Abstract:
Presented herein are biomarkers related to breast cancer. The presently identified salivary biomarkers create the basis for a breast cancer detection bioassay with sensitivity and specificity. Means and methods for evaluating the data generated using multiple biomarkers in order to validate findings and further use of the multiplexed breast cancer assay in clinical, diagnostic and therapeutic uses is also included.

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
       [0001]    The present application claims priority to provisional application U.S. Ser. No. 61/303,200, filed Feb. 10, 2010, herein incorporated by reference in its entirety. 
     
    
     STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    This invention was made with Government support under Grant No. DE016275, awarded by the National Institutes of Health. The Government has certain rights in this invention. 
     
    
     BACKGROUND 
       [0003]    Breast cancer is the most frequent neoplasm and the leading cause of cancer mortality in women worldwide. According to estimates, approximately 41,000 women in the United States and 130,000 women in the European Union die from breast cancer yearly. 
         [0004]    Detection of breast cancer at the earliest stages results in a much greater favorable outcome, with 10-year disease-free survival rate as high as 98% in patients in which the tumor stage is pT1a,bN0M0 (measuring 1 cm or less, with disease-free axillary lymph nodes and no distant metastasis). Needless to say, early detection is of paramount importance in reducing mortality from this major public health burden. 
         [0005]    Current breast cancer detection methods are based on physical examination and imaging (for example, mammography, ultrasound, and MRI). These methods can produce a substantial percentage of false positive and false negative results especially in women with dense parenchymal breast tissue. Consequently, screening results in a number of negative biopsy results yielding a high percentage of false positives. There is also a demonstrated lack of sensitivity in detecting cancerous lesions in younger women yielding a significant percentage of false negatives. Accordingly, a clear need exists for added modalities of screening for breast cancer. 
         [0006]    In the last decade, biomarker discoveries for breast cancer detection have focused on blood/or tissue, using proteomic, transcriptomic, and genomic approaches. In comparison to prognostic biomarkers, the development of detection biomarkers has been limited, mainly due to a lack of sensitivity and specificity for this clinical context. Most importantly, the use of tissue biomarkers for early detection will be limited to patients at very high risk because they rely on invasive procedures. 
         [0007]    As such, a need exists for methods useful for detecting breast cancer, and in particular biomarkers that can detect early stages of the disease and are largely non-invasive. 
       BRIEF SUMMARY OF THE INVENTION 
       [0008]    In accordance with some embodiments of the invention, a method of determining the likelihood of the presence or occurrence of breast cancer in a test subject is provided. The disclosed method includes analyzing a saliva sample from the subject with an assay that specifically detects at least two biomarkers in the saliva sample. The biomarkers are selected from the group of: S100A8 (S100 calcium binding protein A8) (SEQ ID NO: 1), CSTA (cystatin A) (SEQ ID NO:2), GRM1 (glutamate receptor, metabotropic 1) (SEQ ID NO: 3), TPT1 (tumor protein, translationally-controlled 1) (SEQ ID NO:4), GRIK1 (glutamate receptor, ionotropic, kainate 1) (SEQ ID NO: 5), H6PD (hexose-6-phosphate dehydrogenase) (SEQ ID NO: 6), IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1) (SEQ ID NO: 7), MDM4 (3T3 cell double minute 4) (SEQ ID NO: 8), and CA6 (carbonic anhydrase VI) (SEQ ID NO:8). The relative occurrence of at least two of these biomarkers is determined and compared to a control, thereby allowing the breast cancer status of the test subject to be determined. 
         [0009]    In some embodiments, one of the biomarkers of the at least two biomarkers is cystatin A (CSTA). In other embodiments, two of the at least two biomarkers is CSTA and transformed 3T3 cell double minute 4 (MDM4). The relative occurrence of these biomarkers or these biomarkers and others in these instances is determined and compared to a control, for example, thereby allowing the breast cancer status of the test subject to be determined. 
         [0010]    In some embodiments, the method of determining the likelihood of the presence or occurrence of breast cancer entails measuring at least three biomarkers. In some embodiments, two of the at least three biomarkers are CSTA and MDM4. The relative occurrence of these biomarkers or these biomarkers and others in these instances is determined and compared to a control, for example, thereby allowing the breast cancer status of the test subject to be determined. 
         [0011]    In some embodiments, one of the biomarkers of the at least two biomarkers is anhydrase VI (CA6) polypeptide. 
         [0012]    In other embodiments, the method of determining the likelihood of the presence or occurrence of breast cancer in a test subject includes an assay in which a nucleic acid encoding at least one biomarker is detected. The nucleic acid can be detected by, for example, mass spectroscopy, polymerase chain reaction (PCR), microarray hybridization, thermal sequencing, capillary array sequencing, or solid phase sequencing. 
         [0013]    In other embodiments, the method of determining the likelihood of the presence or occurrence of breast cancer in a test subject includes an assay in which a polypeptide encoding at least one biomarker is detected. The polypeptide can be detected by, for example, enzyme-linked immunosorbent assay (ELISA), Western blot, flow cytometry, immunofluorescence, immunohistochemistry, or mass spectroscopy. 
         [0014]    In accordance with other embodiments of the invention, a method for assessing the efficacy of a therapy is disclosed. This method includes analyzing a first saliva sample from the subject with an assay that specifically detects at least two biomarkers selected from the group consisting of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and CA6. This first analysis provides a first expression profile. A therapy is applied to a subject. An analysis of a second saliva sample from the subject is undertaken with an assay that specifically detects at least two biomarkers selected from the group consisting of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and CA6 thereby providing a second expression profile. The first and second expression profiles are compared in order to assess the efficacy of a therapy. 
         [0015]    In another embodiment, a solid support is provided, wherein the solid support includes a capture binding probe selective for at least two biomarkers selected from the group of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4. In some embodiments, a first and a second solid support are provided, wherein the first solid support includes a capture binding probe selective for at least two biomarkers selected from the group consisting of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and wherein the second solid support includes a capture binding ligand for CA6. 
         [0016]    In some embodiments, the capture binding ligand of the kit is an antibody. In another embodiment the kit provides one or more primers for the selective amplification of at least two biomarkers, wherein at least two of the biomarkers are selected from the group of: S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4. In some embodiments one or more of the primers possess a detectable label. 
         [0017]    In accordance with some embodiments of the invention, a method of determining the likelihood of the presence or occurrence of breast cancer in a test subject is provided. The disclosed method includes analyzing a saliva sample from the subject with an assay that specifically detects at least nine biomarkers in the saliva sample. The biomarkers are selected from the group of: S100A8 (S100 calcium binding protein A8) (SEQ ID NO: 1), CSTA (cystatin A) (SEQ ID NO:2), GRM1 (glutamate receptor, metabotropic 1) (SEQ ID NO: 3), TPT1 (tumor protein, translationally-controlled 1) (SEQ ID NO:4), GRIK1 (glutamate receptor, ionotropic, kainate 1) (SEQ ID NO: 5), H6PD (hexose-6-phosphate dehydrogenase) (SEQ ID NO: 6), IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1) (SEQ ID NO: 7), MDM4 (3T3 cell double minute 4) (SEQ ID NO: 8), and CA6 (carbonic anhydrase VI) (SEQ ID NO:8). The relative occurrence of at least nine biomarkers is determined and compared to a control, thereby allowing the breast cancer status of the test subject to be determined. 
         [0018]    In any of the embodiments above, wherein a method for determining the likelihood of the presence or occurrence of breast cancer in a test subject, the number of biomarkers used can be 2, 3, 4, 5, 6, 7, 8, 9, or more. 
         [0019]    These and other embodiments, features and potential advantages will become apparent with reference to the following description and drawings. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0020]      FIG. 1  is a schematic of the study designed to identify and validate biomarkers associated with breast cancer. 
           [0021]      FIG. 2  is a schematic representation of the protocol for saliva collection. 
           [0022]      FIG. 3  represents the demographic information of all the subjects used. 
           [0023]      FIG. 4  represents biomarkers for breast cancer detection and effect of confounding factors (sample set n=93). The Mann-Whitney rank sum test was used to determine marker validation. Possible confounding factors, including age, ethnicity, smoking status, menopausal status, and HRT treatment, were evaluated for the biomarkers by logistic regression model. Linear regression model was constructed for each marker and used the factors cancer/normal and one of the confounders. cv.err:cross validation error rate. 
           [0024]      FIG. 5  demonstrates the sensitivity achieved using a combination of the identified biomarkers. (A) The shading of the contigency table boxes reflects the fraction of each samples type in each quandrant. “Cancer” and “Non’ headings indicate subjects with and withour cancer, respectively. SB+ and SB−, salivary biomarker test positive or negative; NPV, negative predictive value; PPV, positive predictive value; Sen, sensitivity; Spec, specificity. (B) Score plot of principle component analysis (PCA). Combining the nine biomarkers, the control subjects (light shaded) separate from breast cancer patients (dark shading) with cumulative proportions of 66.9% for PC1 and 21.6% for PC2. 
           [0025]      FIG. 6  represents cross-disease comparisons of the salivary mRNA biomarkers. The identified mRNA biomarkers for breast cancer detection were checked against other microarray datasets. t-test p-values were calculated for the identified breast cancer genes to other microarray datasets to check for significant variation (*after Boneferonni correction, P&lt;0.0006) between patients and controls in those diseases. Sample sizes were 10 versus 10 for oral cancer, 10 versus 10 for lung cancer, 12 versus 12 for pancreatic cancer, 11 versus 11 for ovarian cancer, 13 versus 13 for diabetes, 8 versus 10 for primary Sjögren&#39;s Syndrome, and 10 versus 10 for breast cancer. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Introduction 
       [0026]    Early detection of breast cancer offers the promise of easier treatment (smaller surgeries, less radiation or chemotherapy) and improved survival. Conventional screening (physical examination and mammography) has a less-than desirable sensitivity and specificity. A sensitive assay to identify biomarkers using non-invasively collected specimens is therefore ideal for breast cancer detection. 
         [0027]    While saliva is a source of easily accessible bodily fluids, there has been little effort to study its value in cancer diagnosis. Protein, as well as RNA, can be detected in saliva. 
         [0028]    The present invention discloses the diagnostic/prognostic significance of nine salivary biomarkers S100A8 (SEQ ID NO: 1) (S100 calcium binding protein A8, also referred to as myloid-related protein 8 (MRP8) or S100A9 (MRP14)), CSTA (SEQ ID NO: 2)(cystatin A), GRM1 (SEQ ID NO: 3)(glutamate receptor, metabotropic 1), TPT1 (SEQ ID NO: 4)(tumor protein, translationally-controlled 1), GRIK1 (SEQ ID NO: 5) (glutamate receptor, ionotropic, kainate 1), H6PD (SEQ ID NO: 6)(hexose-6-phosphate dehydrogenase or glucose 1-dehydrogenase), IGF2BP1 (SEQ ID NO: 7)(insulin-like growth factor 2 mRNA binding protein 1), MDM4 (SEQ ID NO: 8)(Mdm4, transformed 3T3 cell double minute 4; HDMX; MDMX; MRP1; MGC132766; DKFZp781B1423), and CA6 (carbonic anhydrase VI) and combinations thereof, in breast cancer detection. Detection of these and other biomarkers in saliva are useful for diagnosis and prognosis of breast cancer. 
         [0029]    Methods for detecting salivary biomarkers (proteins and nucleic acids) include techniques such as ELISA, PCR, for example, RT-PCR or mass spectroscopy, alone or in combination with other markers. Any specific probe can be used for detection, such as an antibody, a receptor, a ligand, RT-PCR etc. Mass spectroscopy can also be used for protein detection. Thus, the present invention can be used alone or as a complement to traditional antigen analysis to enhance the diagnosis of breast and other cancers. 
       Definitions 
       [0030]    “S100A8,” “CSTA,” “GRM1,” “TPT1,” “GRIK1,” “H6PD,” “IGF2BP1,” “MDM4,” and “CA6” refer to nucleic acids, e.g., gene, pre-mRNA, mRNA, and polypeptides, polymorphic variants, alleles, mutants, and interspecies homologs that have an amino acid sequence that has greater than about 60% amino acid sequence identity, 65%, 70%, 75%, 80%, 85%, 90%, preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or greater amino acid sequence identity, preferably over a region of over a region of at least about 25, 50, 100, 200, 500, 1000, or more amino acids, to a polypeptide encoded by a referenced nucleic acid or an amino acid sequence described herein. The nucleic acids and proteins of the invention include both naturally occurring or recombinant molecules. The nucleic acid or protein sequence is provided, for example, in SEQ ID NOs: 1-9. 
         [0031]    “Cancer” refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney, breast, lung, kidney, bladder, colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin, uterine, testicular, esophagus, and liver cancer, including hepatocarcinoma, lymphoma, including non-Hodgkin&#39;s lymphomas (e.g., Burkitt&#39;s, Small Cell, and Large Cell lymphomas) and Hodgkin&#39;s lymphoma, leukemia, and multiple myeloma. 
         [0032]    “Therapeutic treatment” and “cancer therapies” refers to chemotherapy, hormonal therapy, radiotherapy, and immunotherapy. 
         [0033]    The terms “overexpress,” “overexpression” or “overexpressed” interchangeably refer to a protein that is transcribed or translated at a detectably greater level, usually in a cancer cell, in comparison to a normal cell. The term includes overexpression due to transcription, post transcriptional processing, translation, post-translational processing, cellular localization (e.g, organelle, cytoplasm, nucleus, cell surface), and RNA and protein stability, as compared to a normal cell. Overexpression can be detected using conventional techniques for detecting mRNA (i.e., RT-PCR, PCR, hybridization) or proteins (i.e., ELISA, immunohistochemical techniques, mass spectroscopy). Overexpression can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a normal cell. In certain instances, overexpression is 1-fold, 2-fold, 3-fold, 4-fold or more higher levels of transcription or translation in comparison to a normal cell. 
         [0034]    The terms “cancer-associated antigen” or “tumor-specific marker” or “tumor marker” interchangeably refers to a molecule (typically protein or nucleic acid such as RNA) that is expressed in the cell, expressed on the surface of a cancer cell or secreted by a cancer cell in comparison to a normal cell, and which is useful for the diagnosis of cancer, for providing a prognosis, and for preferential targeting of a pharmacological agent to the cancer cell. Oftentimes, a cancer-associated antigen is overexpressed in a cancer cell in comparison to a normal cell, for instance, about 1.2-fold over expression, about 2-fold overexpression, about 3-fold overexpression or more in comparison to a normal cell. Oftentimes, a cancer-associated antigen is a cell surface molecule that is inappropriately synthesized in the cancer cell, for instance, a molecule that contains deletions, additions or mutations in comparison to the molecule expressed on a normal cell. Oftentimes, a cancer-associated antigen will be expressed exclusively on the cell surface of a cancer cell and not synthesized or expressed on the surface of a normal cell. Exemplified cell surface tumor markers include the proteins c-erbB-2 and human epidermal growth factor receptor (HER) for breast cancer, PSMA for prostate cancer, and carbohydrate mucins in numerous cancers, including breast, ovarian and colorectal. 
         [0035]    It will be understood by the skilled artisan that markers may be used singly or in combination with other markers for any of the uses, e.g., diagnosis or prognosis of breast cancer, disclosed herein. 
         [0036]    The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site hypertext transfer protocol://www.ncbi.nlm.nih.gov/BLAST/ or the like). Such sequences are then said to be “substantially identical.” This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and/or additions, as well as those that have substitutions. As described below, the preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length. 
         [0037]    For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Preferably, default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. 
         [0038]    A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith &amp; Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman &amp; Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson &amp; Lipman, Proc. Nat&#39;l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Current Protocols in Molecular Biology (Ausubel et al., eds. 1987-2005, Wiley Interscience)). 
         [0039]    An example of algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively. BLAST and BLAST 2.0 are used, with the parameters described herein, to determine percent sequence identity for the nucleic acids and proteins of the invention. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (hypertext transfer protocol://www.ncbi.nlm.nih gov/). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always &gt;0) and N (penalty score for mismatching residues; always &lt;0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff &amp; Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. 
         [0040]    “Nucleic acid” refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof. 
         [0041]    Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (for example, degenerate codon substitutions) and complementary sequences, as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The term nucleic acid is used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide. 
         [0042]    A particular nucleic acid sequence also implicitly encompasses “splice variants” and nucleic acid sequences encoding truncated forms of cancer antigens. Similarly, a particular protein encoded by a nucleic acid implicitly encompasses any protein encoded by a splice variant or truncated form of that nucleic acid. “Splice variants,” as the name suggests, are products of alternative splicing of a gene. After transcription, an initial nucleic acid transcript may be spliced such that different (alternate) nucleic acid splice products encode different polypeptides. Mechanisms for the production of splice variants vary, but include alternate splicing of exons. Alternate polypeptides derived from the same nucleic acid by read-through transcription are also encompassed by this definition. Any products of a splicing reaction, including recombinant forms of the splice products, are included in this definition. Nucleic acids can be truncated at the 5′ end or at the 3′ end. Polypeptides can be truncated at the N-terminal end or the C-terminal end. Truncated versions of nucleic acid or polypeptide sequences can be naturally occurring or recombinantly created. 
         [0043]    The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, .gamma.-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an .alpha. carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. 
         [0044]    Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. 
         [0045]    “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence with respect to the expression product, but not with respect to actual probe sequences. 
         [0046]    As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention. 
         [0047]    The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)). 
         [0048]    A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include fluorescent dyes, electron-dense reagents, enzymes (for example, as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins which can be made detectable, e.g., by incorporating a radiolabel into the peptide or used to detect antibodies specifically reactive with the peptide. 
         [0049]    The tem) “recombinant” when used with reference, e.g., to a cell, or nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express genes that are not found within the native (non-recombinant) form of the cell or express native genes that are otherwise abnormally expressed, under expressed or not expressed at all. 
         [0050]    The phrase “stringent hybridization conditions” refers to conditions under which a probe will hybridize to its target subsequence, typically in a complex mixture of nucleic acids, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures. An extensive guide to the hybridization of nucleic acids is found in Tijssen, Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Probes, “Overview of principles of hybridization and the strategy of nucleic acid assays” (1993). Generally, stringent conditions are selected to be about 5-10° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength pH. The T m  is the temperature (under defined ionic strength, pH, and nucleic concentration) at which 50% of the probes complementary to the target hybridize to the target sequence at equilibrium (as the target sequences are present in excess, at T m , 50% of the probes are occupied at equilibrium). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. For selective or specific hybridization, a positive signal is at least two times background, preferably 10 times background hybridization. Exemplary stringent hybridization conditions can be as following: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or, 5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDS at 65° C. 
         [0051]    Nucleic acids that do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical. This occurs, for example, when a copy of a nucleic acid is created using the maximum codon degeneracy permitted by the genetic code. In such cases, the nucleic acids typically hybridize under moderately stringent hybridization conditions. Exemplary “moderately stringent hybridization conditions” include a hybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C., and a wash in 1×SSC at 45° C. A positive hybridization is at least twice background. Those of ordinary skill will readily recognize that alternative hybridization and wash conditions can be utilized to provide conditions of similar stringency. Additional guidelines for determining hybridization parameters are provided in numerous reference, e.g., and Current Protocols in Molecular Biology, ed. Ausubel, et al., supra. 
         [0052]    For PCR, a temperature of about 36° C. is typical for low stringency amplification, although annealing temperatures may vary between about 32° C. and 48° C. depending on primer length. For high stringency PCR amplification, a temperature of about 62° C. is typical, although high stringency annealing temperatures can range from about 50° C. to about 65° C., depending on the primer length and specificity. Typical cycle conditions for both high and low stringency amplifications include a denaturation phase of 90° C.−95° C. for 30 sec-2 min., an annealing phase lasting 30 sec.-2 min., and an extension phase of about 72° C. for 1-2 min. Protocols and guidelines for low and high stringency amplification reactions are provided, e.g., in Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc. N.Y.). 
         [0053]    “Antibody” means a protein comprising one or more polypeptides substantially encoded by all or part of the recognized immunoglobulin genes. The recognized immunoglobulin genes, for example in humans, include the kappa (κ), lambda (λ) and heavy chain genetic loci, which together compose the myriad variable region genes, and the constant region genes mu (μ), delta (δ), gamma (γ), epsilon (ε) and alpha (α), which encode the IgM, IgD, IgG, IgE, and IgA isotypes respectively. Antibody herein is meant to include full length antibodies and antibody fragments, and may refer to a natural antibody from any organism, an engineered antibody or an antibody generated recombinantly for experimental, therapeutic or other purposes as further defined below. Antibody fragments include Fab, Fab′, F(ab′) 2 , Fv, scFv or other antigen-binding subsequences of antibodies and can include those produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies. The term “antibody” refers to both monoclonal and polyclonal antibodies. Antibodies can be antagonists, agonists, neutralizing, inhibitory or stimulatory. 
       Biomarkers 
       [0054]    Biomarkers may originate from epidemiological studies, animal studies, pathophysiological considerations and end-organ experiments. Ideally, a biomarker will have a high predictive value for a meaningful outcome measure, can be or is validated in appropriately designed prospective trials, reflects therapeutic success by corresponding changes in the surrogate marker results, and should be easy to assess in clinical practice. 
         [0055]    Biomarkers can be used in conjunction with other diagnostic tools or used alone. 
         [0056]    The term “surrogate marker,” “biomolecular marker,” “biomarker” or “marker” (also sometimes referred to herein as a “target analyte,” “target species” or “target sequence”) refers to a molecule whose measurement provides information as to the state of a subject. In various exemplary embodiments, the biomarker is used to assess a pathological state. Measurements of the biomarker may be used alone or combined with other data obtained regarding a subject in order to determine the state of the subject. In one embodiment, the biomarker is “differentially present” in a sample taken from a subject of one phenotypic status (e.g., having a disease) as compared with another phenotypic status (e.g., not having the disease). In one embodiment, the biomarker is “differentially present” in a sample taken from a subject undergoing no therapy or one type of therapy as compared with another type of therapy. Alternatively, the biomarker may be “differentially present” even if there is no phenotypic difference, e.g. the biomarkers may allow the detection of asymptomatic risk. 
         [0057]    A biomarker may be over-expressed (over-abundant) or under-expressed (under abundant) relative to a control. The biomarker can be an allelic variant, truncated or mutated form of a wild-type nucleic acid or protein. The biomarker can be a splice variant. 
         [0058]    A biomarker may be determined to be “differentially present” in a variety of ways, for example, between different phenotypic statuses if the mean or median level (particularly the expression level of the associated mRNAs as described below) of the biomarker in the different groups is calculated to be statistically significant. Common tests for statistical significance include, among others, t-test, ANOVA, Kruskal-Wallis, Wilcoxon, Mann-Whitney and odds ratio. 
         [0059]    As described herein, a biomarker may be, for example, a small molecule, an analyte or target analyte, a nucleic acid, a protein, a metabolite or any derivative thereof or any and all combinations of these molecules, with proteins and nucleic acids finding particular use in the invention. As will be appreciated by those in the art, a large number of analytes may be detected using the present methods; basically, any biomarker for which a binding ligand, described below, may be made may be detected using the methods of the invention. 
         [0060]    In various embodiments, the biomarkers used in the panels of the invention can be detected either as proteins or as nucleic acids (e.g. mRNA or cDNA transcripts) in any combination. In various embodiments, the protein form of a biomarker is measured. As will be appreciated by those in the art, protein assays may be done using standard techniques such as ELISA assays. In various embodiments, the nucleic acid form of a biomarker (e.g., the corresponding mRNA) is measured. In various exemplary embodiments, one or more biomarkers from a particular panel are measured using a protein assay and one or more biomarkers from the same panel are measured using a nucleic acid assay. 
         [0061]    As will be appreciated by those in the art, there are a large number of possible proteinaceous target analytes and target species that may be detected using the present invention. The term “protein,” “polypeptide” or “oligopeptide” refers to at least two or more peptides or amino acids joined by one or more peptide bonds. A protein or an amino acid may be naturally or nonnaturally occurring and may be also be an analog, a derivative or a peptidomimetic structure. The term “protein” refers to wild-type sequences, variants of wild-type sequences and either of these containing analogs or derivatized amino acids. In various embodiments, variants of the sequences described herein, including proteins and nucleic acids based on e.g. splice variants, variants comprising a deletion, addition, substitution, fragments, preproprotein, processed preproprotein (e.g. without a signaling peptide), processed proprotein (e.g. resulting in an active form), nonhuman sequences and variant nonhuman sequences may be used as biomarkers. 
         [0062]    In various embodiments, the biomarker is a nucleic acid. The term “nucleic acid” or “oligonucleotide” or grammatical equivalents herein means at least two nucleotides covalently linked together. A nucleic acid of the present invention will generally contain phosphodiester bonds, although in some cases, as outlined below, for example in the use of binding ligand probes, nucleic acid analogs are included that may have alternate backbones. 
         [0063]    Biomarkers can also be bacterial nucleic acids or proteins. Over 700 species of bacteria have been identified to exist within the mouth. The presence, absence, or level of 16S rRNA from bacteria in a sample may correlate with a disease or condition. “Bacteria” refers to small prokaryotic organisms (linear dimensions of around 1 μm) with non-compartmentalized circular DNA and ribosomes of about 70 S. “16S RNA” refers to a nucleic acid component of the 30S subunit of prokaryotic ribosomes; the gene that encodes the 16S rRNA or the 16S rRNA itself. Bacterial strains of species or phylotypes have less than about a 2% difference in 16S rRNA. Closely related species or phylotypes generally have between about a 2% and about a 4% difference in 16S rRNA, whereas a genus often has between about a 5% and about a 10% difference in 16S rRNA. 
         [0064]    To resolve the identity of bacterial populations, probes on a microarray can be designed, for example, to take advantage of conserved features of the 16S rRNA gene. For example, probes complementary to the more conserved features regions identify species in a large phylogenetic group, each group corresponding to a higher taxon (for example, domain, phylum, class, order, or family). Probes complementary to more variable regions distinguish genera and species. 
