Leveraging a Pharmacogenomics Knowledgebase to Formulate a Drug Response Phenotype Terminology for Genomic Medicine (Preprint)

2021 ◽  
Author(s):  
Yiqing Zhao ◽  
Matthew Brush ◽  
Chen Wang ◽  
Hongfang Liu ◽  
Robert R Freimuth
Keyword(s):  
Drug Response ◽  
Genomic Medicine ◽  
Genetic Mutations ◽  
Gene Products ◽  
Knowledge Model ◽  
Knowledge Models ◽  
Response Phenotype ◽  
Structured Knowledge ◽  
High Level ◽  
Clinical Systems

BACKGROUND Despite the increasing evidence of utility of genomic medicine in clinical practice, systematically integrating genomic medicine information and knowledge into clinical systems with a high-level of consistency, scalability, and computability remains challenging. A comprehensive terminology is required for relevant concepts and the associated knowledge model for representing relationships. OBJECTIVE Our study aims to propose a drug response phenotype terminology to represent relationships between genetic variants and drugs in existing knowledge models. METHODS In this study, we leveraged PharmGKB, a comprehensive pharmacogenomics (PGx) knowledgebase, to formulate a terminology for drug response phenotypes that can represent relationships between genetic mutations and treatments. We evaluated coverage of the terminology through manual review of a randomly selected subset of 200 sentences extracted from genetic reports that contained concepts for “Genes and Gene Products” and “Treatments”. RESULTS Results showed that our proposed drug response phenotype terminology could cover 96% of the drug response phenotypes in genetic reports. Among 18,653 sentences that contained both “Genes and Gene Products” and “Treatments”, 3,011 sentences were able to be mapped to a drug response phenotype in our proposed terminology, among which the most discussed drug response phenotypes were response (994), sensitivity (829), and survival (332). In addition, we were able to re-analyze genetic report context incorporating the proposed terminology and enrich our previously proposed PGx knowledge model to reveal relationships between genetic mutations and treatments. CONCLUSIONS In conclusion, we proposed a drug response phenotype terminology that enhanced structured knowledge representation of genomic medicine.

Regulation of the junB gene by v-src

1992 ◽  
Vol 12 (8) ◽  
pp. 3356-3364
Author(s):  
I Apel ◽  
C L Yu ◽  
T Wang ◽  
C Dobry ◽  
M E Van Antwerp ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Gene Products ◽  
3T3 Cells ◽  
Tyrosine Kinase Activity ◽  
Basal Expression ◽  
High Level ◽  
Transformed Cell Lines ◽  
Point Mutagenesis ◽  
Nih 3T3 ◽  
Nucleotide Region

The proteins encoded by cellular and viral src genes are believed to be involved in the transmission of mitogenic signals, the nuclear recipients of which are largely unknown. In this work, we report that four different v-src-transformed cell lines from three different species possess elevated levels of junB transcripts. Transient expression of junB promoter-chloramphenicol acetyltransferase constructs in NIH 3T3 cells was used to demonstrate that the increase in junB transcripts was specifically associated with v-src expression and could not be recapitulated with a c-src, v-H-ras, or v-raf expression vector. Deletion mutants were used to localize the v-src-responsive region in the junB promoter to a 121-nucleotide region encompassing the CCAAT and TATAA elements. This region is distinct from one in the 5' untranslated region of the junB gene which is required to maintain its high-level basal expression. Point mutagenesis of the junB TATAA box completely abolished v-src responsiveness, suggesting that proteins which bind to this element are modified by src transformation. Several v-src and c-src mutants were used to demonstrate that elevated tyrosine kinase activity of src proteins is required for the observed effects on junB expression. Finally, homology between the TATAA box regions of junB and the unrelated but src-responsive gene 9E3/CEF-4 suggests that modulation of gene activity through proteins which bind to this region may be a recurrent, although not exclusive, theme in src transforming action. Our results suggest that src proteins may modulate some nuclear effectors through pathways not involving cellular ras or raf gene products.

An Ontological Approach to Enterprise Knowledge Modeling in a Shipping Company

2011 ◽  
Vol 7 (4) ◽  
pp. 70-84
Author(s):  
Sung-kwan Kim ◽  
Joe Felan ◽  
Moo Hong Kang
Keyword(s):  
Knowledge Management ◽  
Organizational Knowledge ◽  
Modeling Language ◽  
Knowledge Modeling ◽  
Knowledge Model ◽  
Holistic View ◽  
Knowledge Resources ◽  
Shipping Company ◽  
Knowledge Models ◽  
Ontological Approach

Modeling approaches are gaining popularity in knowledge management (KM), especially in specifying knowledge contents. This paper addresses the enterprise knowledge modeling. An enterprise knowledge model provides users with an integrated, holistic view of organizational knowledge resources. Employing a reliable methodology is critical to building successful enterprise knowledge models. A good methodology provides an effective and efficient mechanism for developing a model. This paper first reviews the enterprise knowledge modeling (EKM) and its methodologies. An ontology-based EKM (OBEKM) methodology is proposed. Its products, procedures, and modeling language are described. The methodology is then applied to the construction of a shipping company’s knowledge model for demonstration.

