Extracting Knowledge From Genomic Experiments By Incorporating the Biomedical Literature. James P. Sluka, Ph.D. InPharmix Incorporated www.InPharmix.com [email protected] (317)-422-1464. Value and Size of the Biomedical Literature. Cost to sequence the Human Genome, ~$3B
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†From: http://www.phrma.org/ and http://123genomics.homestead.com/files/companies.html
Rational framework for the understanding of biological process or disease
User Guidance, Heuristics or NLP
 Scherf, U. et al., "A gene expression database for the molecular pharmacology of cancer". Nature Genetics, 24:3 (2000), 236-44.
 Golub, T.R. et al., "Molecular classification of cancer: class discovery and class prediction by gene expression monitoring", Science, 286 (1999), 531-537.
A refinement to the basic search strategy is to require a higher degree of "dependence" (closer proximity within the document) between two query terms.
In acute lymphoblastic leukemia (ALL), the cell surface … (several sentences). GPRE also decreased the fraction of CD11-bearing ALL M2 and M5 cells.
81 Terms linked with proximity. Links per term limited to 3.
49 Terms linked at the title level. Links per term limited to 7.
The query term that co-occurred most frequently with AML is CD33. The top ranked proximity sentences were:
(AML OR ACUTE MYELOGENOUS LEUK!) AND CD33
9717827 (12.9) Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not.
11060736 (12.0) Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy.
10482193 (11.8) Conjugates composed of anti-CD33 antibodies and the chemotherapy agent, calicheamicin, show promising activity in patients with relapsed or refractory acute myelogenous leukemia.
11041016 (11.6) A genetically engineered, humanized anti-CD33 antibody HuM195 has demonstrated activity against over relapsed acute myelogenous leukemia (AML) and against minimal residual disease in acute promyelocytic leukemia (APL).
10537338 (11.5) A phase I trial of humanized monoclonal antibody HuM195 (anti-CD33) with low-dose interleukin 2 in acute myelogenous leukemia.
10942240 (11.2) Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA-676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse.
Annexin II or Lipocortin II;
10084978 However, the immunolocalized tPA protein was most strongly associated with the amnion and chorion, as was its receptor annexin II, suggesting that the amnion and chorion are the targets for decidual tPA.
10213612 These observations furthermore suggest that AnV may regulate the fusogenic function of annexin II.
10376803 With the use of immunofluorescence, annexin II was found to translocate from cytoplasm to plasma membranes in type II cells upon stimulation with phorbol 12-myristate 13-acetate. …
X-ray "crystal structure"
"drug target" drug
10698261 This activation was not inhibited by CA-074, a specific inhibitor of cathepsin B, but was strongly inhibited by CLIK-066 and CLIK-181, specific inhibitors of cathepsin L.
10713271 The propeptide of cathepsin S was observed to inhibitcathepsin L with a K(i) of 0.08 nM, yet cathepsin L propeptide inhibited cathepsin S only poorly.
10748021 The mushroom protein is a tight binding inhibitor of papain (K(i) = 0.59 nm), cathepsin L (K(i) = 0.41 nm), cathepsin B (K(i) = 0.48 micrometer), and bromelain (K(i) = 0.16 micrometer) but is inactive toward cathepsin H, trypsin, and pepsin.
10748022 Saxiphilin is now characterized as a potent inhibitor of three cysteine proteinases: papain, human cathepsin B, and cathepsin L. …
Another useful analysis of the PDQ_MED results is examination of the list of genes that cannot be linked to AML.
MAP3K5 OR "mitogen-activated protein kinase kinase kinase 5" OR "MAP/ERK kinase kinase 5" OR ASK1 OR MAPKK1 OR MAPKKK5 OR MEK1 OR MEKK5
11423913 Pretreatment with either the MEK1inhibitor U0126 or PI3-kinase inhibitor LY294002 sensitized BAE cells to TNF-induced apoptosis.
11431469 Three different inhibitors of MEK1/2 abolished PE-induced activation of S6K2 whereas expression of constitutively active MEK1 activated S6K2, without affecting the p38 mitogen-activated protein kinase and JNK pathways, indicating that MEK/ERK signaling plays a key role in regulation of S6K2 by PE.
11437382 To determine the involvement of MEK1-p42/p44 MAPK pathway in mediating DAB2 gene expression, we have performed the following experiments and found that (i) there was sustained activation of p42/p44 MAPK, but not p38 MAPK, upon K562 cells differentiation; (ii) application of MEK1inhibitor U0126 reduced the expression of DAB2 protein, mRNA and promoter activity, as well as cell differentiation; (iii) constitutively active MEK1 increased DAB2 promoter activity; and (iv) dominant negative ERK2 abolished constitutively active MEK1-induced DAB2 promoter activity.
11440832 PD98059, a specific inhibitor of ERK kinase (MEK1), reduced H(2)O(2)-induced AR expression.
11444915 The MEK1/2 inhibitor PD098059 abrogated ISO-stimulated ERK activity, albeit the increase in protein synthesis was unaffected.
11454948 In the present study, we examined the effects of PD098059 and U0126, two structurally dissimilar inhibitors of MAP kinase kinase (MEK1/2), on the activation of ERK and Akt stimulated by human 5-hydroxytryptamine(1B) (serotonin) (5-HT1B) receptors.
† e.g., cFos + cJun = AP-1
PDQ_MED: http://www.InPharmix.comPubGene: http://www.PubGene.orgMedMiner: http://discover.nci.nih.gov/textmining/filters.html
Overall, PDQ_MED ensures that the researcher can effectively gather and analyze the relevant literature for large sets of genes, proteins and disease terms providing a key capability for a successful genomics research project.
In the last 10 years, biological research has undergone a paradigm shift. Instead of the detailed study of a single gene or gene product, researchers now examine the expression of thousands of gene simultaneously. Making sense of this type of data has required the development of new bioinformatics tools to track and extract value from these experiments. The largest of the sequence databases, GENBANK, currently contains about 13 billion characters of sequence data.
There is a second public database containing critical information which has been under-utilized. The biomedical literature, such as represented by the MEDLINE database, contains a representation of the cumulative understanding of biological processes. Currently, MEDLINE is comparable in size (12 billion characters) to GENBANK. Effectively incorporating the wealth of information in the literature into genomic research projects presents a new challenge to researchers.
Bioinformatics tools have not been developed to deal with the natural language of the literature. A new paradigm is needed for the analysis of the literature which compliments the paradigm shift in biological research. InPharmix Inc. is developing the tools needed to rationalize and extract value from genomic research projects by incorporating the biomedical literature.
49 Terms linked at the title level.