         [0065]    Biomarkers can also include micro RNAs. “MicroRNAs” (miRs) refers to a class of small naturally occurring non-coding RNAs (18-24 nucleotides) that regulate gene expression. Many microRNAs are well conserved across species and they are present in a broad range of species: plants, nematodes, fruit flies and humans. MicroRNAs have partially or perfect complementary sequence to one or more messenger RNA molecules (mRNAs) and their main function is to negatively regulate the expression of genes. In particular, microRNAs bind to the 3′ untranslated regions of mRNAs (3-UTR) thus leading to down regulation of mRNAs in a variety of ways such as mRNA cleavage, translational repression and deadenylation. 
         [0066]    A variety of experimental approaches and different techniques have been used to identify new microRNAs, as well as to study their expression pattern in the different biological processes. The cloning and identification of new microRNAs have been successfully done from size fractioned RNA samples using small RNA cloning approaches. Other approaches is as putative microRNAs homologues to microRNAs that already have been described in other species or using computational approaches alone or in combination with microarray analysis and sequence-directed cloning. 
         [0067]    One of the first techniques used for detection and profiling of microRNAs was Northern Blotting, where hybridization is done with a complementary 32P, digoxigenin-labeled oligo or modified Locked-nucleic-acid (LNA) oligonucleotides after gel separation. 
         [0068]    Other techniques that have been developed to specifically detect microRNAs are a modified invader assay (a synthetic oligonucleotide, the probe, which is in an appropriate overlap-flap structure is enzymatically cleavage by a structure-specific 5* nuclease) and in situ hybridization (using fluorescent-labeled complementary probes containing chemically modified nucleotides e.g. LNAs). Another widely used technique for detection and profiling of microRNAs is the use of oligonucleotide micro-array based detection platforms either with DNA capture probes or using modified Locked-nucleic-acid (LNA) oligonucleotides in which the ribose moiety is modified with an extra bridge that connects the 2′-0 and 4′-C atoms. 
         [0069]    In addition, quantitative real-time PCR (reverse transcriptase/polymerase chain reaction using Taqman or SYBR green technology) has been used for detection and profiling of precursor or mature microRNAs. This technique is sensitive and requires low amounts of starting material for the detection of individual mature microRNAs. Taqman microRNA arrays have been developed that provide the sensitivity of the qRT-PCR, while at the same time enables the simultaneously detection of different microRNAs in one sample. 
         [0070]    Biomarkers can also include metabolites. “Metabolite” or “small molecule” refers to organic and inorganic molecules which are present in a sample. The term does not include large macromolecules, such as large proteins (e.g., proteins with molecular weights over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), large nucleic acids (e.g., nucleic acids with molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000), or large polysaccharides (e.g., polysaccharides with a molecular weights of over 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or 10,000). 
         [0071]    The metabolites of the cell are generally found free in solution. A “metabolic profile”, or “small molecule profile”, means a complete or partial inventory of small molecules within a targeted cell, tissue, organ, organism, or fraction thereof (e.g., cellular compartment). The inventory may include the quantity and/or type of small molecules present. The “small molecule profile” may be determined using a single technique or multiple different techniques. 
         [0072]    A metabolic profile can be developed by analyzing a sample using for example, techniques such as GC-MS (gas chromatography-mass spectrometry) and LC-MS (liquid chromatography-mass spectrometry). 
       Biomarker Panels 
       [0073]    Any combination of the biomarkers described herein is used to assemble a biomarker panel, which is detected or measured as described herein. As is generally understood in the art, a combination may refer to an entire set or any subset or subcombination thereof. The term “biomarker panel,” “biomarker profile,” or “biomarker fingerprint” refers to a set of biomarkers. As used herein, these terms can also refer to any form of the biomarker that is measured. Thus, if cystatin A is part of a biomarker panel, then either cystatin A mRNA, for example, or protein could be considered to be part of the panel. While individual biomarkers are useful as diagnostics, combination of biomarkers can sometimes provide greater value in determining a particular status than single biomarkers alone. Specifically, the detection of a plurality of biomarkers in a sample can increase the sensitivity and/or specificity of the test. Thus, in various embodiments, a biomarker panel may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more types of biomarkers. In various exemplary embodiments, the biomarker panel consists of a minimum number of biomarkers to generate a maximum amount of information. Thus, in various embodiments, the biomarker panel consists of 2, 3, 4, 5, 6, 7, 8, 9 or more types of biomarkers. Where a biomarker panel “consists of” a set of biomarkers, no biomarkers other than those of the set are present. In exemplary embodiments, the biomarker panel consists of 2 biomarkers disclosed herein. In various embodiments, the biomarker panel consists of 3 biomarkers disclosed herein. In various embodiments, the biomarker panel consists of 4 biomarkers disclosed herein. In various embodiments, the biomarker paenl consists of 5 biomarkers disclosed herein. 
         [0074]    In various exemplary embodiments, the biomarker panel comprises cystatin A. In various exemplary embodiments, the biomarker panel comprises carbonic anhydrase VI. 
         [0075]    In various exemplary embodiments, the biomarker panel comprises or consists of two or more of the biomarkers selected from the group of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and CA6. In various exemplary embodiments two or more of the biomarkers selected from the group of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and CA6 can be combined with 1, 2, 3, 4 or more additional biomarkers. It should be understood that in this embodiment, the biomarker panel can include any combination of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4 and the remainder of these markers. 
         [0076]    A biomarker can also be a clinical parameter. The term “clinical parameter” refers to all non-sample or non-analyte biomarkers of subject health status or other characteristics, such as, without limitation, age, ethnicity, gender, family history, height, and weight. 
         [0077]    The biomarkers of the invention show a statistically significant difference in breast cancer diagnosis. In various embodiments, diagnostic tests that use these biomarkers alone or in combination show a sensitivity and specificity of at least about 85%, at least about 90%, at least about 95%, at least about 98% and about 100%. 
       Measurement and Detection of Biomarkers 
       [0078]    Biomarkers generally can be measured and detected through a variety of assays, methods and detection systems known to one of skill in the art. The term “measuring,” “detecting,” or “taking a measurement” refers to a quantitative or qualitative determination of a property of an entity, for example, quantifying the amount or concentration of a molecule or the activity level of a molecule. The term “concentration” or “level” can refer to an absolute or relative quantity. Measuring a molecule may also include determining the absence or presence of the molecule. Various methods include but are not limited to refractive index spectroscopy (RI), ultra-violet spectroscopy (UV), fluorescence analysis, electrochemical analysis, radiochemical analysis, near-infrared spectroscopy (near-IR), infrared (IR) spectroscopy, nuclear magnetic resonance spectroscopy (NMR), light scattering analysis (LS), mass spectrometry, pyrolysis mass spectrometry, nephelometry, dispersive Raman spectroscopy, gas chromatography, liquid chromatography, gas chromatography combined with mass spectrometry, liquid chromatography combined with mass spectrometry, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) combined with mass spectrometry, ion spray spectroscopy combined with mass spectrometry, capillary electrophoresis, colorimetry and surface plasmon resonance (such as according to systems provided by Biacore Life Sciences). See also PCT Publications WO/2004/056456 and WO/2004/088309. In this regard, biomarkers can be measured using the above-mentioned detection methods, or other methods known to the skilled artisan. Other biomarkers can be similarly detected using reagents that are specifically designed or tailored to detect them. 
         [0079]    Different types of biomarkers and their measurements can be combined in the compositions and methods of the present invention. In various embodiments, the protein form of the biomarkers is measured. In various embodiments, the nucleic acid form of the biomarkers is measured. In exemplary embodiments, the nucleic acid form is mRNA. In various embodiments, measurements of protein biomarkers are used in conjunction with measurements of nucleic acid biomarkers. 
         [0080]    Methods for detecting mRNA, such as RT-PCR, real time PCR, branch DNA, NASBA and others, are well known in the art. Using sequence information provided by the database entries for the biomarker sequences, expression of the biomarker sequences can be detected (if present) and measured using techniques well known to one of ordinary skill in the art. For example, sequences in sequence database entries or sequences disclosed herein can be used to construct probes for detecting biomarker RNA sequences in, e.g., Northern blot hybridization analyses or methods which specifically, and, preferably, quantitatively amplify specific nucleic acid sequences. As another example, the sequences can be used to construct primers for specifically amplifying the biomarker sequences in, e.g., amplification-based detection methods such as reverse-transcription based polymerase chain reaction (RT-PCR). When alterations in gene expression are associated with gene amplification, deletion, polymorphisms and mutations, sequence comparisons in test and reference populations can be made by comparing relative amounts of the examined DNA sequences in the test and reference cell populations. In addition to Northern blot and RT-PCR, RNA can also be measured using, for example, other target amplification methods (e.g., TMA, SDA, NASBA), signal amplification methods (e.g., bDNA), nuclease protection assays, in situ hybridization and the like. 
         [0081]    In one embodiment in the present invention are biochip assays. By “biochip” or “chip” herein is meant a composition generally comprising a solid support or substrate to which a capture binding ligand (also called an adsorbent, affinity reagent or binding ligand, or when nucleic acid is measured, a capture probe) is attached and can bind either proteins, nucleic acids or both. Generally, where a biochip is used for measurements of protein and nucleic acid biomarkers, the protein biomarkers are measured on a chip separate from that used to measure the nucleic acid biomarkers. For nonlimiting examples of additional platforms and methods useful for measuring nucleic acids, see Publications US/2006/0275782, US/2005/0064469 and DE10201463. In various embodiments, biomarkers are measured on the same platform, such as on one chip. In various embodiments, biomarkers are measured using different platforms and/or different experimental runs. 
         [0082]    By “binding ligand,” “capture binding ligand,” “capture binding species,” “capture probe” or grammatical equivalents herein is meant a compound that is used to detect the presence of or to quantify, relatively or absolutely, a target analyte, target species or target sequence (all used interchangeably) and that will bind to the target analyte, target species or target sequence. Generally, the capture binding ligand or capture probe allows the attachment of a target species or target sequence to a solid support for the purposes of detection as further described herein. Attachment of the target species to the capture binding ligand may be direct or indirect. In exemplary embodiments, the target species is a biomarker. As will be appreciated by those in the art, the composition of the binding ligand will depend on the composition of the biomarker. Binding ligands for a wide variety of biomarkers are known or can be readily found using known techniques. For example, when the biomarker is a protein, the binding ligands include proteins (particularly including antibodies or fragments thereof (F ab s, etc.) as discussed further below) or small molecules. The binding ligand may also have cross-reactivity with proteins of other species. Antigen-antibody pairs, receptor-ligands, and carbohydrates and their binding partners are also suitable analyte-binding ligand pairs. In various embodiments, the binding ligand may be nucleic acid. Nucleic acid binding ligands find particular use when proteins are the targets; alternatively, as is generally described in U.S. Pat. Nos. 5,270,163; 5,475,096; 5,567,588; 5,595,877; 5,637,459; 5,683,867; 5,705,337 and related patents, hereby incorporated by reference, nucleic acid “aptamers” can be developed for binding to virtually any biomarker. Nucleic acid binding ligands also find particular use when nucleic acids are binding targets. There is a wide body of literature relating to the development of binding partners based on combinatorial chemistry methods. In these embodiments, when the binding ligand is a nucleic acid, preferred compositions and techniques are outlined in PCT Publication WO/1998/020162, hereby incorporated by reference. 
         [0083]    In various exemplary embodiments, the capture binding ligand is an antibody. These embodiments are particularly useful for the detection of the protein form of a biomarker. 
         [0084]    Detecting or measuring the level (e.g. the transcription level) of a biomarker involves binding of the biomarker to a capture binding ligand, generally referred to herein as a “capture probe” when the mRNA of the biomarker is to be detected on a solid support. In that sense, the biomarker is a target sequence. The term “target sequence” or “target nucleic acid” or grammatical equivalents herein means a nucleic acid sequence that may be a portion of a gene, a regulatory sequence, genomic DNA, cDNA, RNA including mRNA and rRNA, or others. As is outlined herein, the target sequence may be a target sequence from a sample, or a secondary target such as a product of an amplification reaction such as PCR etc. In some embodiments, measuring a nucleic acid can thus refer to measuring the complement of the nucleic acid. It may be any length, with the understanding that longer sequences are more specific. 
         [0085]    The target sequence may also comprise different target domains; for example, a first target domain of the sample target sequence may hybridize to a first capture probe, a second target domain may hybridize to a label probe (e.g. a “sandwich assay” format), etc. The target domains may be adjacent or separated as indicated. Unless specified, the terms “first” and “second” are not meant to confer an orientation of the sequences with respect to the 5′-3′ orientation of the target sequence. For example, assuming a 5′-3′ orientation of the target sequence, the first target domain may be located either 5′ to the second domain, or 3′ to the second domain. 
         [0086]    When nucleic acids are used as the target analyte, the assays of the invention can take on a number of embodiments. In one embodiment, the assays are done in solution format, using any number of solution based formats. In one embodiment, end-point or real time PCR formats are used, as are well known in the art. These assays can be done either as a panel, in individual tubes or wells, or as multiplex assays, using sets of primers and different labels within a single tube or well. In addition to PCR-based solution formats, other formats can be utilized, including, but not limited to for example ligation based assays utilizing FRET dye pairs. In this embodiment, only upon ligation of two (or more) probes hybridized to the target sequence is a signal generated. 
         [0087]    In many embodiments, the assays are done on a solid support, utilizing a capture probe associated with the surface. As discussed herein, the capture probes (or capture binding ligands, as they are sometimes referred to) can be covalently attached to the surface, for example using capture probes terminally modified with functional groups, for example amino groups, that are attached to modified surfaces such as silanized glass. Alternatively, non-covalent attachment, such as electrostatic, hydrophobic/hydrophilic adhesion can be utilized. As is appreciated by those in the art and discussed herein, a large number of attachments are possible on a wide variety of surfaces. 
         [0088]    In this embodiment, the assays can take on a number of formats. In one embodiment, the target sequence comprises a detectable label, as described herein. In this embodiment, the label is generally added to the target sequence during amplification of the target in one of two ways: either labeled primers are utilized during the amplification step or labeled dNTPs are used, both of which are well known in the art. The label can either be a primary or secondary label as discussed herein. For example, in one embodiment, the label on the primer and/or a dNTP is a primary label such as a fluorophore. Alternatively, the label may be a secondary label such as biotin or an enzyme; for example, in one embodiment, the primers or dNTPs are labeled with biotin, and then a streptavidin/label complex is added. In one embodiment, the streptavidin/label complex contains a label such as a fluorophore. In an alternative embodiment, the streptavidin/label complex comprises an enzymatic label. For example, the complex can comprise horseradish peroxidase, and upon addition of TMB, the action of the horseradish peroxidase causes the TMB to precipitate, causing an optically detectable event. This has a particular benefit in that the optics for detection does not require the use of a fluorimeter. 
         [0089]    In alternate embodiments, the solid phase assay relies on the use of a labeled soluble capture ligand, sometimes referred to as a “label probe” or “signaling probe” when the target analyte is a nucleic acid. In this format, the assay is a “sandwich” type assay, where the capture probe binds to a first domain of the target sequence and the label probe binds to a second domain. In this embodiment, the label probe can also be either a primary (e.g. a fluorophore) or a secondary (biotin or enzyme) label. In one embodiment, the label probe comprises biotin, and a streptavidin/enzyme complex is used, as discussed herein. As above, for example, the complex can comprise horseradish peroxidase, and upon addition of TMB, the action of the horseradish peroxidase causes the TMB to precipitate, causing an optically detectable event. 
         [0090]    Detection of a target species in some embodiments requires a “label” or “detectable marker” (as described below) that can be incorporated in a variety of ways. Thus, in various embodiments, the composition comprises a “label” or a “detectable marker.” In one embodiment, the target species (or target analyte or target sequence) is labeled; binding of the target species thus provides the label at the surface of the solid support. 
         [0091]    In embodiments finding particular use herein, a sandwich format is utilized, in which target species are unlabeled. In these embodiments, a “capture” or “anchor” binding ligand is attached to the detection surface as described herein, and a soluble binding ligand (frequently referred to herein as a “signaling probe,” “label probe” or “soluble capture ligand”) binds independently to the target species and either directly or indirectly comprises at least one label or detectable marker. 
         [0092]    By “label” or “labeled” herein is meant that a compound has at least one molecule, element, isotope or chemical compound attached to enable the detection of the compound. In general, labels fall into four classes: a) isotopic labels, which may be radioactive or heavy isotopes; b) magnetic, electrical, thermal; c) colored or luminescent dyes; and d) enzymes; although labels include particles such as magnetic particles as well. The dyes may be chromophores or phosphors but are preferably fluorescent dyes, which due to their strong signals provide a good signal-to-noise ratio for decoding. Suitable dyes for use in the invention include, but are not limited to, fluorescent lanthanide complexes, including those of Europium and Terbium, fluorescein, rhodamine, tetramethylrhodamine, eosin, erythrosin, coumarin, methyl-coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow, Cascade Blue, Texas Red, Alexa dyes and others described in the 6th Edition of the Molecular Probes Handbook by Richard P. Haugland, hereby expressly incorporated by reference. Additional labels include nanocrystals or Q-dots as described in U.S. Pat. No. 6,544,732 incorporated by reference. 
         [0093]    In various embodiments, a secondary detectable label is used. A secondary label is one that is indirectly detected; for example, a secondary label can bind or react with a primary label for detection, can act on an additional product to generate a primary label (e.g. enzymes), or may allow the separation of the compound comprising the secondary label from unlabeled materials, etc. Secondary labels include, but are not limited to, one of a binding partner pair; chemically modifiable moieties; nuclease inhibitors, enzymes such as horseradish peroxidase, alkaline phosphatases, lucifierases, etc. Secondary labels can also include additional labels. 
         [0094]    In various embodiments, the secondary label is a binding partner pair. For example, the label may be a hapten or antigen, which will bind its binding partner. For example, suitable binding partner pairs include, but are not limited to: antigens (such as proteins (including peptides)) and antibodies (including fragments thereof (F ab s, etc.)); proteins and small molecules, including biotin/streptavidin; enzymes and substrates or inhibitors; other protein-protein interacting pairs; receptor-ligands; and carbohydrates and their binding partners. Nucleic acid-nucleic acid binding proteins pairs are also useful. In general, the smaller of the pair is attached to the NTP for incorporation into the primer. Preferred binding partner pairs include, but are not limited to, biotin (or imino-biotin) and streptavidin, digeoxinin and Abs, and Prolinx™ reagents. 
         [0095]    In the sandwich formats of the invention, an enzyme serves as the secondary label, bound to the soluble capture ligand. Of particular use in some embodiments is the use of horseradish peroxidase, which when combined with 3,3′,5,5′-tetramethylbenzidine (TMB) forms a colored precipitate which is then detected. In some cases, the soluble capture ligand comprises biotin, which is then bound to a enzyme-streptavidin complex and forms a colored precipitate with the addition of TMB. 
         [0096]    In various embodiments, the label or detectable marker is a conjugated enzyme (for example, horseradish peroxidase). In various embodiments, the system relies on detecting the precipitation of a reaction product or on a change in, for example, electronic properties for detection. In various embodiments, none of the compounds comprises a label. 
         [0097]    As used herein, the term “fluorescent signal generating moiety” or “fluorophore” refers to a molecule or part of a molecule that absorbs energy at one wavelength and re-emits energy at another wavelength. Fluorescent properties that can be measured include fluorescence intensity, fluorescence lifetime, emission spectrum characteristics, energy transfer, and the like. 
         [0098]    Signals from single molecules can be generated and detected by a number of detection systems, including, but not limited to, scanning electron microscopy, near field scanning optical microscopy (NSOM), total internal reflection fluorescence microscopy (TIRFM), and the like. Abundant guidance is found in the literature for applying such techniques for analyzing and detecting nanoscale structures on surfaces, as evidenced by the following references that are incorporated by reference: Reimer et al, editors,  Scanning Electron Microscopy: Physics of Image Formation and Microanalysis,  2nd Edition (Springer, 1998); Nie et al,  Anal. Chem.,  78: 1528-1534 (2006); Hecht et al,  Journal Chemical Physics,  112: 7761-7774 (2000); Zhu et al, editors,  Near - Field Optics: Principles and Applications  (World Scientific Publishing, Singapore, 1999); Drmanac, PCT Publication WO/2004/076683; Lehr et al,  Anal. Chem.,  75: 2414-2420 (2003); Neuschafer et al,  Biosensors  &amp;  Bioelectronics,  18: 489-497 (2003); Neuschafer et al, U.S. Pat. No. 6,289,144; and the like. 
         [0099]    Thus, a detection system for fluorophores includes any device that can be used to measure fluorescent properties as discussed above. In various embodiments, the detection system comprises an excitation source, a fluorophore, a wavelength filter to isolate emission photons from excitation photons and a detector that registers emission photons and produces a recordable output, in some embodiments as an electrical signal or a photographic image. Examples of detection devices include without limitation spectrofluorometers and microplate readers, fluorescence microscopes, fluorescence scanners (including e.g. microarray readers) and flow cytometers. 
         [0100]    In various exemplary embodiments, the binding of the biomarker to the binding ligand is specific or selective, and the binding ligand is part of a binding pair. By “specifically bind” or “selectively bind” or “selective for” a biomarker herein is meant that the ligand binds the biomarker with specificity sufficient to differentiate between the biomarker and other components or contaminants of the test sample. 
         [0101]    The term “solid support” or “substrate” refers to any material that can be modified to contain discrete individual sites appropriate for the attachment or association of a capture binding ligand. Suitable substrates include metal surfaces such as gold, electrodes, glass and modified or functionalized glass, plastics (including acrylics, polystyrene and copolymers of styrene and other materials, polypropylene, polyethylene, polybutylene, polycarbonate, polyurethanes, Teflon, derivatives thereof, etc.), polysaccharides, nylon or nitrocellulose, resins, mica, silica or silica-based materials including silicon and modified silicon, carbon, metals, inorganic glasses, fiberglass, ceramics, GETEK (a blend of polypropylene oxide and fiberglass) and a variety of other polymers. Of particular use in the present invention are the ClonDiag materials described below. 
         [0102]    Frequently, the surface of a biochip comprises a plurality of addressable locations, each of which comprises a capture binding ligand. An “array location,” “addressable location,” “pad” or “site” herein means a location on the substrate that comprises a covalently attached capture binding ligand. An “array” herein means a plurality of capture binding ligands in a regular, ordered format, such as a matrix. The size of the array will depend on the composition and end use of the array. Arrays containing from about two or more different capture binding ligands to many thousands can be made. Generally, the array will comprise 3, 4, 5, 6, 7 or more types of capture binding ligands depending on the end use of the array. In the present invention, the array can include controls, replicates of the markers and the like. Exemplary ranges are from about 3 to about 50. In some embodiments, the compositions of the invention may not be in array format; that is, for some embodiments, compositions comprising a single capture ligand may be made as well. In addition, in some arrays, multiple substrates may be used, either of different or identical compositions. Thus for example, large arrays may comprise a plurality of smaller substrates. 
         [0103]    Accordingly, in one aspect, the invention provides a composition comprising a solid support comprising a capture binding ligand for each biomarker of a biomarker panel. In various embodiments, the capture ligand is a nucleic acid. In various embodiments, the capture binding ligand is an antibody. In various embodiments, the composition further comprises a soluble binding ligand for each biomarker of a biomarker panel. 
         [0104]    A number of different biochip array platforms as known in the art may be used. For example, the compositions and methods of the present invention can be implemented with array platforms such as GeneChip® (Affymetrix), CodeLink™ Bioarray (Amersham), Expression Array System (Applied Biosystems), SurePrint microarrays (Agilent), Sentrix® LD BeadChip or Sentrix® Array Matrix (Illumina) and Verigene (Nanosphere). 
         [0105]    In various exemplary embodiments, detection and measurement of biomarkers utilizes colorimetric methods and systems in order to provide an indication of binding of a target analyte or target species. In colorimetric methods, the presence of a bound target species such as a biomarker will result in a change in the absorbance or transmission of light by a sample or substrate at one or more wavelengths. Detection of the absorbance or transmission of light at such wavelengths thus provides an indication of the presence of the target species. 
         [0106]    A detection system for colorimetric methods includes any device that can be used to measure colorimetric properties as discussed above. Generally, the device is a spectrophotometer, a colorimeter or any device that measures absorbance or transmission of light at one or more wavelengths. In various embodiments, the detection system comprises a light source; a wavelength filter or monochromator; a sample container such as a cuvette or a reaction vial; a detector, such as a photoresistor, that registers transmitted light; and a display or imaging element. 
         [0107]    In various exemplary embodiments, a ClonDiag chip platform is used for the colorimetric detection of biomarkers. In various embodiments, a ClonDiag ArrayTube (AT) is used. One unique feature of the ArrayTube is the combination of a micro probe array (the biochip) and micro reaction vial. In various embodiments, where a target sequence is a nucleic acid, detection of the target sequence is done by amplifying and biotinylating the target sequence contained in a sample and optionally digesting the amplification products. The amplification product is then allowed to hybridize with probes contained on the ClonDiag chip. A solution of a streptavidin-enzyme conjugate, such as Poly horseradish peroxidase (HRP) conjugate solution, is contacted with the ClonDiag chip. After washing, a dye solution such as o-dianisidine substrate solution is contacted with the chip. Oxidation of the dye results in precipitation that can be detected colorimetrically. Further description of the ClonDiag platform is found in Monecke S, Slickers P, Hotzel H et al.,  Clin Microbiol Infect  2006, 12: 718-728; Monecke S, Berger-Bächi B, Coombs C et al.,  Clin Microbiol Infect  2007, 13: 236-249; Monecke S, Leube I and Ehricht R,  Genome Lett  2003, 2: 106-118; Monecke S and Ehricht R,  Clin Microbiol Infect  2005, 11: 825-833; German Patent DE 10201463; US Publication US/2005/0064469 and ClonDiag,  ArrayTube  ( AT )  Experiment Guideline for DNA - Based Applications , version 1.2, 2007, all incorporated by reference in their entirety. One of skill in the art will appreciate that numerous other dyes that react with a peroxidase can be utilized to produce a colorimetric change, such as 3,3′,5,5′-tetramethylbenzidine (TMB). For information on specific assay protocols, see www.clondiag.com/technologies/publications.php. 
