2310
    Abstract: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. Patients and Methods Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. Results YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P 〈 .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. Conclusion These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2014.59.3590
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 4
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    Online Resource
    A Data-Mining Scheme for Identifying Peptide Structural Motifs Responsible for Different MS/MS Fragmentation Intensity Patterns
    American Chemical Society (ACS) ; 2008
    In:  Journal of Proteome Research Vol. 7, No. 1 ( 2008-01-01), p. 70-79
    Details
    In: Journal of Proteome Research, American Chemical Society (ACS), Vol. 7, No. 1 ( 2008-01-01), p. 70-79
    Type of Medium: Online Resource
    ISSN: 1535-3893 , 1535-3907
    URL: Article
    DOI: 10.1021/pr070106u
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2008
    detail.hit.zdb_id: 2065254-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Study of coordinative gene expression at the biological process level
    Oxford University Press (OUP) ; 2005
    In:  Bioinformatics Vol. 21, No. 18 ( 2005-09-15), p. 3651-3657
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 21, No. 18 ( 2005-09-15), p. 3651-3657
    Abstract: Motivation: Cellular processes are not isolated groups of events. Nevertheless, in most microarray analyses, they tend to be treated as standalone units. To shed light on how various parts of the interlocked biological processes are coordinated at the transcription level, there is a need to study the between-unit expressional relationship directly. Results: We approach this issue by constructing an index of correlation function to convey the global pattern of coexpression between genes from one process and genes from the entire genome. Processes with similar signatures are then identified and projected to a process-to-process association graph. This top–down method allows for detailed gene-level analysis between linked processes to follow up. Using the cell-cycle gene-expression profiles for Saccharomyces cerevisiae, we report well-organized networks of biological processes that would be difficult to find otherwise. Using another dataset, we report a sharply different network structure featuring cellular responses under environmental stress. Contact:  kcli@stat.ucla.edu Supplementary information:  http://kiefer.stat.ucla.edu/lap2/download/KL_supplement.pdf
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/bti599
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2005
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Finding disease candidate genes by liquid association
    Springer Science and Business Media LLC ; 2007
    In:  Genome Biology Vol. 8, No. 10 ( 2007), p. R205-
    Details
    In: Genome Biology, Springer Science and Business Media LLC, Vol. 8, No. 10 ( 2007), p. R205-
    Type of Medium: Online Resource
    ISSN: 1465-6906
    URL: Article
    DOI: 10.1186/gb-2007-8-10-r205
    Language: Unknown
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2007
    detail.hit.zdb_id: 2040529-7
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Human protein–protein interaction prediction by a novel sequence-based co-evolution method: co-evolutionary divergence
    Oxford University Press (OUP) ; 2013
    In:  Bioinformatics Vol. 29, No. 1 ( 2013-01-01), p. 92-98
    Details
    In: Bioinformatics, Oxford University Press (OUP), Vol. 29, No. 1 ( 2013-01-01), p. 92-98
    Abstract: Motivation: Protein–protein interaction (PPI) plays an important role in understanding gene functions, and many computational PPI prediction methods have been proposed in recent years. Despite the extensive efforts, PPI prediction still has much room to improve. Sequence-based co-evolution methods include the substitution rate method and the mirror tree method, which compare sequence substitution rates and topological similarity of phylogenetic trees, respectively. Although they have been used to predict PPI in species with small genomes like Escherichia coli, such methods have not been tested in large scale proteome like Homo sapiens. Result: In this study, we propose a novel sequence-based co-evolution method, co-evolutionary divergence (CD), for human PPI prediction. Built on the basic assumption that protein pairs with similar substitution rates are likely to interact with each other, the CD method converts the evolutionary information from 14 species of vertebrates into likelihood ratios and combined them together to infer PPI. We showed that the CD method outperformed the mirror tree method in three independent human PPI datasets by a large margin. With the arrival of more species genome information generated by next generation sequencing, the performance of the CD method can be further improved. Availability: Source code and support are available at http://mib.stat.sinica.edu.tw/LAP/tmp/CD.rar. Contact:  syuan@stat.sinica.edu.tw Supplementary information:  Supplementary data are available at Bioinformatics online.