Isolation of Listeria monocytogenes mutants with high-level in vitro expression of host cytosol-induced gene products

2003 ◽  
Vol 48 (6) ◽  
pp. 1537-1551 ◽  
Author(s):  
Lynne M. Shetron-Rama ◽  
Kimberly Mueller ◽  
Juan M. Bravo ◽  
H. G. Archie Bouwer ◽  
Sing Sing Way ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Gene Products ◽  
In Vitro Expression ◽  
High Level

scholarly journals Structural and functional analysis of a promoter of the human granulin/epithelin gene

1996 ◽  
Vol 319 (2) ◽  
pp. 441-447 ◽  
Author(s):  
Vijay BHANDARI ◽  
Rachael DANIEL ◽  
Pheng Siew LIM ◽  
Andrew BATEMAN
Keyword(s):  
Promoter Activity ◽  
Biologically Active ◽  
Gene Products ◽  
High Level Expression ◽  
Haematopoietic Cells ◽  
Molecular Masses ◽  
Chloramphenicol Acetyltransferase Gene ◽  
High Level

Granulins (grns) or epithelins (epis) are peptides with molecular masses of approx. 6 kDa that modulate the growth of cells. The precursor for the grns/epis, which might itself be biologically active, is a secreted glycoprotein containing multiple repeats of the grn/epi motif. Grn/epi mRNA occurs widely in vivo, particularly in tissues rich in epithelial and haematopoietic cells. To understand better the role of the gene products for grn/epi it is important to determine the patterns of grn/epi gene expression and how this is regulated. To assist in this we have obtained the 5´ sequence of the human grn/epi gene, and using chimaeras of the grn/epi -5´ sequence and the chloramphenicol acetyltransferase gene we have shown a strong promoter activity associated with the 5´ sequence of the human grn/epi gene. We have further delineated regions of the 5´ sequence that confer high-level expression on the chimaeric gene.

scholarly journals Posttranslational control of Ty1 retrotransposition occurs at the level of protein processing.

1992 ◽  
Vol 12 (6) ◽  
pp. 2813-2825 ◽  
Author(s):  
M J Curcio ◽  
D J Garfinkel
Keyword(s):  
Protein Processing ◽  
Yeast Cells ◽  
Translational Efficiency ◽  
Gene Products ◽  
Protease Domain ◽  
High Level Expression ◽  
Gal1 Promoter ◽  
Low Levels ◽  
Ty1 Retrotransposition ◽  
High Level

High-level expression of a transpositionally competent Ty1 element fused to the inducible GAL1 promoter on a 2 microns plasmid (pGTy1) overcomes transpositional dormancy in Saccharomyces cerevisiae. To investigate the mechanisms controlling the rate of Ty1 retrotransposition, we quantitated transposition and Ty1 gene products in cells induced and uninduced for expression of pGTy1. The increase in Ty1 transposition was 45- to 125-fold greater than the increase in Ty1 RNA effected by pGTy1 induction. Translational efficiency of Ty1 RNA was not altered in transposition-induced cells, since p190TYA1-TYB1 protein synthesis increased in proportion to steady-state Ty1 RNA levels. Therefore, expression of a pGTy1 element increases the efficiency of Ty1 transposition at a posttranslational level. Galactose induction of pGTy1 enhanced TYA1 protein processing and allowed detection of processed TYB1 proteins, which are normally present at very low levels in uninduced cells. When the ability of genomic Ty1 elements to complement defined mutations in HIS3-marked pGTy1 elements was examined, mutations in the protease domain or certain mutations in the integrase domain failed to be complemented, but mutations in the reverse transcriptase domain were partially complemented by genomic Ty1 elements. Therefore, the activity of Ty1 elements in yeast cells may be limited by the availability of Ty1 protease and possibly integrase. These results suggest that Ty1 transposition is regulated at the level of protein processing and that this regulation is overcome by expression of a pGTy1 element.

Market Knowledge Management, Innovation and Product Performance

2010 ◽  
pp. 32-50
Author(s):  
Cid Gonçalves Filho ◽  
Rodrigo Baroni de Carvalho ◽  
George Leal Jamil
Keyword(s):  
Knowledge Management ◽  
Organizational Performance ◽  
Structural Equation ◽  
New Products ◽  
Product Performance ◽  
Management Innovation ◽  
Market Knowledge ◽  
Industrial Firms ◽  
Knowledge Models ◽  
High Level

In a business environment characterized by a high level of competitiveness, the impact of new products on an organization’s revenue is an important factor. This research was developed with the objective of examining empirically the relationships between market knowledge management, innovation and the performance of new products in the market. This chapter analyzes KM (Knowledge Management) success trough a market-oriented perspective because, at the end of the day, KM success must lead to better organizational performance. The research model was generated by the combination of market knowledge models and KM success and maturity models. By means of a survey, based on 387 medium and large industrial firms, and the use of structural equation modeling, the supremacy of the competitor knowledge management process over other constructs was verified, as the most important antecedent of new product performance in the market. The results also revealed that innovation was strongly impacted from technology knowledge management and customer knowledge management.

scholarly journals Challenges of Identifying Clinically Actionable Genetic Variants for Precision Medicine

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Tonia C. Carter ◽  
Max M. He
Keyword(s):  
Precision Medicine ◽  
Genetic Variants ◽  
Genomic Medicine ◽  
Genetic Mutations ◽  
Healthcare Outcomes ◽  
Health Records ◽  
Data Infrastructure ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Generation Sequencing

Advances in genomic medicine have the potential to change the way we treat human disease, but translating these advances into reality for improving healthcare outcomes depends essentially on our ability to discover disease- and/or drug-associated clinically actionable genetic mutations. Integration and manipulation of diverse genomic data and comprehensive electronic health records (EHRs) on a big data infrastructure can provide an efficient and effective way to identify clinically actionable genetic variants for personalized treatments and reduce healthcare costs. We review bioinformatics processing of next-generation sequencing (NGS) data, bioinformatics infrastructures for implementing precision medicine, and bioinformatics approaches for identifying clinically actionable genetic variants using high-throughput NGS data and EHRs.

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