         [0108]    In various embodiments, where a target species is a protein, the ArrayTube biochip comprises capture binding ligands such as antibodies. A sample is contacted with the biochip, and any target species present in the sample is allowed to bind to the capture binding ligand antibodies. A soluble capture binding ligand or a detection compound such as a horseradish peroxidase conjugated antibody is allowed to bind to the target species. A dye, such as TMB, is then added and allowed to react with the horseradish peroxidase, causing precipitation and a color change that is detected by a suitable detection device. Further description of protein detection using ArrayTube is found in, for example, Huelseweh B, Ehricht R and Marschall H-J,  Proteomics,  2006, 6, 2972-2981; and ClonDiag,  ArrayTube  ( AT )  Experiment Guideline for Protein - Based Applications , version 1.2, 2007, all incorporated by reference in their entirety. 
         [0109]    Transmission detection and analysis is performed with a ClonDiag AT reader instrument. Suitable reader instruments and detection devices include the ArrayTube Workstation ATS and the ATR 03. 
         [0110]    In addition to ArrayTube, the ClonDiag ArrayStrip (AS) can be used. The ArrayStrip provides a 96-well format for high volume testing. Each ArrayStrip consists of a standard 8-well strip with a microarray integrated into the bottom of each well. Up to 12 ArrayStrips can be inserted into one microplate frame enabling the parallel multiparameter testing of up to 96 samples. The ArrayStrip can be processed using the ArrayStrip Processor ASP, which performs all liquid handling, incubation, and detection steps required in array based analysis. In various embodiments, where a protein is detected, a method of using the ArrayStrip to detect the protein comprises conditioning the AS array with buffer or blocking solution; loading of up to 96 sample solutions in the AS wells to allow for binding of the protein; 3×washing; conjugating with a secondary antibody linked to HRP; 3×washing; precipitation staining with TMB; and AS array imaging and optional data storage. 
         [0111]    Those skilled in the art will be familiar with numerous additional immunoassay formats and variations thereof which may be useful for carrying out the method disclosed herein. See generally E. Maggio,  Enzyme - Immunoassay , (CRC Press, Inc., Boca Raton, Fla., 1980); see also U.S. Pat. Nos. 4,727,022; 4,659,678; 4,376,110; 4,275,149; 4,233,402; and 4,230,767. 
         [0112]    In general, immunoassays carried out in accordance with the present invention may be homogeneous assays or heterogeneous assays. In a homogeneous assay the immunological reaction usually involves the specific antibody (e.g., anti-biomarker protein antibody), a labeled analyte, and the sample of interest. The signal arising from the label is modified, directly or indirectly, upon the binding of the antibody to the labeled analyte. Both the immunological reaction and detection of the extent thereof can be carried out in a homogeneous solution. Immunochemical labels which may be employed include free radicals, radioisotopes, fluorescent dyes, enzymes, bacteriophages, or coenzymes. 
         [0113]    In a heterogeneous assay approach, the reagents are usually the sample, the antibody, and means for producing a detectable signal. Samples as described above may be used. The antibody can be immobilized on a support, such as a bead (such as protein A and protein G agarose beads), plate or slide, and contacted with the specimen suspected of containing the antigen in a liquid phase. The support is then separated from the liquid phase and either the support phase or the liquid phase is examined for a detectable signal employing means for producing such signal. The signal is related to the presence of the analyte in the sample. Means for producing a detectable signal include the use of radioactive labels, fluorescent labels, or enzyme labels. For example, if the antigen to be detected contains a second binding site, an antibody which binds to that site can be conjugated to a detectable group and added to the liquid phase reaction solution before the separation step. The presence of the detectable group on the solid support indicates the presence of the antigen in the test sample. Examples of suitable immunoassays include immunoblotting, immunofluorescence methods, immunoprecipitation, chemiluminescence methods, electrochemiluminescence (ECL) or enzyme-linked immunoassays. 
         [0114]    Antibodies can be conjugated to a solid support suitable for a diagnostic assay (e.g., beads such as protein A or protein G agarose, microspheres, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as passive binding. Antibodies as described herein may likewise be conjugated to detectable labels or groups such as radiolabels (e.g.,  35 S,  125 I,  131 I), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescent labels (e.g., fluorescein, Alexa, green fluorescent protein, rhodamine) in accordance with known techniques. 
         [0115]    Using any of the methods and compositions described herein, a sample can be assayed to determine levels of a biomarker panel. Thus, in one aspect, the invention provides a method of assaying a sample from a patient to determine concentrations of a biomarker panel in the sample. In some embodiments, the method comprises contacting the sample with a composition comprising a solid support comprising a capture binding ligand or capture probe for each biomarker of a biomarker panel. 
         [0116]    The invention further provides kits for use in determining breast health or breast cancer status for a number of medical (including diagnostic and therapeutic), industrial, forensic and research applications. Kits may comprise a carrier, such as a box, carton, tube or the like, having in close confinement therein one or more containers, such as vials, tubes, ampoules, bottles, pouches, envelopes and the like. In various embodiments, the kits comprise one or more components selected from one or more media or media ingredients and reagents for the measurement of the various biomarkers and biomarker panels disclosed herein. For example, kits of the invention may also comprise, in the same or different containers, one or more DNA polymerases, one or more primers, one or more suitable buffers, one or more nucleotides (such as deoxynucleoside triphosphates (dNTPs) and preferably fluorescently labeled dNTPs) and labeling components. The one or more components may be contained within the same container, or may be in separate containers to be admixed prior to use. The kits of the present invention may also comprise one or more instructions or protocols for carrying out the methods of the present invention. The kits may also comprise a computer or a component of a computer, such as a computer-readable storage medium or device. Examples of storage media include, without limitation, optical disks such as CD, DVD and Blu-ray Discs (BD); magneto-optical disks; magnetic media such as magnetic tape and internal hard disks and removable disks; semi-conductor memory devices such as EPROM, EEPROM and flash memory; and RAM. The computer-readable storage medium may comprise software encoding references to the various therapies and treatment regimens disclosed herein. The software may be interpreted by a computer to provide the practitioner with treatments according to various measured concentrations of biomarkers as provided herein. In various embodiments, the kit comprises a biomarker assay involving a lateral-flow-based point-of-care rapid test with detection of risk thresholds, or a biochip with quantitative assays for the constituent biomarkers. 
       Methods of Diagnosing and Treating 
       [0117]    The compositions and methods of the present invention can be used in the prognosis, diagnosis and treatment of disease in a subject. The invention provides compositions and methods for laboratory and point-of-care tests for measuring biomarkers in a sample from a subject. The invention can be generally applied for a number of different diseases. In exemplary embodiments, the disease is breast cancer. 
         [0118]    The biomarkers and biomarker panels disclosed herein can be used in methods to diagnose, identify or screen subjects that have, do not have or are at risk for having disease; to monitor subjects that are undergoing therapies for disease; to determine or suggest a new therapy or a change in therapy; to differentially diagnose disease states associated with the disease from other diseases or within sub-classifications of disease; to evaluate the severity or changes in severity of disease in a patient; to stage a subject with the disease and to select or modify therapies or interventions for use in treating subjects with the disease. In an exemplary embodiment, the methods of the present invention are used to identify and/or diagnose subjects who are asymptomatic or presymptomatic for a disease. In this context, “asymptomatic” or “presymptomatic” means not exhibiting the traditional symptoms or enough abnormality for disease. 
         [0119]    In various embodiments, a method of determining a prognosis of a disease in a subject, diagnosing a disease in a subject, or treating a disease in a subject comprises taking a measurement of a biomarker panel in a sample from the subject. In various exemplary embodiments, the biomarker panel consists of two or more of S100A8, CSTA, GRM1, TPT1, GRIK1, H6PD, IGF2BP1, MDM4, and/or CA6. 
         [0120]    The term “disease status” includes any distinguishable manifestation of the disease, including non-disease. For example, disease status includes, without limitation, the presence or absence of disease, the risk of developing disease, the stage of the disease, the progression of disease (e.g., progress of disease or remission of disease over time), the severity of disease and the effectiveness or response to treatment of disease. 
         [0121]    A “subject” in the context of the present invention is an animal, preferably a mammal. The mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples. In various exemplary embodiments, a subject is human and may be referred to as a patient. Mammals other than humans can be advantageously used as subjects that represent animal models of a disease or for veterinarian applications. A subject can be one who has been previously diagnosed or identified as having a disease, and optionally has already undergone, or is undergoing, a therapeutic intervention for a disease. Alternatively, a subject can also be one who has not been previously diagnosed as having a disease. For example, a subject can be one who exhibits one or more risk factors for a disease, or one who does not exhibit a disease risk factor, or one who is asymptomatic for a disease. A subject can also be one who is suffering from or at risk of developing a disease. In certain embodiments, the subject can be already undergoing therapy or can be a candidate for therapy. 
         [0122]    As will be appreciated by those in the art, the biomarkers may be measured in using several techniques designed to achieve more predictable subject and analytical variability. 
         [0123]    The term “sample” refers to a specimen or culture obtained from a subject and includes fluids, gases and solids including for example tissue. In various exemplary embodiments, the sample comprises saliva. As will be appreciated by those in the art, virtually any experimental manipulation or sample preparation steps may have been done on the sample. For example, wash steps and/or fragmentation may be applied to a sample. In various embodiments, a biomarker panel is measured directly in a subject without the need to obtain a separate sample from the patient. 
         [0124]    In one aspect, the invention provides a method of diagnosing a subject for a disease comprising taking a measurement of a biomarker panel; and correlating the measurement with the disease. The term “correlating” generally refers to determining a relationship between one type of data with another or with a state. In various embodiments, correlating the measurement with disease comprises comparing the measurement with a reference biomarker profile or some other reference value. In various embodiments, correlating the measurement with disease comprises determining whether the subject is currently in a state of disease. 
         [0125]    The quantity or activity measurements of a biomarker panel can be compared to a reference value. Differences in the measurements of biomarkers in the subject sample compared to the reference value are then identified. In exemplary embodiments, the reference value is given by a risk category as described further below. 
         [0126]    In various embodiments, the reference value is a baseline value. A baseline value is a composite sample of an effective amount of biomarkers from one or more subjects who do not have a disease, who are asymptomatic for a disease or who have a certain level of a disease. A baseline value can also comprise the amounts of biomarkers in a sample derived from a subject who has shown an improvement in risk factors of a disease as a result of treatments or therapies. In these embodiments, to make comparisons to the subject-derived sample, the amounts of biomarkers are similarly calculated. A reference value can also comprise the amounts of biomarkers derived from subjects who have a disease confirmed by an invasive or non-invasive technique, or are at high risk for developing a disease. Optionally, subjects identified as having a disease, or being at increased risk of developing a disease are chosen to receive a therapeutic regimen to slow the progression of a disease, or decrease or prevent the risk of developing a disease. A disease is considered to be progressive (or, alternatively, the treatment does not prevent progression) if the amount of biomarker changes over time relative to the reference value, whereas a disease is not progressive if the amount of biomarkers remains constant over time (relative to the reference population, or “constant” as used herein). The term “constant” as used in the context of the present invention is construed to include changes over time with respect to the reference value. 
         [0127]    The biomarkers of the present invention can be used to generate a “reference biomarker profile” of those subjects who do not have a disease according to a certain threshold, are not at risk of having a disease or would not be expected to develop a disease. The biomarkers disclosed herein can also be used to generate a “subject biomarker profile” taken from subjects who have a disease or are at risk for having a disease. The subject biomarker profiles can be compared to a reference biomarker profile to diagnose or identify subjects at risk for developing a disease, to monitor the progression of disease, as well as the rate of progression of disease, and to monitor the effectiveness of disease treatment modalities. The reference and subject biomarker profiles of the present invention can be contained in a machine-readable medium, such as but not limited to, analog tapes like those readable by a VCR; optical media such as CD-ROM, DVD-ROM and the like; and solid state memory, among others. 
         [0128]    Measurements of the biomarker panels of the invention can lead a practitioner to affect a therapy with respect to a subject. Thus, the invention provides methods of treating a disease in a subject comprising taking a measurement of a biomarker panel in a sample from the subject, and affecting a therapy with respect to the subject. The terms “therapy” and “treatment” may be used interchangeably. In certain embodiments, the therapy can be selected from, without limitation, initiating therapy, continuing therapy, modifying therapy or ending therapy. A therapy also includes any prophylactic measures that may be taken to prevent disease. 
         [0129]    In certain embodiments, treatment comprises administering a disease-modulating drug to a subject. The drug can be a therapeutic or prophylactic used in subjects diagnosed or identified with a disease or at risk of having the disease. In certain embodiments, modifying therapy refers to altering the duration, frequency or intensity of therapy, for example, altering dosage levels. 
         [0130]    In various embodiments, effecting a therapy comprises causing a subject to or communicating to a subject the need to make a change in lifestyle, for example, increasing exercise, changing diet, reducing or eliminating smoking and so on. The therapy can also include surgery, for example, mastectomy. 
         [0131]    Measurement of biomarker levels allow for the course of treatment of a disease to be monitored. The effectiveness of a treatment regimen for a disease can be monitored by detecting one or more biomarkers in an effective amount from samples obtained from a subject over time and comparing the amount of biomarkers detected. For example, a first sample can be obtained prior to the subject receiving treatment and one or more subsequent samples are taken after or during treatment of the subject. Changes in biomarker levels across the samples may provide an indication as to the effectiveness of the therapy. 
         [0132]    To identify therapeutics or drugs that are appropriate for a specific subject, a test sample from the subject can also be exposed to a therapeutic agent or a drug, and the level of one or more biomarkers can be determined. Biomarker levels can be compared to a sample derived from the subject before and after treatment or exposure to a therapeutic agent or a drug, or can be compared to samples derived from one or more subjects who have shown improvements relative to a disease as a result of such treatment or exposure. Thus, in one aspect, the invention provides a method of assessing the efficacy of a therapy with respect to a subject comprising taking a first measurement of a biomarker panel in a first sample from the subject; effecting the therapy with respect to the subject; taking a second measurement of the biomarker panel in a second sample from the subject and comparing the first and second measurements to assess the efficacy of the therapy. 
         [0133]    Additionally, therapeutic or prophylactic agents suitable for administration to a particular subject can be identified by detecting a biomarker (which may be two or more) in an effective amount from a sample obtained from a subject and exposing the subject-derived sample to a test compound that determines the amount of the biomarker(s) in the subject-derived sample. Accordingly, treatments or therapeutic regimens for use in subjects having a disease or subjects at risk for developing a disease can be selected based on the amounts of biomarkers in samples obtained from the subjects and compared to a reference value. Two or more treatments or therapeutic regimens can be evaluated in parallel to determine which treatment or therapeutic regimen would be the most efficacious for use in a subject to delay onset, or slow progression of a disease. In various embodiments, a recommendation is made on whether to initiate or continue treatment of a disease. 
       Drug Treatments 
       [0134]    In various exemplary embodiments, effecting a therapy comprises administering a disease-modulating drug to the subject. The subject may be treated with one or more disease-modulating drugs until altered levels of the measured biomarkers return to a baseline value measured in a population not suffering from the disease, experiencing a less severe stage or form of a disease or showing improvements in disease biomarkers as a result of treatment with a disease-modulating drug. Additionally, improvements related to a changed level of a biomarker or clinical parameter may be the result of treatment with a disease-modulating drug. 
         [0135]    A number of compounds such as a disease-modulating drug may be used to treat a subject and to monitor progress using the methods of the invention. In certain embodiments, the disease-modulating drug comprises 
         [0136]    The beneficial effects of these and other drugs can be visualized by assessment of clinical and laboratory biomarkers. 
         [0137]    Any drug or combination of drugs disclosed herein may be administered to a subject to treat a disease. The drugs herein can be formulated in any number of ways, often according to various known formulations in the art or as disclosed or referenced herein. 
         [0138]    In various embodiments, any drug or combination of drugs disclosed herein is not administered to a subject to treat a disease. In these embodiments, the practitioner may refrain from administering the drug or combination of drugs, may recommend that the subject not be administered the drug or combination of drugs or may prevent the subject from being administered the drug or combination of drugs. 
         [0139]    In various embodiments, one or more additional drugs may be optionally administered in addition to those that are recommended or have been administered. An additional drug will typically not be any drug that is not recommended or that should be avoided. In exemplary embodiments, one or more additional drugs comprise one or more glucose lowering drugs. 
       Decision Matrices 
       [0140]    The therapy chosen by a practitioner can depend on the concentrations of biomarkers determined in a sample. In various exemplary embodiments, the therapy depends on which category from a range of categories particular to each biomarker the measured concentration of each biomarker falls in. In various exemplary embodiments, the therapy depends on the combination of risk levels for different symptoms or diseases that are indicated by a biomarker panel. 
         [0141]    With respect to concentration measurements of a biomarker, the term “category” refers to a subset of a partition of the possible concentrations that a biomarker may have. Each category may be associated with a label or classification chosen by the practitioner. The labels may be refer to, for example, the risk level of an individual for having or being subject to a disease state. The categories and labels may be derived from the current literature or according to the findings of the practitioner. 
         [0142]    Each biomarker of a biomarker panel can thus be associated with a discrete set of categories, for example, risk categories. Combining one category from each biomarker forms a “decision point.” In various exemplary embodiments, the complete set of decision points comprises all possible n-tuples of categories, wherein n is the number of biomarkers in the biomarker panel. This complete set will have m 1 ×m 2 × . . . m n  possible decision points, wherein in is the number of categories for biomarker i. 
         [0143]    Every decision point can be associated with a condition or a disease state, which is not necessarily unique. That is, one or more decision points can be associated with the same disease state. The association of every possible decision point with a condition or disease state can be referred to as a “disease classification matrix” or a “disease classification tree.” Thus, by correlating a measurement of a biomarker panel with a decision point, the practitioner can classify the condition or disease state of a patient. 
         [0144]    Every decision point can also be associated with a particular therapy, which is not necessarily unique. That is, one or more decision points can be associated with the same therapy. The association of every possible decision point with one or more therapies can be referred to as a “therapy decision matrix” or “therapy decision tree.” 
         [0145]    Each decision point can be associated with more than one type of information. For example, both disease state and therapy can be indicated by a decision point. 
         [0146]    The articles “a,” “an” and “the” as used herein do not exclude a plural number of the referent, unless context clearly dictates otherwise. The conjunction “or” is not mutually exclusive, unless context clearly dictates otherwise. The term “include” is used to refer to non-limiting examples. 
       EXAMPLES 
       [0147]    The following examples are offered to illustrate, but not to limit the invention. 
       Example 1: Salivary Transciptomic Profiling and Analysis 
     Saliva Collection 
       [0148]    Unstimulated whole saliva samples were collected with previously established protocols. Subjects were asked to refrain from eating, drinking, smoking, or oral hygiene procedures for at least 30 minutes before the collection. Lipstick was wiped off, and the subject rinsed her mouth once with plain water. Typically, patients donated approximately 5-10 ml of saliva. Samples were then centrifuged at 2,600 g for 15 minutes at 4° C. The supernatant was then stored at −80° C. until use. Of note, protease inhibitors cocktail, containing 1 μl aprotinin, 10 μl PMSF (phenylmethanesulfonyl fluoride) and 3 μl sodium orthovanadate (all from Sigma, St. Louis, Mo.) were added to each 1 ml saliva sample. 
         [0000]    mRNA Isolation and Analysis 
         [0149]    RNA was isolated from 330 μl of saliva supernatant using MagMax™ Viral RNA Isolation Kit (Ambion, Austin, Tex.). This process was automated using KingFisher® mL technology (Thermo Fisher Scientific, Waltham, Mass.), followed by TURBO™ DNase treatment (Ambion, Austin, Tex.) to remove contaminating DNA. 90 μl of extracted RNA (out of 100 μl) was concentrated to 11 μl and was linearly amplified using the RiboAmp® RNA Amplification kit (Molecular Devices, Sunnyvale, Calif.). After purification, cDNA was transcribed and biotinylated using GeneChip® Expression 3′-Amplification Reagents for in vitro transcription labeling (Affymetrix, Santa Clara, Calif.). Approximately 20 μg of labeled RNA were subsequently submitted for GeneChip® analysis using an Affymetrix Human Genome U133 Plus 2.0 Array. Chip hybridization and scanning were performed using the MIAME (Minimum Information About a Microarray Experiment) criteria. All Affymetrix Human Genome U133 Plus 2.0 Array data generated in this study were uploaded to the GEO database, accession number GSE20266. 
       Gene Array Statistical Analysis 
       [0150]    The CEL files from all databases were imported into the statistical R 2.7.0 (hypertext transfer protocol://www.r-project.org) with same and ROC packages. The Probe Logarithmic Intensity Error Estimation (PLIER) expression measures were computed after background correction and quantile normalization for each microarray dataset. Probeset-level quantile normalization was performed across all samples to make the effect sizes similar among all datasets. Finally, for every probeset, significance analysis of microarray (SAM) was applied to identify differential expression between the cancer and healthy control samples. The probesets were then ranked by the false discovery rate (FDR) corrected p-values. 
       Screening of Biomarker Candidates 
       [0151]    The biomarker candidates generated by microarray profiling were subjected to further screening by real-time quantitative RT-PCR (qPCR) on the same set of samples used for the microarray analysis. To accomplish this, total RNA was reverse-transcribed using reverse transcriptase and gene-specific primers using the following thermal cycling conditions: 1 min at 60° C., 30 min at 50° C., 2 min at 95° C., followed by 15 cycles of 15s at 95° C., 30s at 50° C., 10 s at 72° C. These steps were followed with a final extension of 5 min. at 72° C. and then cooling to 4° C. The preamplified product was cleaned using ExoSAP-IT (USB Corporation) and diluted 1/40 in water. 2 μl of the cDNA was used for qPCR. 
         [0152]    qPCR was carried out in a 96-well plate in a reaction volume of 10 μl using power SYBR®-Green Master Mix (Applied Biosystems, Foster City, Calif.) for 15 min at 95° C. for initial denaturing, followed by 40 cycles of 95° C. for 30 s and 60° C. for 30 s in the ABI 7500HT Fast Real Time PCR system (Applied Biosystems, Foster City, Calif.). All qPCRS were performed in duplicate for all candidate mRNA. The specificity of the PCR was confirmed according to the melting curve of each gene, and the average threshold cycle (Ct) was examined. 
         [0153]    Amplicon lengths were around 100-130 by for the outer primer pairs used in preamplification and 60-80 bp for the inner primer pairs used in qPCR. RT-qPCR primers were designed using Primer Express 3.0 software (Applied Biosystems, Foster City, Calif.). All primers were synthesized by Sigma-Genosys (Woodlands, Tex.), and the amplicons were intron spanning whenever possible. 
         [0154]    Raw data were normalized by subtracting GAPDH Ct values from the biomarker Ct values to generate ΔCt. The Mann-Whitney rank sum test was used for between-group biomarker comparisons. 
       Primers for 11 Candidate Biomarkers and GAPDH 
       [0155]      
         [0000]                    Gene symbol Primer name Primer sequences (5′-3′)       ATXN3       ATXN3-OF        GAAAAACAGCAGCAAAAGCA               ATXN3-IF        GGGGGACCTATCAGGACAGA               ATXN3-IR        CAAGTGCTCCTGAACTGGTG               ATXN3-OR        CCAAGTGCTCCTGAACTGGT               GRIK1       GRIK1-OF        CCGGACTGGTCCTTTCTGTA               GRIK1-IF        CCGGACTGGTCCTTTCTGTA               GRIK1-IR        AGCGTTGAAAGAGAGACACTG               GRIK1-OR        CAGTGAGATTCCCAGTTCTTCC               GRM1        GRM1-OF        GCAGGGAATGCCAATTCTAA               GRM1-IF        TGGCAAGTCTGTGTCATGGT               GRM1-IR        GCCACATATGCTGTCCCTTG               GRM1-OR       GCCGTCTCATTGGTCTTCAC               TPT1        TPT1-OF        TACCGTGAGGATGGTGTGAC               TPT1-IF        CAAATGTGGCAATTATTTTGGA               TPT1-IR        GATGACAAGCAGAAGCCAGTT               TPT1-OR        GATGACAAGCAGAAGCCAGT               RGS13         RGS13-OF       CTCACGGTGGAGCAGAATTT               RGS13-IF        CTCACGGTGGAGCAGAATTT               RGS13-IR        GGGACTGTGGCTGGATGTAA               RGS13-OR        TGGGTTCCTGAATGTTCCTG               S100A8        S100A8-OF        TCAGGAAAAAGGGTGCAGAC               S100A8-IF        TCAGGAAAAAGGGTGCAGAC               S100A8-IR        TGGAAGTTAACTGCACCATCA               S100A8-OR        ACGCCCATCTTTATCACCAG               CLDN15        CLDN15-OF        TTGTACCCCGGAACCAAGTA               CLDN15-IF        CGGAACCAAGTACGAGCTG               CLDN15-IR        CACCCAGGATGGAGATCAGT               CLDN15-OR        CTGGGTCCTCGTCAGAGC               IGF2BP1        IGF2B P1-OF        AGAATTTGACGGCAGCTGAG               IGF2BP1-IF        CCAGGTCATCGTGAAAATCA               IGF2BP1-IR        ATCTTCCGTTGAGCCATCTG               IGF2BP1-OR       ATGTCTCGGATCTTCCGTTG               CSTA        CSTA-OF       ACGGAAAATTGGAAGCTGTG               CSTA-IF        CATTAAGGTACGAGCAGGTGA               CSTA-IR        TTTGTCCGGGAAGACTTTTG               CSTA-OR        TTTGTCCGGGAAGACTTTTG               MDM4         MDM4-OF       GTGGCAGTGTACTGAATGCAA               MDM4-IF        TGGCAGTGTACTGAATGCAA               MDM4-IR       AAGGCCCAACAACGAAAAC               MDM4-OR       TCAGACGTGGAGAGAGAATGG               H6PD        H6PD-OF        GGCACAAGCTTCAGGTCTTC               H6PD-IF        GTCGTGGGCCAGTACCAGT               H6PD-IR        GTGGAAGCTGTCTGGCTTCT               H6PD-OR        GTGGAAGCTGTCTGGCTTCT               GAPDH        GAPDH-OF        CATTGCCCTCAACGACCACTT               GAPDH-IF        ACCACTTTGTCAAGCTCATTTCCT               GAPDH-IR        CACCCTGTTGCTGTAGCCAAAT               GAPDH-OR        ATGTGGGCCATGAGGTCCA            
OF=Outer forward, IF=Inner forward, IR=Inner reverse, OR=Outer reverse. All primers were designed using Primer Express 3.0 software (Applied Biosystems, FosterCity, Calif.). The specificity of primers was checked using NCBI&#39;s GenBank BLAST search.
 