    Type of Medium: Online Resource
    ISSN: 1367-4811 , 1367-4803
    URL: Article
    DOI: 10.1093/bioinformatics/bts620
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2013
    detail.hit.zdb_id: 1468345-3
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    A method for analyzing censored survival phenotype with gene expression data
    Springer Science and Business Media LLC ; 2008
    In:  BMC Bioinformatics Vol. 9, No. 1 ( 2008-12)
    Details
    In: BMC Bioinformatics, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2008-12)
    Abstract: Survival time is an important clinical trait for many disease studies. Previous works have shown certain relationship between patients' gene expression profiles and survival time. However, due to the censoring effects of survival time and the high dimensionality of gene expression data, effective and unbiased selection of a gene expression signature to predict survival probabilities requires further study. Method We propose a method for an integrated study of survival time and gene expression. This method can be summarized as a two-step procedure: in the first step, a moderate number of genes are pre-selected using correlation or liquid association (LA). Imputation and transformation methods are employed for the correlation/LA calculation. In the second step, the dimension of the predictors is further reduced using the modified sliced inverse regression for censored data (censorSIR). Results The new method is tested via both simulated and real data. For the real data application, we employed a set of 295 breast cancer patients and found a linear combination of 22 gene expression profiles that are significantly correlated with patients' survival rate. Conclusion By an appropriate combination of feature selection and dimension reduction, we find a method of identifying gene expression signatures which is effective for survival prediction.
    Type of Medium: Online Resource
    ISSN: 1471-2105
    URL: Article
    DOI: 10.1186/1471-2105-9-417
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 2041484-5
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    A system for enhancing genome-wide coexpression dynamics study
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 44 ( 2004-11-02), p. 15561-15566
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 44 ( 2004-11-02), p. 15561-15566
    Abstract: Statistical similarity analysis has been instrumental in elucidation of the voluminous microarray data. Genes with correlated expression profiles tend to be functionally associated. However, the majority of functionally associated genes turn out to be uncorrelated. One conceivable reason is that the expression of a gene can be sensitively dependent on the often-varying cellular state. The intrinsic state change has to be plastically accommodated by gene-regulatory mechanisms. To capture such dynamic coexpression between genes, a concept termed “liquid association” (LA) has been introduced recently. LA offers a scoring system to guide a genome-wide search for critical cellular players that may interfere with the coexpression of a pair of genes, thereby weakening their overall correlation. Although the LA method works in many cases, a direct extension to more than two genes is hindered by the “curse of dimensionality.” Here we introduce a strategy of finding an informative 2D projection to generalize LA for multiple genes. A web site is constructed that performs on-line LA computation for any user-specified group of genes. We apply this scoring system to study yeast protein complexes by using the Saccharomyces cerevisiae protein complexes database of the Munich Information Center for Protein Sequences. Human genes are also investigated by profiling of 60 cancer cell lines of the National Cancer Institute. In particular, our system links the expression of the Alzheimer's disease hallmark gene APP (amyloid-β precursor protein) to the β-site-cleaving enzymes BACE and BACE2, the γ-site-cleaving enzymes presenilin 1 and 2, apolipoprotein E, and other Alzheimer's disease-related genes.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0402962101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 10
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    Online Resource
    A Four-Gene Signature from NCI-60 Cell Line for Survival Prediction in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 23 ( 2009-12-01), p. 7309-7315
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 23 ( 2009-12-01), p. 7309-7315
    Abstract: Purpose: Metastasis is the main cause of mortality in non–small cell lung cancer (NSCLC) patients. Genes that can discriminate the invasion ability of cancer cells may become useful candidates for clinical outcome prediction. We identify invasion-associated genes through computational and laboratorial approach that supported this idea in NSCLC. Experimental Design: We first conducted invasion assay to characterize the invasion abilities of NCI-60 lung cancer cell lines. We then systematically exploited NCI-60 microarray databases to identify invasion-associated genes that showed differential expression between the high and the low invasion cell line groups. Furthermore, using the microarray data of Duke lung cancer cohort (GSE 3141), invasion-associated genes with good survival prediction potentials were obtained. Finally, we validated the findings by conducting quantitative PCR assay on an in-house collected patient group (n = 69) and by using microarray data from two public western cohorts (n = 257 and 186). Results: The invasion-associated four-gene signature (ANKRD49, LPHN1, RABAC1, and EGLN2) had significant prediction in three validation cohorts (P = 0.0184, 0.002, and 0.017, log-rank test). Moreover, we showed that four-gene signature was an independent prognostic factor (hazard ratio, 2.354, 1.480, and 1.670; P = 0.028, 0.014, and 0.033), independent of other clinical covariates, such as age, gender, and stage. Conclusion: The invasion-associated four-gene signature derived from NCI-60 lung cancer cell lines had good survival prediction power for NSCLC patients. (Clin Cancer Res 2009;15(23):7309–15)
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-1572
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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