         [0156]    The data analysis for qPCR was performed using the 2 −Ct  method, where GAPDH is used as the reference gene. The qPCR based gene expression values between two groups were compared using the non-parametric Wilcoxon test. To normalize for RNA input, qPCR was also performed for GAPDH. Raw data were normalized by subtracting GAPDH Ct values from the marker Ct values to provide ΔCt and then analyze with the stats, utilities packages from R 2.7.0 (world wide web.r-project.org) and the ROC package from Bioconductor 2.2 (world wide web.bioconductor.org). Statistical comparisons were made with the use of the Mann-Whitney U test with consideration of two different distributions for control and pancreatic cancer groups. Biomarkers that differentiated between groups of subjects (P value &lt;0.05) were identified and compared by Area Under Curve (AUC) value. The AUC is based on constructing a receiver operating characteristic (ROC) curve which plots the sensitivity versus one minus the specificity. The AUC value is computed by numerical integration of the ROC curve. The range of this value can be 0.5 to 1.0. A value of 0.5 indicates that the biomarker is no better that a coin toss, while 1.0 indicates the relatively best diagnostic accuracy. 
       Example 2: Salivary Proteomic Profiling and Analysis 
     Protein Isolation and Analysis 
       [0157]    Saliva from 13 healthy control subjects and 13 breast cancer subjects were centrifuged at 2600 g at 4° C. for 15 minutes. Saliva supernatant from the 13 health control subjects and 13 breast cancer subjects were pooled to form a control sample and a cancer sample for proteomic profiling. 250 μg of proteins in the pooled saliva samples were precipitated by methanol and then resuspended in 2-D cell lysis buffer (30 mM Tris-HCl, pH 8.8, containing 7M urea, 2M thiourea and 4% CHAPS detergent). The total proteins of each pooled sample, breast cancer and control, were labeled with the cyanine dyes Cy2 and Cy5 respectively. The two labeled sample sets were then combined and subjected to two-dimensional difference gel electrophoresis. After loading the labeled samples, isoelectric focusing (IEF) (pH3-10) was run following the protocol provided by Amersham BioSciences. The IPG strips were rinses in the SDS-gel running buffer before transferring to 13.5% SDS-gels. The SDS-gels were run at 15° C. until the dye front ran out of the gels. Gel images were scanned immediately following the SDS-PAGE using Typhoon TRIO™ (Amersham BioSciences). The fold change of the protein expression levels was obtained from in-gel DeCyder™ analysis. 
         [0158]    Spots with fold changes larger than 1.5 on the gel were cut and then were washed multiple times to remove staining dye and other chemicals. Gel spots were dried to absorb maximum volume of digestion buffer. Dried 2D gel spots were rehydrated in digestion buffer containing sequencing grade modified trypsin (Promega, USA). Proteins were digested in-gel at 37° C. overnight. Digested peptides were extracted from the gel with TFA extraction buffer and with shaking. The digested tryptic peptides were desalted using C-18 Zip-tips (Millipore). The desalted peptides were mixed with CHCA matrix (α-cyano-4-hydroxycinnamic acid) and spotted into wells of a MALDI plate for MALDI-TOF MS (ABI4800) identification. Protein identification was based on peptide fingerprint mass mapping (using MS spectra) and peptide fragmentation mapping (using MS/MS spectra). Combined MS and MS/MS spectra were submitted for database search using GPS Explorer software equipped with the MASCOT search engine to identify proteins from primary sequence databases. 
       Screening of Biomarker Candidates 
       [0159]    Four proteins (carbonic anhydrase VI, psoriasin, Transthyretin and Cyclophilin A) identified in the 2-D gel analysis (above) were subjected to Western blot analysis on the original sample set. Reduced protein samples (15 μs total protein per lane) were loaded onto a 10% bis-Tris gel and run at 150V in MES SDS running buffer for one hour. Pre-stained protein standard (Invitrogen) was used to track protein migration. The proteins were transferred to nitrocellulose membrane by using iBlot® (Invitrogen). The membrane was then washed in wash buffer containing 10 mM Tris-HCl, pH 7.6, 150 mM NaCl, and 0.1% (v/v) Tween®-20 (Sigma-Aldrich) before blocking for one hour in wash buffer containing 5% non-fat dry milk. After further washes in wash buffer, the membrane was incubated with primary antibody (mouse anti-human carbonic anhydrase VI (Lifespan Biotech) at 1 μg/ml, mouse anti-psoriasin (Abeam) at 1 μg/ml, mouse anti-actin (Sigma-Aldrich) at 1 μg/ml according to manufacturers instructions in blocking buffer at room temperature for 2 h. The membrane was then washed before applying the secondary antibody (anti-mouse IgG peroxidase-linked species specific whole antibody from sheep, GE Healthcare) according to manufacturer&#39;s instructions for one hour at room temperature. Finally, the membrane was washed and visualized using ECL Plus™ detection kit (GE Healthcare). The signal intensity of the bands was measured using Image J software (NIH, Bethesda, Md., USA). The intensity of a band representing the protein of interest was divided by the intensity of it corresponding (3-actin expression on the same blot for normalization. 
         [0160]    The protein expression pattern of carbonic anhydrase VI and psoriasin was further tested by Western blot with a new subject sample set including 31 cancer subject samples and 62 control subject samples. All the samples were coded with a random number from 1 to 93 and used for blind testing by Western blot. The distribution of carbonic anhydrase VI shows significant difference in the cancer group as compared to the control group (p=0.009949). 
       Example 4: Screening Method 
       [0161]    A patient undergoing routine dental care is screened during the visit. For example, a 62 year old female patient, and former smoker, prior to oral exam is asked to provide a saliva sample. A saliva sample is collected and analyzed either at the point of care or is submitted for analysis by a reference laboratory. The saliva sample is tested for the biomarkers of the instant invention and optionally other biomarkers. Results from the analysis are provided to the dental professional and the patient is informed as to whether she has breast cancer. 
         [0000]    
       
         
               
             
           
               
                 (S100A8)(NM_002964.4)  
               
               
                 SEQ ID NO: 1 
               
               
                 gagaaaccag agactgtagc aactctggca gggagaagct 
               
               
                   
               
               
                 gtctctgatg gcctgaagctgtgggcagct ggccaagcct 
               
               
                   
               
               
                 aaccgctata aaaaggagct gcctctcagc 
               
               
                   
               
               
                 cctgcatgtctcagtcagc tgtattcag aagacctggt 
               
               
                   
               
               
                 ggggcaagtc cgtgggcatc atgttgaccgagctggagaa 
               
               
                   
               
               
                 agccttgaac tctatcatcg acgtctacca caagtactcc 
               
               
                   
               
               
                 ctgataaaggggaatttcca tgccgtctac agggatgacc 
               
               
                   
               
               
                 tgaagaaatt gctagagacc gagtgtcctcagtatatcag 
               
               
                   
               
               
                 gaaaaagggt gcagacgtct ggttcaaaga gttggatatc 
               
               
                   
               
               
                 aacactgatggtgcagttaa cttccaggag ttcctcattc 
               
               
                   
               
               
                 tggtgataaa gatgggcgtg gcagcccaca aaaaaagcca 
               
               
                   
               
               
                 tgaagaaagc cacaaagagt agctgagtta ctgggcccag 
               
               
                   
               
               
                 aggctgggcc cctggacatg tacctgcaga ataataaagt 
               
               
                   
               
               
                 catcaatacc tcaaaaaaaa aa 
               
               
                   
               
               
                 (CSTA)(NM_005213)  
               
               
                 SEQ ID NO: 2 
               
               
                 tgctgtttgt ggaaaataaa gcattctata ggcggagcta 
               
               
                   
               
               
                 gtgaacgcct cttttaaaacacgagtctcc acacttccct 
               
               
                   
               
               
                 gttcactttg gttccagcat cctgtccagc aaagaagcaa 
               
               
                   
               
               
                 tcagccaaaa tgatacctgg aggcttatct gaggccaaac 
               
               
                   
               
               
                 ccgccactcc agaaatccag gagattgttg ataaggttaa 
               
               
                   
               
               
                 accacagctt gaagaaaaaa caaatgagac ttacggaaaa 
               
               
                   
               
               
                 ttggaagctg tgcagtataa aactcaagtt gttgctggaa 
               
               
                   
               
               
                 caaattacta cattaaggta cgagcaggtg ataataaata 
               
               
                   
               
               
                 tatgcacttg aaagtattca aaagtcttcc cggacaaaat 
               
               
                   
               
               
                 gaggacttgg tacttactgg ataccaggtt gacaaaaaca  
               
               
                   
               
               
                 aggatgacga gctgacgggc ttttagcagc atgtacccaa 
               
               
                   
               
               
                 agtgttctga ttccttcaac tggctactga gtcatgatcc 
               
               
                   
               
               
                 ttgctgataa atataaccat caataaagaa gcattctttt 
               
               
                   
               
               
                 ccaaagaaat tatttatca attatttctc atttattgta 
               
               
                   
               
               
                 ttaagcagaa attacctttt ctttctcaaa atcagtgtta 
               
               
                   
               
               
                 ttgctttaga gtataaactc catataaatt gatggcaatt 
               
               
                   
               
               
                 ggaaatctta taaaaactag tcaagcctaa tgcaactggc 
               
               
                   
               
               
                 taaaggatag taccaccctc acccccacca taggcaggct 
               
               
                   
               
               
                 ggatcgtgga ctatcaattc accagcctcc ttgttccctg 
               
               
                   
               
               
                 tggctgctga taacccaaca ttccatctct accctcatac 
               
               
                   
               
               
                 ttcaaaatta aatcaagtat tttacaaaaa aaaaaaaa  
               
               
                   
               
               
                 (GRM1)(NM_001114329) 
               
               
                 SEQ ID NO: 3 
               
               
                 agtgctgaag aaagagggca ctagtgtaca gcccagatcg 
               
               
                   
               
               
                 catccttgca ccgtctggat tagagctgag gcgtctgcaa 
               
               
                   
               
               
                 gccgagcgtg gccacggtcc tctggccccg ggaccatagc 
               
               
                   
               
               
                 gctgtctacc ccgactcagg tactcagcag catctagctc  
               
               
                   
               
               
                 accgctgcca acacgacttc cactgtactc ttgatcaatt 
               
               
                   
               
               
                 taccttgatg cactaccggt gaagaacggg gactcgaatt 
               
               
                   
               
               
                 cccttacaaa cgcctccagc ttgtagaggc ggtcgtggag 
               
               
                   
               
               
                 gacccagagg aggagacgaa ggggaaggag gcggtggtgg 
               
               
                   
               
               
                 aggaggcaaa ggccttggac gaccattgtt ggcgaggggc 
               
               
                   
               
               
                 accactccgg gagaggcggc gctgggcgtc ttgggggtgc 
               
               
                   
               
               
                 gcgccgggag cctgcagcgg gaccagcgtg ggaacgcggc  
               
               
                   
               
               
                 tggcaggctg tggacctcgt cctcaccacc atggtcgggc 
               
               
                   
               
               
                 tccttttgtt ttttttccca gcgatctttt tggaggtgtc  
               
               
                   
               
               
                 ccttctcccc agaagccccg gcaggaaagt gttgctggca 
               
               
                   
               
               
                 ggagcgtcgt ctcagcgctc ggtggccaga atggacggag 
               
               
                   
               
               
                 atgtcatcat tggagccctc ttctcagtcc atcaccagcc 
               
               
                   
               
               
                 tccggccgag aaagtgcccg agaggaagtg tggggagatc 
               
               
                   
               
               
                 agggagcagt atggcatcca gagggtggag gccatgttcc 
               
               
                   
               
               
                 acacgttgga taagatcaac gcggacccgg tcctcctgcc 
               
               
                   
               
               
                 caacatcacc ctgggcagtg agatccggga ctcctgctgg  
               
               
                   
               
               
                 cactatccg tggctctgga acagagcatt gagttcatta 
               
               
                   
               
               
                 gggactctct gatttccatt cgagatgaga aggatgggat 
               
               
                   
               
               
                 caaccggtgt ctgcctgacg gccagtccct ccccccaggc 
               
               
                   
               
               
                 aggactaaga agcccattgc gggagtgatc ggtcccggct 
               
               
                   
               
               
                 ccagctctgt agccattcaa gtgcagaacc tgctccagct 
               
               
                   
               
               
                 cttcgacatc ccccagatcg cttattcagc cacaagcatc 
               
               
                   
               
               
                 gacctgagtg acaaaacttt gtacaaatac ttcctgaggg 
               
               
                   
               
               
                 ttgtcccttc tgacactttg caggcaaggg ccatgcttga 
               
               
                   
               
               
                 catagtcaaa cgttacaatt ggacctatgt ctctgcagtc  
               
               
                   
               
               
                 cacacggaag ggaattatgg ggagagcgga atggacgctt 
               
               
                   
               
               
                 tcaaagagct ggctgcccag gaaggcctct gtatcgccca 
               
               
                   
               
               
                 ttctgacaaa atctacagca acgctgggga gaagagcta 
               
               
                   
               
               
                 gaccgactct tgcgcaaact ccgagagagg cttcccaagg 
               
               
                   
               
               
                 ctagagtggt ggtctgcttc tgtgaaggca tgacagtgcg 
               
               
                   
               
               
                 aggactcctg agcgccatgc ggcgccttgg cgtcgtgggc 
               
               
                   
               
               
                 gagttctcac tcattggaag tgatggatgg gcagacagag  
               
               
                   
               
               
                 atgaagtcat tgaaggttat gaggtggaag ccaacggggg 
               
               
                   
               
               
                 aatcacgata aagctgcagt ctccagaggt caggtcattt 
               
               
                   
               
               
                 gatgattatt tcctgaaact gaggctggac actaacacga 
               
               
                   
               
               
                 ggaatccctg gttccctgag ttctggcaac atcggttcca 
               
               
                   
               
               
                 gtgccgcctt ccaggacacc ttctggaaaa tcccaacttt 
               
               
                   
               
               
                 aaacgaatct gcacaggcaa tgaaagctta gaagaaaact 
               
               
                   
               
               
                 atgtccagga cagtaagatg gggtttgtca tcaatgccat  
               
               
                   
               
               
                 ctatgccatg gcacatgggc tgcagaacat gcaccatgcc 
               
               
                   
               
               
                 ctctgccctg gccacgtggg cctctgcgat gccatgaagc 
               
               
                   
               
               
                 ccatcgacgg cagcaagctg ctggacttcc tcatcaagtc 
               
               
                   
               
               
                 ctcattcatt ggagtatctg gagaggaggt gtggtttgat 
               
               
                   
               
               
                 gagaaaggag acgctcctgg aaggtatgat atcatgaatc 
               
               
                   
               
               
                 tgcagtacac tgaagctaat cgctatgact atgtgcacgt 
               
               
                   
               
               
                 tggaacctgg catgaaggag tgctgaacat tgatgattac  
               
               
                   
               
               
                 aaaatccaga tgaacaagag tggagtggtg cggtctgtgt 
               
               
                   
               
               
                 gcagtgagcc ttgcttaaag ggccagatta aggttatacg 
               
               
                   
               
               
                 gaaaggagaa gtgagctgct gctggatttg cacggcctgc 
               
               
                   
               
               
                 aaagagaatg aatatgtgca agatgagttc acctgcaaag 
               
               
                   
               
               
                 cttgtgactt gggatggtgg cccaatgcag atctaacagg 
               
               
                   
               
               
                 ctgtgagccc attcctgtgc gctatcttga gtggagcaac 
               
               
                   
               
               
                 atcgaatcca ttatagccat cgccttttca tgcctgggaa 
               
               
                   
               
               
                 tccttgttac cttgtttgtc accctaatct ttgtactgta 
               
               
                   
               
               
                 ccgggacaca ccagtggtca aatcctccag tcgggagctc 
               
               
                   
               
               
                 tgctacatca tcctagctgg catcttcctt ggttatgtgt 
               
               
                   
               
               
                 gcccattcac tctcattgcc aaacctacta ccacctcctg 
               
               
                   
               
               
                 ctacctccag cgcctcttgg ttggcctctc ctctgcgatg 
               
               
                   
               
               
                 tgctactctg ctttagtgac taaaaccaat cgtattgcac 
               
               
                   
               
               
                 gcatcctggc tggcagcaag aagaagatct gcacccggaa 
               
               
                   
               
               
                 gcccaggttc atgagtgcct gggctcaggt gatcattgcc  
               
               
                   
               
               
                 tcaattctga ttagtgtgca actaaccctg gtggtaaccc 
               
               
                   
               
               
                 tgatcatcat ggaaccccct atgcccattc tgtcctaccc  
               
               
                   
               
               
                 aagtatcaag gaagtctacc ttatctgcaa taccagcaac 
               
               
                   
               
               
                 ctgggtgtgg tggccccttt gggctacaat ggactcctca 
               
               
                   
               
               
                 tcatgagctg tacctactat gccttcaaga cccgcaacgt 
               
               
                   
               
               
                 gcccgccaac ttcaacgagg ccaaatatat cgcgttcacc 
               
               
                   
               
               
                 atgtacacca cctgtatcat ctggctagct tttgtgccca 
               
               
                   
               
               
                 tttactttgg gagcaactac aagatcatca caacttgat 
               
               
                   
               
               
                 tgcagtgagt ctcagtgtaa cagtggctct ggggtgcatg 
               
               
                   
               
               
                 ttcactccca agatgtacat cattattgcc aagcctgaga 
               
               
                   
               
               
                 ggaatgtccg cagtgccttc accacctctg atgttgtccg 
               
               
                   
               
               
                 catgcatgtt ggcgatggca agctgccctg ccgctccaac 
               
               
                   
               
               
                 actttcctca acatcttccg aagaaagaag gcaggggcag  
               
               
                   
               
               
                 ggaatgccaa gaagaggcag ccagaattct cgcccaccag 
               
               
                   
               
               
                 ccaatgtccg tcggcacatg tgcagctttg aaaaccccca 
               
               
                   
               
               
                 cactgcagtg aatgtttcta atggcaagtc tgtgtcatgg 
               
               
                   
               
               
                 tctgaaccag gtggaggaca ggtgcccaag ggacagcata 
               
               
                   
               
               
                 tgtggcaccg cctctctgtg cacgtgaaga ccaatgagac 
               
               
                   
               
               
                 ggcctgcaac caaacagccg tcatcaagcc cctcactaaa 
               
               
                   
               
               
                 agttaccaag gctctggcaa gagcctgacc tatcagata  
               
               
                   
               
               
                 ccagcaccaa gaccattac aacgtagagg aggaggagga 
               
               
                   
               
               
                 tgcccagccg attcgcttta gcccgcctgg tagccatcc 
               
               
                   
               
               
                 atggtggtgc acaggcgcgt gccaagcgcg gcgaccactc 
               
               
                   
               
               
                 cgcctctgcc gtcccacctg accgcagagg agacccccct 
               
               
                   
               
               
                 cttcctggcc gaaccagccc tccccaaggg cttgccccct 
               
               
                   
               
               
                 cctctccagc agcagcagca accccctcca cagcagaaat 
               
               
                   
               
               
                 cgctgatgga ccagctccag ggagtggtca gcaacttcag  
               
               
                   
               
               
                 taccgcgatc ccggattttc acgcggtgct ggcaggcccc 
               
               
                   
               
               
                 ggtggtcccg ggaacgggct gcggtccctg tacccgcccc 
               
               
                   
               
               
                 cgccacctcc gcagcacctg cagatgctgc cgctgcagct 
               
               
                   
               
               
                 gagcaccttt ggggaggagc tggtctcccc gcccgcggac 
               
               
                   
               
               
                 gacgacgacg acagcgagag gtttaagctc ctccaggagt 
               
               
                   
               
               
                 acgtgtatga gcacgagcgg gaagggaaca cggaagaaga 
               
               
                   
               
               
                 cgaactggaa gaggaggagg aggacctgca ggcggccagc  
               
               
                   
               
               
                 aaactgaccc cggatgattc gcctgcgctg acgcctccgt 
               
               
                   
               
               
                 cgcctttccg cgactcggtg gcctcgggca gctcggtgcc 
               
               
                   
               
               
                 cagctccccc gtgtccgagt cggtgctctg cacccctccc 
               
               
                   
               
               
                 aacgtatcct acgcctctgt cattctgcgg gactacaagc 
               
               
                   
               
               
                 aaagctcttc caccctgtaa gggggaaggg tccacataga 
               
               
                   
               
               
                 aaagcaagac aagccagaga tctcccacac ctccagagat 
               
               
                   
               
               
                 gtgcaaacag ctgggaggaa aagcctggga gtggggggcc  
               
               
                   
               
               
                 tcgtcgggag gacaggagac cgctgctgct gctgccgcta 
               
               
                   
               
               
                 ctgctgctgc tgccttaagt aggaagagag ggaaggacac 
               
               
                   
               
               
                 caagcaaaaa atgttccagg ccaggattcg gattcttgaa 
               
               
                   
               
               
                 ttactcgaag ccttctctgg gaagaaaggg aattctgaca 
               
               
                   
               
               
                 aagcacaatt ccatatggta tgtaactttt atcacaaatc 
               
               
                   
               
               
                 aaatagtgac atcacaaaca taatgtcctc ttttgcacaa 
               
               
                   
               
               
                 ttgtgcatag atatatatat gcccacacac actgggccat 
               
               
                   
               
               
                 gcttgccaag gaacagccca cgtggacatg ccagtcggat 
               
               
                   
               
               
                 catgagttca cctgatggca ttcggagtga gctggtggag  
               
               
                   
               
               
                 ccagacagag caggtgcggg gaagggaagg gcccaggcca 
               
               
                   
               
               
                 gacccatccc aaacggatga tgggatgatg ggacagcagc 
               
               
                   
               
               
                 tccttgctca gaagcccttc tccccgctgg gctgacagac 
               
               
                   
               
               
                 tcctcatctt caggagactc aggaatggag cggcacaggg 
               
               
                   
               
               
                 gtctctcttc atccactgca acccatccag tgccagatt 
               
               
                   
               
               
                 gagattgcac ttgaagaaag gtgcatggac cccctgctgc 
               
               
                   
               
               
                 tctgcagatt ccctttattt aggaaaacag gaataagagc  
               
               
                   
               
               
                 aaaattatca ccaaaaagtg cttcatcagg cgtgctacag 
               
               
                   
               
               
                 gaggaaggag ctagaaatag aacaatccat cagcatgaga 
               
               
                   
               
               
                 ctttgaaaaa aaaacacatg atcagcttct catgttccat 
               
               
                   
               
               
                 attcacttat tggcgatttg gggaaaaggc cggaacaaga 
               
               
                   
               
               
                 gattgttacg agagtggcag aaaccctttt gtagattgac 
               
               
                   
               
               
                 ttgtgtttgt gccaagcggg ctttccattg accttcagtt 
               
               
                   
               
               
                 aaagaacaaa ccatgtgaca aaattgttac cttccactta 
               
               
                   
               
               
                 ctgtagcaaa taatacctac aagttgaact tctaagatgc 
               
               
                   
               
               
                 gtatatgtac aatttggtgc cattatttct cctacgtatt 
               
               
                   
               
               
                 agagaaacaa atccatcttt gaatctaatg gtgtactcat 
               
               
                   
               
               
                 agcaactatt actggtttaa atgacaaata attctatcct 
               
               
                   
               
               
                 attgtcactg aagtccttgt aactagcgag tgaatgtgtt 
               
               
                   
               
               
                 cctgtgtcct tgtatatgtg cgatcgtaaa atttgtgcaa 
               
               
                   
               
               
                 tgtaatgtca aattgactgg tcaatgtcaa cctagtagtc 
               
               
                   
               
               
                 aatctaactg caattagaaa ttgtcttttg aatatactat 
               
               
                   
               
               
                 atatattttt tatgttccaa taatgttttg tacatcattg 
               
               
                   
               
               
                 tcatcaatat ctacagaagc tctttgacgg tttgaatact 
               
               
                   
               
               
                 atggctcaag gttttcatat gcagctcgga tggacatttt 
               
               
                   
               
               
                 tcttctaaga tggaacttat ttttcagata ttttctgatg 
               
               
                   
               
               
                 tggagatatg ttattaatga agtggtttga aaatttgtta 
               
               
                   
               
               
                 tattaaaagt gcacaaaaac tgagagtgaa aataaaaggt 
               
               
                   
               
               
                 acattttata agcttgcaca cattattaac acataagatt 
               
               
                   
               
               
                 gaacaaagca tttagattat tccaggttat atcatttttt 
               
               
                   
               
               
                 taaagatttt ccacagctac ttgagtgtct aacatacagt 
               
               
                   
               
               
                 aacatctaac tcagctaata atttgtaaaa tctttatcaa 
               
               
                   
               
               
                 tcacattttg ccttctttta atttttatgt tcatggactt 
               
               
                   
               
               
                 ttattcctgt gtcttggctg tcataacttt ttatttctgc 
               
               
                   
               
               
                 tatttgctgt tgtgtaatat ccatggacat gtaatccact 
               
               
                   
               
               
                 tactccatct ttacaatccc tttttaccac caataaaagg 
               
               
                   
               
               
                 atttttcttg ctgttttgat ttcttctatt atttgtggaa 
               
               
                   
               
               
                 tgaattatac cccccttaaa tatctttgtt tatgccttat 
               
               
                   
               
               
                 gttcagtcat attttaatat gatccttca tattgaagct 
               
               
                   
               
               
                 gctgatttct cagccaaaaa tcatcttaga atctttaaat 
               
               
                   
               
               
                 atccattgca tcatttgac agaatttaac atccattcca 
               
               
                   
               
               
                 atgttggagg cttgtattac ttatatttca tcatattcta 
               
               
                   
               
               
                 ttgccaagtt tagtcagttc cacaccaaga atgaactgca 
               
               
                   
               
               
                 tttcctttaa aaattatttt aaaacacctt tattgaaaag 
               
               
                   
               
               
                 atctcatgac tgagatgtgg actttggttc catgttttca 
               
               
                   
               
               
                 ttgtaagaaa gcagagagcg gaaaatcaat ggctccagtg 
               
               
                   
               
               
                 attaatagat gggtttttag taattgacaa attcatgagg 
               
               
                   
               
               
                 gaaagcatat gatctcttta ttagtgaatc atgcttattt 
               
               
                   
               
               
                 tttactata atgccactaa tatacatccc taatatcaca 
               
               
                   
               
               
                 gggcttgtgc attcagattt ttaaaaaatt aggatagata 
               
               
                   
               
               
                 aggaaacaac ttatattcaa gtgtaagatg atatcaggtt 
               
               
                   
               
               
                 ggtctaagac ttttggtgaa cacgttcatt caactgtgat 
               
               
                   
               
               
                 cactttatta ctctgaatgc ctactattat cctgattatg 
               
               
                   
               
               
                 gggtctcctg aataaataga gtattagtcc ttatgtcatc 
               
               
                   
               
               
                 attgttcaaa attggagatg tacacataca taccctatac 
               
               
                   
               
               
                 caagagggcc gaaactcttc accttgatgt atgttctgat 
               
               
                   
               
               
                 acaagttgtt cagcttcttg taaatgtgtt ttccttcggc 
               
               
                   
               
               
                 ttgttactgc cttttgtcaa ataatcttga caatgctgta 
               
               
                   
               
               
                 taataaatat tttctattt  
               
               
                   
               
               
                 (TPT1)(NM_003295.2) 
               
               
                 SEQ ID NO: 4 
               
               
                 ccccccgagc gccgctccgg ctgcaccgcg ctcgctccga 
               
               
                   
               
               
                 gtttcaggct cgtgctaagctagcgccgtc gtcgtctccc 
               
               
                   
               
               
                 ttcagtcgcc atcatgatta tctaccggga cctcatcagc 
               
               
                   
               
               
                 cacgatgaga tgttctccga catctacaag atccgggaga 
               
               
                   
               
               
                 tcgcggacgg gttgtgcctg gaggtggagg ggaagatggt 
               
               
                   
               
               
                 cagtaggaca gaaggtaaca ttgatgactc gctcattggt 
               
               
                   
               
               
                 ggaaatgcct ccgctgaagg ccccgagggc gaaggtaccg 
               
               
                   
               
               
                 aaagcacagt aatcactggt gtcgatattg tcatgaacca  
               
               
                   
               
               
                 tcacctgcag gaaacaagtt tcacaaaaga agcctacaag 
               
               
                   
               
               
                 aagtacatca aagattacat gaaatcaatc aaagggaaac 
               
               
                   
               
               
                 ttgaagaaca gagaccagaa agagtaaaac cttttatgac 
               
               
                   
               
               
                 aggggctgca gaacaaatca agcacatcct tgctaatttc 
               
               
                   
               
               
                 aaaaactacc agttctttat tggtgaaaac atgaatccag 
               
               
                   
               
               
                 atggcatggt tgctctattg gactaccgtg aggatggtgt 
               
               
                   
               
               
                 gaccccatat atgattact ttaaggatgg tttagaaatg 
               
               
                   
               
               
                 gaaaaatgtt aacaaatgtg gcaattattt tggatctatc 
               
               
                   
               
               
                 acctgtcatc ataactggct tctgcttgtc atccacacaa 
               
               
                   
               
               
                 caccaggact taagacaaat gggactgatg tcatcttgag 
               
               
                   
               
               
                 ctcttcattt attttgactg tgatttattt ggagtggagg 
               
               
                   
               
               
                 cattgttttt aagaaaaaca tgtcatgtag gttgtctaaa 
               
               
                   
               
               
                 aataaaatgc atttaaactc atttgagag  
               
               
                   
               
               
                 (GRIK1)(NM_000830.3; mRNA variant 1 of 2 shown)  
               
               
                 SEQ ID NO: 5 
               
               
                 agagcccctg caccaactca ccctgtaccc tctctccttc 
               
               
                   
               
               
                 ttcgttagtc ttctttcccc cttttccctc ctctgtctgt  
               
               
                   
               
               
                 gcctatcccc cgacttttgc atctgaccaa aggacgaatg 
               
               
                   
               
               
                 agggagacgt tcctgcagat cggggcagca actttcctca 
               
               
                   
               
               
                 gctggtctct gggctccggg agccagagag cgctgatcct 
               
               
                   
               
               
                 ccgcggtctg cggcccatgg aagaggagga ggaggagccg 
               
               
                   
               
               
                 tgatgggcta gcgacagcac tgaggagccc cgagagagct 
               
               
                   
               
               
                 cagccttgcc agccagctcc gcggtcccac gcgggttccc 
               
               
                   
               
               
                 tcgagctcgc tccgtgggga gcgcgcagcg tgcttggaac  
               
               
                   
               
               
                 cggagcatcc agagaggatg aggcggggac ccggcccaag 
               
               
                   
               
               
                 ttgggtgcat ctctcgggcg tccggcagcg gctgtatctc 
               
               
                   
               
               
                 ggcatgaatt aagaagctag gaagatggag cacggcacac 
               
               
                   
               
               
                 tcctcgccca gcccgggctc tggaccaggg acaccagctg 
               
               
                   
               
               
                 ggcactcctc tatttcctct gctatatcct ccctcagacc 
               
               
                   
               
               
                 gccccgcaag tactcaggat cggagggatt tttgaaacag 
               
               
                   
               
               
                 tggaaaatga gcctgttaat gttgaagaat tagctttcaa 
               
               
                   
               
               
                 gtttgcagtc accagcatta acagaaaccg aaccctgatg 
               
               
                   
               
               
                 cctaacacca cattaaccta tgacatccag agaattaacc  
               
               
                   
               
               
                 tttttgatag ttttgaagcc tcgcggagag catgtgacca 
               
               
                   
               
               
                 gctggctctt ggtgtggctg ctctctttgg cccttcccat  
               
               
                   
               
               
                 agctcctccg tcagtgctgt gcagtctatt tgcaatgctc 
               
               
                   
               
               
                 tcgaagttcc acacatacag acccgctgga aacacccctc 
               
               
                   
               
               
                 ggtggacaac aaagatttgt tttacatcaa cctttaccca 
               
               
                   
               
               
                 gattatgcag ctatcagcag ggcgatcctg gatctggtcc 
               
               
                   
               
               
                 tctattacaa ctggaaaaca gtgacagtgg tgtatgaaga 
               
               
                   
               
               
                 cagcacaggt ctaattcgtc tacaagagct catcaaagct 
               
               
                   
               
               
                 ccctccagat ataatattaa aatcaaaatc cgccagctgc  
               
               
                   
               
               
                 cctctgggaa taaagatgcc aagcctttac tcaaggagat 
               
               
                   
               
               
                 gaagaaaggc aaggagttct atgtgatatt tgattgttca 
               
               
                   
               
               
                 catgaaacag ccgctgaaat ccttaagcag attctgttca 
               
               
                   
               
               
                 tgggcatgat gaccgagtac tatcactact ttttcacaac 
               
               
                   
               
               
                 cctggactta tttgctttgg atctggaact ctataggtac 
               
               
                   
               
               
                 agtggcgtaa acatgaccgg gtttcggctg cttaacattg 
               
               
                   
               
               
                 acaaccctca cgtgtcatcc atcattgaga agtggtccat 
               
               
                   
               
               
                 ggagagactg caggccccac ccaggcccga gactggcctt 
               
               
                   
               
               
                 ttggatggca tgatgacaac tgaagcggct ctgatgtacg 
               
               
                   
               
               
                 atgctgtgta catggtggcc attgcctcgc accgggcatc 
               
               
                   
               
               
                 ccagctgacc gtcagctccc tgcagtgcca tagacataag  
               
               
                   
               
               
                 ccatggcgcc tcggacccag atttatgaac ctgatcaaag 
               
               
                   
               
               
                 aggcccggtg ggatggcttg actgggcata tcacctttaa 
               
               
                   
               
               
                 taaaaccaat ggcttgagga aggattttga tctggacatt 
               
               
                   
               
               
                 attagtctca aagaggaagg aactgaaaag gctgctggcg 
               
               
                   
               
               
                 aagtgtctaa acacttgtat aaagtgtgga agaagattgg 
               
               
                   
               
               
                 gatttggaat tccaacagtg ggcttaacat gacggacagc 
               
               
                   
               
               
                 aacaaagaca agtccagcaa tatcactgat tcattggcca  
               
               
                   
               
               
                 acagaacact cattgtcacc accattctgg aagaacccta 
               
               
                   
               
               
                 tgttatgtac aggaaatctg ataagcctct atatggaaat 
               
               
                   
               
               
                 gacagatttg aaggatattg cctagacctg ttgaaagaat 
               
               
                   
               
               
                 tgtcaaacat cctgggtttc atttatgatg ttaaactagt  
               
               
                   
               
               
                 tcccgatggc aaatatgggg cccagaatga caaaggggag 
               
               
                   
               
               
                 tggaacggga tggttaaaga actcatagat cacagggctg 
               
               
                   
               
               
                 acctggcagt ggctcctctt accatcacct acgtgcggga 
               
               
                   
               
               
                 gaaagtcatt gacttctcca aacccttcat gaccctaggc 
               
               
                   
               
               
                 atcagcattc tctaccggaa gcccaatggt accaatccag 
               
               
                   
               
               
                 gcgttttctc cttcctcaac cccctgtctc cagatatttg 
               
               
                   
               
               
                 gatgtatgtg ctcttagcct gcttgggagt cagctgtgta 
               
               
                   
               
               
                 ctctttgtga ttgcaaggtt tacaccctac gagtggtata 
               
               
                   
               
               
                 acccccaccc atgcaaccct gactcagacg tggtggaaaa 
               
               
                   
               
               
                 caattttact ttactaaata gtttctggtt tggagttgga 
               
               
                   
               
               
                 gctctcatgc agcaaggatc agagctgatg cccaaagctc  
               
               
                   
               
               
                 tatcgaccag aatagttgga gggatatggt ggtttttcac 
               
               
                   
               
               
                 cctaatcatc atttcatcct acacggccaa tctggctgcc  
               
               
                   
               
               
                 ttcttgacag tagagagaat ggaatccccc atagattcgg 
               
               
                   
               
               
                 cagatgatct ggcaaagcaa accaagatag aatatggggc 
               
               
                   
               
               
                 ggttagagat ggatcaacaa tgaccttctt caagaaatca 
               
               
                   
               
               
                 aaaatctcca cctatgagaa gatgtgggct ttcatgagca 
               
               
                   
               
               
                 gcaggcagca gaccgccctg gtaagaaaca gtgatgaggg 
               
               
                   
               
               
                 gatccagaga gtgctcacca cagactacgc gctgctgatg 
               
               
                   
               
               
                 gagtccacca gcattgagta tgtgacgcag agaaactgca  
               
               
                   
               
               
                 acctcactca gatcgggggc ctcattgact ccaaaggtta 
               
               
                   
               
               
                 cggagtggga acacctattg gttctcctta ccgggataaa 
               
               
                   
               
               
                 attactattg ctattcttca actccaagaa gaagggaagc 
               
               
                   
               
               
                 tgcatatgat gaaagagaag tggtggcgtg ggaatggctg 
               
               
                   
               
               
                 ccccgaggaa gacaacaaag aagccagtgc cctgggagtg 
               
               
                   
               
               
                 gaaaatattg gaggcatctt cattgttctg gctgccggac 
               
               
                   
               
               
                 tggtcctttc tgtatttgta gctattggag aattcatata 
               
               
                   
               
               
                 caaatcacgg aagaataatg atattgaaca ggattttgt 
               
               
                   
               
               
                 ttatttatg gactgcaatg taagcaaacc catccaacca 
               
               
                   
               
               
                 actccacttc tggaactact ttatctacgg atttagaatg 
               
               
                   
               
               
                 tggtaaatta attcgagagg agagagggat tcgaaaacag 
               
               
                   
               
               
                 tcctcagttc atactgtgta atcagtttaa a  
               
               
                   
               
               
                 (H6PD)(NM_004285) 
               
               
                 SEQ ID NO: 6 
               
               
                 tgaggcctga ggcctggggc ggggtggcgg ccgggctggc 
               
               
                   
               
               
                 cttggcctcg cgccttcccc tgcggccgcc gcgggctccg 
               
               
                   
               
               
                 cgggcggtat cggagtgtcg tgcggcgcgt ggccgcgtga 
               
               
                   
               
               
                 cacgcgcact tgtcggagtg acgggccctg cggaagagga 
               
               
                   
               
               
                 ggtgcggccc agggcgcagg ggagccctcg ggagcgggcc 
               
               
                   
               
               
                 cggccctcag cgccgccccg gccgtgtccc ggaggagcgg  
               
               
                   
               
               
                 cctgcgccgc cgcgcgagag gaagcaccca ggcatgtgga 
               
               
                   
               
               
                 atatgctcat agtggcgatg tgcttggccc ttctgggctg 
               
               
                   
               
               
                 cctgcaagcc caggagctcc agggacatgt ctccataatc 
               
               
                   
               
               
                 ctgctgggag caactgggga cctggctaag aagtacttat 
               
               
                   
               
               
                 ggcagggact gttccagctg tacctggatg aagcggggag 
               
               
                   
               
               
                 gggtcacagt tttagcttcc atggagctgc tctgacagcc 
               
               
                   
               
               
                 ccaagcagg gtcaagagct catggccaag gccctggaat  
               
               
                   
               
               
                 ccctctcctg ccccaaggac tggcaccca gtcactgtgc 
               
               
                   
               
               
                 agagcacaag gatcagttcc tgcagctgag ccagtaccgc 
               
               
                   
               
               
                 aactgaaga cggccgagga ctatcaggcc ctgaacaagg 
               
               
                   
               
               
                 acatcgaggc acagctccag acgcaggcc tccgggaggc 
               
               
                   
               
               
                 tggcaggatc ttctacttct cagtgccacc cttcgcctat 
               
               
                   
               
               
                 aagacattg cccgcaacat caacagtagc tgccggccag 
               
               
                   
               
               
                 gcccgggcgc ctggctgcgg ttgtccttg agaaaccctt 
               
               
                   
               
               
                 tggccatgac cacttctcag cccagcagct ggccacagaa 
               
               
                   
               
               
                 tcgggacct ttttccagga ggaggagatg taccgggtgg  
               
               
                   
               
               
                 accattactt aggcaagcag ctgtggcgc agatcctgcc 
               
               
                   
               
               
                 tttccgagac cagaaccgca aggctttgga cggcctctgg 
               
               
                   
               
               
                 accggcacc atgtggagcg ggtggagatc atcatgaaag 
               
               
                   
               
               
                 agaccgtgga tgctgaaggc gcaccagct tctatgagga 
               
               
                   
               
               
                 gtacggtgtc attcgcgacg tcctccagaa ccatctgacg 
               
               
                   
               
               
                 aggtcctca ccctcgtggc catggagctg ccccacaatg 
               
               
                   
               
               
                 tcagcagtgc ggaggctgtg ctgcggcaca agcttcaggt  
               
               
                   
               
               
                 cttccaggcg ctgcggggcc tgcagagggg cagtgccgtc 
               
               
                   
               
               
                 tgggccagt accagtctta cagtgagcag gtgcgcagag 
               
               
                   
               
               
                 agctgcagaa gccagacagc tccacagcc tgacgccgac 
               
               
                   
               
               
                 cttcgcagcc gtcctagtgc acattgacaa ccttcgctgg 
               
               
                   
               
               
                 agggcgtgc ctttcatcct gatgtctggc aaagccttgg 
               
               
                   
               
               
                 acgagagagt gggctacgct ggatcttgt tcaagaacca 
               
               
                   
               
               
                 ggcctgctgt gtgcagagcg aaaagcactg ggccgcggcg  
               
               
                   
               
               
                 agagccagt gcctgccccg gcagctcgtc ttccacatcg 
               
               
                   
               
               
                 gccatggcga cctgggcagc ctgccgtgc tggtcagcag 
               
               
                   
               
               
                 gaacctgttc aggccctccc tgccctccag ctggaaggaa 
               
               
                   
               
               
                 tggagggac cacctgggct ccgccttttc ggcagccctc 
               
               
                   
               
               
                 tgtccgatta ctacgcctac gccctgtgc gggagcggga 
               
               
                   
               
               
                 cgcccactcc gtcctcttat cccatatctt ccatggccgg 
               
               
                   
               
               
                 agaatttct tcatcaccac agagaacttg ctggcctcct 
               
               
                   
               
               
                 ggaacttctg gacccctctg tggagagcc tggcccataa 
               
               
                   
               
               
                 ggccccacgc ctctaccctg gaggagctga 
               
               
                   
               
               
                 gaatggccgtctgaggact ttgagttcag tagcggccgg 
               
               
                   
               
               
                 ttgactat cccagcagca gccggagcagctggtgccag 
               
               
                   
               
               
                 ggccagggcc ggccccaatg cccagtgact tccaggtcct 
               
               
                   
               
               
                 cagggccaag taccgagaga gcccgctggt ctccgcctgg 
               
               
                   
               
               
                 tccgaggagc tgatctctaa gctggctaat gacatcgagg  
               
               
                   
               
               
                 ccaccgctgt gcgagccgtg cggcgctttg gccagttcca 
               
               
                   
               
               
                 cctggcactg tcggggggct cgagccccgt ggccctgttc 
               
               
                   
               
               
                 cagcagctgg ccacggcgca ctatggcttc ccctgggccc 
               
               
                   
               
               
                 acacgcacct gtggctggtt gacgagcgct gcgtcccact 
               
               
                   
               
               
                 ctcagacccg gagtccaact tccagggcct gcaggcccac 
               
               
                   
               
               
                 ctgctgcagc acgtccggat cccctactac aacatccacc 
               
               
                   
               
               
                 ccatgcctgt gcacctgcag cagcggctct gcgccgagga  
               
               
                   
               
               
                 ggaccagggc gcccagatct atgccaggga gatctcagcc 
               
               
                   
               
               
                 ctggtggcca acagcagctt cgacctggtg ctgctgggca 
               
               
                   
               
               
                 tgggtgccga cgggcacaca gcctccctct tcccacagtc 
               
               
                   
               
               
                 acccactggc ctggatggcg agcagctggt cgtgctgacc 
               
               
                   
               
               
                 acgagcccct cccagccaca ccgccgcatg agccttagcc 
               
               
                   
               
               
                 tgcctctcat caaccgcgcc aagaaggtgg cagtcctggt 
               
               
                   
               
               
                 catgggcagg atgaagcgtg agatcaccac gctggtgagc  
               
               
                   
               
               
                 cgggtgggcc atgagcccaa gaagtggccc atctcgggtg 
               
               
                   
               
               
                 tcctgccgca ctccggccag ctggtgtggt acatggacta 
               
               
                   
               
               
                 cgacgccttc ctgggatgag ggcgcctgtg ccccttgccc 
               
               
                   
               
               
                 gcttcgctcc tgtgctttcc ttcgcccgtg tcttccctcc 
               
               
                   
               
               
                 cttctcggcc ccgccacctg cccagcgtgc cctggctctc 
               
               
                   
               
               
                 cagaaccttc tatcccacag tcaggcccca gagagggcag 
               
               
                   
               
               
                 gacaagcctt gtcccgatgc ctttgaccgg cagctctgtg  
               
               
                   
               
               
                 tattggtgga tagatgcaga aacaaggaag aaatggagtc 
               
               
                   
               
               
                 tgctcctgag aagcttcaaa ttcaggccag gagagaagtc 
               
               
                   
               
               
                 ttaagaaaag acctccagca gttacacatt catatcaacc 
               
               
                   
               
               
                 agcacaacac gggatggcgc ccaaactccg gcgttcacaa 
               
               
                   
               
               
                 gaggagacgt gacgtggtgg gctgaggtta atcagggaag 
               
               
                   
               
               
                 gtttcctggg ggaggtgatc cttgaactgg ctcccgggga 
               
               
                   
               
               
                 acattcagag catgattggt agacagaagg gtgcagaggc  
               
               
                   
               
               
                 gcccagggga gtacattgcc ccgtgcaaag caggggcatt 
               
               
                   
               
               
                 ggggactgtc ttgagaccct gagggggtca agcccctcct 
               
               
                   
               
               
                 tccccagctg cccctccttc tagaacctct gcacatctag 
               
               
                   
               
               
                 cctctggccc tcctcttcac tgcctccacc tgctcccgct 
               
               
                   
               
               
                 tgccatccct gtctcctcca tcctggctgt gcagtaggaa 
               
               
                   
               
               
                 ttccaggctc ctccctgtgt ctttgctgtt cttcagactc 
               
               
                   
               
               
                 catttataga gaatgagggc tgataacagg aatacagtgg 
               
               
                   
               
               
                 caaagactag actgtggaaa gggttccaga aatctttttt 
               
               
                   
               
               
                 cttttttaat taaaaaaaat atttgcagag atgagctctt 
               
               
                   
               
               
                 gctatgttgc ccaggctggt ctcaaactcc tgggctcaag 
               
               
                   
               
               
                 cgatcctccc atctcagcct cccagagtgc tgggattaca 
               
               
                   
               
               
                 ggtgtgagct actgcgccca gccccagaaa tctcagtgct 
               
               
                   
               
               
                 gtttggagct ccatttctca tttgatgact tgctctgcgt  
               
               
                   
               
               
                 ggggaggtgg ggtctcattc ccccaacttc ctcagggagg 
               
               
                   
               
               
                 acccctgccc tccgctgctc ctctgtcctg ctagccttcc 
               
               
                   
               
               
                 tccaggaagc acactgggtg cagataatca ggacattcca 
               
               
                   
               
               
                 gagatcccca atttaagagg gtcatttcca tctcagggga 
               
               
                   
               
               
                 ctcccggatg ggtgtttccg ctctcaatag cccctcttgt 
               
               
                   
               
               
                 tttaccagga aagatccagt taaatcaccc actgaggtga 
               
               
                   
               
               
                 cagctcatta gcggggagag agatggagca tcgagtgaca 
               
               
                   
               
               
                 ctgggccatc caggcggctc tgctcccacc agacaggagc 
               
               
                   
               
               
                 taggcctcac tggcaggggg gctgcccaca gccttttcag  
               
               
                   
               
               
                 gggctcgctt ggcgggtgac ggggccgcag ccaggccttc 
               
               
                   
               
               
                 tctccctgcc ccttggtgac cccgtggctt cctgtctgct 
               
               
                   
               
               
                 ggcctctcct gctacttatc acttcaccac gaactctctg 
               
               
                   
               
               
                 cctgagactg gggaagtaag cgggtatctt ctcagtgagc 
               
               
                   
               
               
                 ataggttggg gactgtgatc ttgagaagcc atgggccagc 
               
               
                   
               
               
                 aatacctgct tttctgaagc ccccaaggag ggctctgaca 
               
               
                   
               
               
                 ttctttttaa aaacaccaca aagcaaaatt cccaggacat 
               
               
                   
               
               
                 gtgtagtttt gtttgttcag tatcccacaa cttaaggctg 
               
               
                   
               
               
                 ggagatggaa ctcttggtta aggtcgattt ttctgtctgg 
               
               
                   
               
               
                 cttctccgca ccttccactt gctctctgga tcaggcagat 
               
               
                   
               
               
                 ataaactttc tagcgcattt tgagagaggg ctttcttggg 
               
               
                   
               
               
                 tgagggagca tggcaaagtc ggtttctctc tggactgttt 
               
               
                   
               
               
                 acacttcaag gcggtggatt tagaggaatc ctggattca 
               
               
                   
               
               
                 ttttcaatgc cagtctgaga catgttccca agccggggct 
               
               
                   
               
               
                 cttgttcaca ccacttactc tggccaccaa caacaaccca  
               
               
                   
               
               
                 ggccagacag agcatctat tttttttttt ttgagacaga 
               
               
                   
               
               
                 gtctctgtcg cccaggctgg agcccagtgg cgagatcttg  
               
               
                   
               
               
                 gctcactaca acctccacct cccgggttca ggcaattctc 
               
               
                   
               
               
                 gtgcctaagc ctcccgagta gctgcgacta caggcgccgg 
               
               
                   
               
               
                 ccagcatgcc tgtctaattt ttgtatttta gtagagacag 
               
               
                   
               
               
                 ggtttcacca tgttgcccag gctggtctcg aactcctgag 
               
               
                   
               
               
                 ctcaggcagt ctacccacct cagcctccca aagtgctggg 
               
               
                   
               
               
                 attacaggcg tgagccaccg cgcccagcca gaacatctgt 
               
               
                   
               
               
                 ttttacaccc agagagcgcc cctcgttagg acagaaccac 
               
               
                   
               
               
                 ggtgcccaga gccaggaagc cgccctcctg gcgcccagca 
               
               
                   
               
               
                 tctgagcttc tacacgtgat gggcgggctc aggagaggac  
               
               
                   
               
               
                 agggagtcgt ggtggaagtt ccacagctgg ccgcgtgggg 
               
               
                   
               
               
                 gggcccttgc accgcactgc cgcctcctga ctgcccctat 
               
               
                   
               
               
                 ccccgcagcc cctgtgccgg atttcatttc cctcctctct 
               
               
                   
               
               
                 cccagggtac ctggccccag cactctccca tctgttcttc 
               
               
                   
               
               
                 aggaaccgac tcctctccag ttgcaacacc agggagaaag 
               
               
                   
               
               
                 gggcctccac atgcccaagt acccctgcag gatgaagggc 
               
               
                   
               
               
                 aggccggccc ttgatgtgcc atttctgaat aatagtcact  
               
               
                   
               
               
                 gccgccgagt ctaggatgtc ctgttctaac tcagccctgc 
               
               
                   
               
               
                 ctcggatgca ccaccgatct gtgcagagtg ggtgtgggag 
               
               
                   
               
               
                 tgtgggtgag ggtcgaaatg ccaaaggtct actttccaga 
               
               
                   
               
               
                 atcaagtgcc ttctgcaaat catgttggaa aagtccaaac 
               
               
                   
               
               
                 ctggagatgt ccctgtgcct ccgcccctac ccaccccttt 
               
               
                   
               
               
                 tccttcagct gtgttaggaa ggagaagttt tcagaaccct 
               
               
                   
               
               
                 ctaggctggt ggctttcaaa cttcagacca gatctgcag  
               
               
                   
               
               
                 caagaaacgt gccttccatc ataaatcagt ccatttgttt 
               
               
                   
               
               
                 acaactgtgt ccaagcagg tttcataaag aaattcttaa  
               
               
                   
               
               
                 ccttagaacc tcggatatcc tctatgtttt agttttcatt 
               
               
                   
               
               
                 tttttaaaat gcttcttaaa attcactaaa ttgggctagg  
               
               
                   
               
               
                 tgtggctcat gcctgtaatc ccagcactat gggaggctga 
               
               
                   
               
               
                 ggtgagagga tcacttgagc ccagaaggtt gaaaccagcc 
               
               
                   
               
               
                 tgggcaacat agtgagaccc catctctaca aaaagtttta 
               
               
                   
               
               
                 aaaccaggta tggtggtgcc ctcctgtggt cccagctact 
               
               
                   
               
               
                 cgggagtctg aggtgggagg atcacctgag cccaggagac 
               
               
                   
               
               
                 tgaggctgca gtaaggtgtg attgcactat tgctctctag 
               
               
                   
               
               
                 caggaaaac agagtgagac cctatctcaa aaaaaaaaaa  
               
               
                   
               
               
                 aaaaaaaaag gaaagagtga tgacaacagc ccagggagca 
               
               
                   
               
               
                 gccccgctca gaacccaagt cccaagttcc agcactgtgt 
               
               
                   
               
               
                 tcccaggcag gctgtttgcc tcttcctggt ctggaagccc 
               
               
                   
               
               
                 ttgggtccta tggtggcggc agctcccaca tccaggttc 
               
               
                   
               
               
                 cctggtgggg accaatgatt ccatccgcat ggaagcccac 
               
               
                   
               
               
                 gtgtgcactt aggggcccat aaatggcaga agggcccctc 
               
               
                   
               
               
                 ctttgggaga ccttgtcagt cagcatctct agggcaaccg  
               
               
                   
               
               
                 tgattgccat ttgtagaggg gaaggaatca agggacttta 
               
               
                   
               
               
                 agctagatca aaatctgggg acaaattctc ctgctaactg 
               
               
                   
               
               
                 caagttaaaa taggcccttc ttactgaatt tccctgtttg 
               
               
                   
               
               
                 tttctctgca gacaatgctt tagccctact cttgggcccc 
               
               
                   
               
               
                 caagttagca gagtaatcaa agcttcctac cgtttggcct 
               
               
                   
               
               
                 actattccag actagtccct cgaggggttc ccttccaaaa 
               
               
                   
               
               
                 tatgcagggc tcaggctccc aattccgggc ctgtctgctt 
               
               
                   
               
               
                 tgcttgtgtt tctcctgtcc ctgttctccc ggagggccca 
               
               
                   
               
               
                 ggtggaactc acgacaggga gggagacgct tcccaaaaac 
               
               
                   
               
               
                 ctgcagggct atttcccaga atttggtttt caagtacaaa 
               
               
                   
               
               
                 actttttgtc ctgtaagata tatgcagcct cacagaagca 
               
               
                   
               
               
                 gcctctgcct ccactttacc agctacgttt ttatcttaag 
               
               
                   
               
               
                 cacatggggc tcccttagaa cttactccac tgatttaaaa 
               
               
                   
               
               
                 aaaaaaaact gcctggcagc atctcagtgt cagagtgagc 
               
               
                   
               
               
                 acggcacagg aaaggcccgt ggtgacgagg gtgaggtggc  
               
               
                   
               
               
                 cacagtgacc ggacgacaaa tgagactctg caaatgagac 
               
               
                   
               
               
                 tccagagggt gaagatctgc ggtctccaga catcataggc 
               
               
                   
               
               
                 catgtgaccc actaggggcc gcttacccct ggccgtccgc 
               
               
                   
               
               
                 tggctgaact gaacgcattc cctctctccg caactctccc 
               
               
                   
               
               
                 gtgaggctgc acccgtgtgg gtagcactgg aagcggcact 
               
               
                   
               
               
                 gtttgcattg tacataggaa ggaaggaagt tatccagcc 
               
               
                   
               
               
                 tcaccagcac ctggcagcga gtcagagcct gtgagggcat  
               
               
                   
               
               
                 ccgaagcagt gatgcagtgt caacctccca gctggtgcca 
               
               
                   
               
               
                 ctctgccctc gggggctcca agcattgtaa ctcagtcatg 
               
               
                   
               
               
                 ggagctgcct ctttggaagt gcagatttat tcctgtaata 
               
               
                   
               
               
                 atcctgcctg cttttacctc tcgtccactg accagcaagt 
               
               
                   
               
               
                 gtgagtcccg gtgtcagtcg gcacagtcca gtgtccatct 
               
               
                   
               
               
                 gcatttgctc atgcagaggg ggtgagttgg gcactccctg 
               
               
                   
               
               
                 ttgaggttt tccttttgca gcacactggg cagtctccct 
               
               
                   
               
               
                 ataaaacaaa aaccccacct tctgtgcctt ctgctttaga 
               
               
                   
               
               
                 gcagagctcc ccctcccatt tcctcagtct tccctgcaaa 
               
               
                   
               
               
                 atctgtccac cggggaaggc agcaggaacc ctgggcagcg 
               
               
                   
               
               
                 ggtgttctgg gaaggctagt gacagcagat gtcatccagg 
               
               
                   
               
               
                 aacagccaca cacggttctc caggccgccg tcagcagctc 
               
               
                   
               
               
                 aaggtggggt atgagtgaga agctgaggat ctcgcagctt  
               
               
                   
               
               
                 gttgctgagc aaggtgcaac cgggctcatg ctgtcatcag 
               
               
                   
               
               
                 cacaagacgg gatggcaagg gctttcagac gcatttccaa 
               
               
                   
               
               
                 gagtccagca agccaggggg aagatgatcc ctttgccgaa 
               
               
                   
               
               
                 gtgtaccctc tagccaactt ttgggagcgc ttctgtttgc 
               
               
                   
               
               
                 aaagcgctgg ggatgtgcct gtctctgtgt gacccacgaa 
               
               
                   
               
               
                 cgggaaggga gagcactgga gtaatgacac ttctgctgct 
               
               
                   
               
               
                 gctttgattc tcaaggctga tattaaaac cctcgccttg 
               
               
                   
               
               
                 ctgacaggtg ctttaaaggc agtctgcatc ttttatccc 
               
               
                   
               
               
                 ttggtgtggg agaggtaaac actttgattt gctgaaagct 
               
               
                   
               
               
                 gtatggagta tatttgaaca gctagtagtt agctttgaaa 
               
               
                   
               
               
                 gtggaagtgt gaacagacac tacttgtgtc gctttgggtc 
               
               
                   
               
               
                 cttcacttta cccccacaga agtctagagg cgtctgttat 
               
               
                   
               
               
                 aaagcgttac ggggcgcctg catgcaggag gaaggacctg  
               
               
                   
               
               
                 tattagctgg aaatcatcag gaacccagct tgcctccatc 
               
               
                   
               
               
                 tctctgagat gtgctgggta cagcctgccc ctcctagttc  
               
               
                   
               
               
                 tgtccaccgg gaagagccgg ctggcggcag atccccaggg 
               
               
                   
               
               
                 gcagagcccc tgctggatcc tgggagctca tctttacctg 
               
               
                   
               
               
                 tgccggagtg ggaactgtga ttccagccgg gcaggtcaga 
               
               
                   
               
               
                 gtggagcagt gctaagaggc tgttgcagga gaactagacg 
               
               
                   
               
               
                 ggcggggcct gctgcatctg gatcatgttt ctgtgctctg 
               
               
                   
               
               
                 ccccgcgcta gggactcagg gtctgggctt ctgccaggtg 
               
               
                   
               
               
                 aggagcagag agactgttcc cttgggtgga gaggtgtggg  
               
               
                   
               
               
                 catgagagcc acccattgcc aagcagcaag aatgttcgtg 
               
               
                   
               
               
                 cttttttcca gagaggggaa ccccactggt ttttgtggaa 
               
               
                   
               
               
                 acaatggaaa cttacagatg cctgcctggg atgatgaggc 
               
               
                   
               
               
                 acattcagaa caaatgcttt tttttttttg agacagagtc 
               
               
                   
               
               
                 tcgctctgac gcccaggctg gagtgcagtg gcgcgatctc 
               
               
                   
               
               
                 ggctcactgc aaactttgcc tcccaggttc aagtgattct 
               
               
                   
               
               
                 cctacctcag ccttccgagt agagggatt acaccaccat 
               
               
                   
               
               
                 gcccagcaaa tttngtgtt tttagtagag acggagtttc 
               
               
                   
               
               
                 accatgttgg ccaggctggt ctcgaactcc tgacctcagg 
               
               
                   
               
               
                 tgatccatcc gccttggcct cccaaagtgc tgggattaca 
               
               
                   
               
               
                 ggcgggagcc accatgcctg gccagaacaa atgccttttt  
               
               
                   
               
               
                 aaacctttta agaacatttt taaaatgtct ttttctatgt 
               
               
                   
               
               
                 caaatgtaac gtttattttt ttaaacaata aaattgattt  
               
               
                   
               
               
                 gccaaaa  
               
               
                   
               
               
                 (IGF2BP1)(NM_001160423.1 version 1 of two mRNA 
               
               
                 speies) 
               
               
                 SEQ ID NO: 7 
               
               
                 atttagaggc ggcgccaggg cggccgcgga gaaacgtgac 
               
               
                   
               
               
                 acaccagccc tctcggaggg gtttcggacc gaagggaaga 
               
               
                   
               
               
                 agctgcgccg tgtcgtccgt ctccctgcgc gccgcgggca 
               
               
                   
               
               
                 cttctcctgg gctctccccg aactctcccg cgacctctgc 
               
               
                   
               
               
                 gcgccctcag gccgccttcc ccgccctggg ctcgggacaa  
               
               
                   
               
               
                 cttctggggt ggggtgcaaa gaaagtttgc ggctcctgcc 
               
               
                   
               
               
                 gccggcctct ccgcctcttg gcctaggagg ctcgccgccc 
               
               
                   
               
               
                 gcgcccgctc gttcggcctt gcccgggacc gcgtcctgcc 
               
               
                   
               
               
                 ccgagaccgc caccatgaac aagattaca tcggcaacct 
               
               
                   
               
               
                 caacgagagc gtgacccccg cggacttgga gaaagtgttt 
               
               
                   
               
               
                 gcggagcaca agatctccta cagcggccag ttcttggtca 
               
               
                   
               
               
                 aatccggcta cgccttcgtg gactgcccgg acgagcactg  
               
               
                   
               
               
                 ggcgatgaag gccatcgaaa ctttctccgg gaaagtagaa 
               
               
                   
               
               
                 ttacaaggaa aacgcttaga gattgaacat tcggtgccca 
               
               
                   
               
               
                 aaaaacaaag gagccggaaa attcaaatcc gaaatattcc 
               
               
                   
               
               
                 accccagctc cgatgggaag tactggacag cctgctggct 
               
               
                   
               
               
                 cagtatggta cagtagagaa ctgtgagcaa gtgaacaccg 
               
               
                   
               
               
                 agagtgagac ggcagtggtg aatgtcacct attccaaccg 
               
               
                   
               
               
                 ggagcagacc aggcaggctg acgaggttcc cctgaagatc  
               
               
                   
               
               
                 ctggcccata ataactttgt agggcgtctc attggcaagg 
               
               
                   
               
               
                 aaggacggaa cctgaagaag gtagagcaag ataccgagac 
               
               
                   
               
               
                 aaaaatcacc atctcctcgt tgcaagacct taccctttac 
               
               
                   
               
               
                 aaccctgaga ggaccatcac tgtgaagggg gccatcgaga 
               
               
                   
               
               
                 attgagcag ggccgagcag gaaataatga agaaagttcg 
               
               
                   
               
               
                 ggaggcctat gagaatgatg tggctgccat gagcctgcag 
               
               
                   
               
               
                 tctcacctga tccctggcct gaacctggct gctgtaggtc  
               
               
                   
               
               
                 ttttcccagc ttcatccagc gcagtcccgc cgcctcccag 
               
               
                   
               
               
                 cagcgttact ggggctgctc cctatagctc ctttatgcag 
               
               
                   
               
               
                 gctcccgagc aggagatggt gcaggtgttt atccccgccc 
               
               
                   
               
               
                 aggcagtggg cgccatcatc ggcaagaagg ggcagcacat 
               
               
                   
               
               
                 caaacagctc tcccggtttg ccagcgcctc catcaagatt 
               
               
                   
               
               
                 gcaccacccg aaacacctga ctccaaagtt cgtatggtta 
               
               
                   
               
               
                 tcatcactgg accgccagag gcccaattca aggctcaggg  
               
               
                   
               
               
                 aagaatctat ggcaaactca aggaggagaa cttctttggt 
               
               
                   
               
               
                 cccaaggagg aagtgaagct ggagacccac atacgtgtgc 
               
               
                   
               
               
                 cagcatcagc agctggccgg gtcattggca aaggtggaaa 
               
               
                   
               
               
                 aacggtgaac gagttgcaga atttgacggc agctgaggtg 
               
               
                   
               
               
                 gtagtaccaa gagaccagac ccctgatgag aacgaccagg 
               
               
                   
               
               
                 tcatcgtgaa aatcatcgga catttctatg ccagtcagat 
               
               
                   
               
               
                 ggctcaacgg aagatccgag acatcctggc ccaggttaag  
               
               
                   
               
               
                 cagcagcatc agaagggaca gagtaaccag gcccaggcac 
               
               
                   
               
               
                 ggaggaagtg accagcccct ccctgtccct tcgagtccag 
               
               
                   
               
               
                 gacaacaacg ggcagaaatc gagagtgtgc tctccccggc 
               
               
                   
               
               
                 aggcctgaga atgagtggga atccgggaca cctgggccgg 
               
               
                   
               
               
                 gctgtagatc aggtttgccc acttgattga gaaagatgtt 
               
               
                   
               
               
                 ccagtgagga accctgatct ctcagcccca aacacccacc 
               
               
                   
               
               
                 caattggccc aacactgtct gcccctcggg gtgtcagaaa  
               
               
                   
               
               
                 ttctagcgca aggcactttt aaacgtggat tgtttaaaga 
               
               
                   
               
               
                 agctctccag gccccaccaa gagggtggat cacacctcag 
               
               
                   
               
               
                 tgggaagaaa aataaaattt ccttcaggtt ttaaaaacat 
               
               
                   
               
               
                 gcagagaggt gttttaatca gccttaaagg atggttcatt 
               
               
                   
               
               
                 tcttgacctt aatgtttttc caatcttctt ccccctactt 
               
               
                   
               
               
                 gggtaattga ttaaaatacc tccatttacg gcctattct 
               
               
                   
               
               
                 atatttacac taattttttt atctttattg ctaccagaaa 
               
               
                   
               
               
                 aaaatgcgaa cgaatgcatt gattgctta cagtattgac 
               
               
                   
               
               
                 tcaagggaaa agaactgtca gtatctgtag attaattcca 
               
               
                   
               
               
                 atcactccct aaccaatagg tacaatacgg aatgaagaag 
               
               
                   
               
               
                 aggggaaaat ggggagaaag atggttaaaa tacataataa 
               
               
                   
               
               
                 tccacgttta aaaggagcgc acttgtggct gatctatgcc 
               
               
                   
               
               
                 agatcaccat cttcaaattg gcacaactga aatttcccca  
               
               
                   
               
               
                 ctctgttggg gcttccccac cacattcatg tccctctccc 
               
               
                   
               
               
                 gtgtaggttt cacattatgt ccaggtgcac ataggtggta 
               
               
                   
               
               
                 ttgaatgctc agcagggtag gggctgacca ctgtccctga 
               
               
                   
               
               
                 ttcccatcgt tctcaggcgg attttatatt tttttaaagt  
               
               
                   
               
               
                 ctattttaat gattggatat gagcactggg aaggggacgc 
               
               
                   
               
               
                 taactcccct tgataaagtc tcggttccat ggaggacttg 
               
               
                   
               
               
                 agtggcccca aaggctgcca cggtgccctc accccagccc 
               
               
                   
               
               
                 atgtgctccc ataagggctg gttcctagag gcaggggttg 
               
               
                   
               
               
                 tggggcactc ccagccacgg cactgttacc ttggtggtgg 
               
               
                   
               
               
                 gacttggaac ccaaccctga gctcccgata aagctaaagt 
               
               
                   
               
               
                 ccatcatctg gcaaattcag taaattggag agtacttgct 
               
               
                   
               
               
                 tctgtttgta tctgagagga atttttaact gacggcttct 
               
               
                   
               
               
                 gtctccatga atcattatca gcatgatgaa aggtgtgtct 
               
               
                   
               
               
                 aaaaaacaat tcagaatacc agcagcattg tacagcaagg 
               
               
                   
               
               
                 ggtaaataag cttaatttat taatttacca ggcttaatta 
               
               
                   
               
               
                 agatcccatg gagtgtttag cccttgtggg agacagaagc 
               
               
                   
               
               
                 catcagttaa atgaggttag gcctctcctc ctaatatact 
               
               
                   
               
               
                 gattgacaat gcatattagc caggtaatgc actttagcta 
               
               
                   
               
               
                 ccctggacaa tgctatcaag tgtgctggga agggaggaag  
               
               
                   
               
               
                 gcctctctac atatggaaaa gcccatgcgt ggagttcccc 
               
               
                   
               
               
                 tcctttcaac attgcaacaa cagtaacaac aagacaaccg 
               
               
                   
               
               
                 caacatgtgg gcgtagtcag gcaatgctgt gtgcgaagta 
               
               
                   
               
               
                 aactacctca aggtatgaag ttacctcagc aattattttc 
               
               
                   
               
               
                 ctttttgttc cccccaaccc cattaaaaaa attttttttt 
               
               
                   
               
               
                 gatttttgtt tttttgcagc ttgctgatat tttatataaa 
               
               
                   
               
               
                 aaagaaaagc aaagcaaaag agaagctgat agtcttgaat 
               
               
                   
               
               
                 attttatttt tttaatgaaa agaaaaaaca agaaagttat 
               
               
                   
               
               
                 gtttcataat ttcttacaac atgagccagt aaccctttag 
               
               
                   
               
               
                 gaactctcta tggagaacag gcctggtggg aaaggctttg 
               
               
                   
               
               
                 ggggctgccc ccttaggagg aggctagtgc taagagggaa 
               
               
                   
               
               
                 ggcccaggtt tgagagagcc cagaggggca gagcccagag 
               
               
                   
               
               
                 ccttgtttgg ccctgatctc tgacttctag agccccagct  
               
               
                   
               
               
                 gctggcggct gaggaatat cctacctgat aggattaaaa 
               
               
                   
               
               
                 ggcctagtgg agctgggggc tctcagtggt taaacaatgc 
               
               
                   
               
               
                 ccaacaacca accagctggc cttggtctc ctctctttcc 
               
               
                   
               
               
                 tcctttggtt aaagagcatc tcagccagct tttcccacca 
               
               
                   
               
               
                 gtggtgctgt tgagatattt taaaatattg cctccgtttt 
               
               
                   
               
               
                 atcgaggaga gaaataataa ctaaaaaata taccattaa 
               
               
                   
               
               
                 aaaaacctat atttctctgt ctaaaaatat gggagctgag 
               
               
                   
               
               
                 attccgttcg tggaaaaaag acaaggccac cctctcgccc 
               
               
                   
               
               
                 tcagagaggt ccacctggtt tgtcattgca atgcttttca 
               
               
                   
               
               
                 tttttttttt ttgttattgt ttcatttcag ttccgtcttg 
               
               
                   
               
               
                 tattatcc taatctatat ccatagatct aaggggcaaa 
               
               
                   
               
               
                 cagatactag ttaactgccc cacctctgt ctccctgtct 
               
               
                   
               
               
                 tctttagatc ggtctgattg attttaaaag tggacccaaa 
               
               
                   
               
               
                 ttagggaat tcttgattta gggtggctgg tggcaaggag 
               
               
                   
               
               
                 gggcagggga tatggggacg tgactgggac aggttcctgc 
               
               
                   
               
               
                 cttatcattt tctccctagg acattccctt gtagccccca 
               
               
                   
               
               
                 gaattgtctg gcccaaattg aatagaagca gaaaaacatt 
               
               
                   
               
               
                 tagggataac atcaggccag tagaattaag cctctccacc 
               
               
                   
               
               
                 tgtcccaacc ataaaaaggg tctcccagct ttccatctct 
               
               
                   
               
               
                 ggctctatat gctttatccc aaaacaaagc agataacgtt 
               
               
                   
               
               
                 cagacgtcgg ccatttagta atttaaagcg aatttccagc  
               
               
                   
               
               
                 agcaagcatg ctttgatatc tggttcagac tatcatcagg 
               
               
                   
               
               
                 aagaaaaaaa aatcccacag tacctgaaat gtgattgttg 
               
               
                   
               
               
                 cagtgttcag tttccttggg ggcctgctcc cttcacacct 
               
               
                   
               
               
                 tgagcccaag tccttttccg ttggctgatt cagctcccag 
               
               
                   
               
               
                 aagagacgag gaagtgtgtg gcaagggact ggaaaacttc 
               
               
                   
               
               
                 acttgcttgg attaggcaag gctccactca ttgttgatat 
               
               
                   
               
               
                 ttgcccagca ggaaaatcat gtaagttata ccaccagaaa 
               
               
                   
               
               
                 gcaaaaggag catggtttgg tggttaaggt ttagtgggat 
               
               
                   
               
               
                 gaaggacctg tcttggtggg cogggccctc ttgtgccccg  
               
               
                   
               
               
                 taggctaggt cttagggcaa ctccttgccc tcctgctcag 
               
               
                   
               
               
                 cacctccatt tccccatcct tggtgagata acaagctatc  
               
               
                   
               
               
                 gcgaaaagca cttgggagat ttggatgatt tgagaagagt 
               
               
                   
               
               
                 gacttaaaaa aaatgcttct gtgctctaag atatatatgt  
               
               
                   
               
               
                 gtgtgtgtgt gctacatata tattataag aaaggaccat 
               
               
                   
               
               
                 ctattagga tatattata aattattga aacacataac  
               
               
                   
               
               
                 caaaatggtt tgattcactg actgactttg aagctgcatc 
               
               
                   
               
               
                 tgccagttac accccaaatg gattaatcc cctctcgggt  
               
               
                   
               
               
                 ctggttgcct tttgcagttt gggttgtgga ctcagctcct 
               
               
                   
               
               
                 gtgaggggtc tggttaggag agagccattt ttaaggacag  
               
               
                   
               
               
                 ggagttttat agcccttttc tactttcctc ccctcctccc 
               
               
                   
               
               
                 agtccttatc aatctttttt cctttttcct gaccccctcc  
               
               
                   
               
               
                 ttctggaggc agttgggagc tatccttgtt tatgcctcac 
               
               
                   
               
               
                 tattggcaga aaagacccca tttaaaaccc agagaacact 
               
               
                   
               
               
                 ggagggggat gctctagttg gttctgtgtc cattttcctc 
               
               
                   
               
               
                 tgtgccaaag acagacagac agaggctgag agaggctgtt 
               
               
                   
               
               
                 cctgaatcaa agcaatagcc agctttcgac acatacctgg 
               
               
                   
               
               
                 ctgtctgagg aggaaggcct cctggaaact gggagctaag 
               
               
                   
               
               
                 ggcgaggccc ttcccttcag aggctcctgg gggattaggg  
               
               
                   
               
               
                 tgtggtgttt gccaagccaa ggggtaggga gccgagaaat 
               
               
                   
               
               
                 tggtctgtcg gctcctggtt gcactttggg gaaggagagg 
               
               
                   
               
               
                 aagtttgggg ctccaggtag ctccctgttg tgggactgct 
               
               
                   
               
               
                 ctgtcccctg cccctactgc agagatagca ctgccgagtt 
               
               
                   
               
               
                 cccttcaggc ctggcagacg ggcagtgagg aggggcctca 
               
               
                   
               
               
                 gttagctctc aagggtgcct tcccctcctc ccaacccaga 
               
               
                   
               
               
                 cataccctct gccaaactgg gaaccagcag tgctagtaac  
               
               
                   
               
               
                 tacctcacag agccccagag ggcctgcttg agccttcttg 
               
               
                   
               
               
                 ctccacagga gaagctggtg cctctaggca accccttcct 
               
               
                   
               
               
                 cccacctctc atcaggggtg ggggttctcc tttctttccc 
               
               
                   
               
               
                 ctgaagtgtt tatggggaga tcctagtggc tttgccattc 
               
               
                   
               
               
                 aaaccactcg actgtttgcc tgtttcttga aaaccagtag 
               
               
                   
               
               
                 aagggaaaca gcacagcctg tcacagtaat tgcaggaaga 
               
               
                   
               
               
                 ttgaagaaaa atcctcatca atgccagggg acataaaagc 
               
               
                   
               
               
                 catttccctt ccaaatactc gacaatttag atgcagaaca 
               
               
                   
               
               
                 tttctctgta ttcagactta gagtaacacc agctgaaaac 
               
               
                   
               
               
                 tgcagtttct ttcattgga tacataaggc ttctctatcg 
               
               
                   
               
               
                 gggtacggga cagggaggag gcctcatgtc tgaaggggga 
               
               
                   
               
               
                 ttaggggcg agagccccag ccctgaccct cggtcctgtg 
               
               
                   
               
               
                 caccgctttg gggcacagtc tgatggcgcc tttgctggcg  
               
               
                   
               
               
                 ccttagtatg gttgactccg gatggacaaa agaaaaaaaa 
               
               
                   
               
               
                 ttttttttct tgaatgaaat agcaggaagc tcctcgggag 
               
               
                   
               
               
                 catgtgatt gattaaccgc aggtgatgga tgctacgagt 
               
               
                   
               
               
                 ataaatggat taactacctc aatccttaca gtaagattgg 
               
               
                   
               
               
                 aactaagggc agggactcat gcataagggt atgaatccca 
               
               
                   
               
               
                 gccaggacaa gtgagttgag gcttgtgcca caaaaggttt 
               
               
                   
               
               
                 gtccttgggg aacaggcagg cctgccagga tcccccccat 
               
               
                   
               
               
                 atcgattggg ctgggagggc tggccatgag gtccccactt 
               
               
                   
               
               
                 tctgctttcc ttgcccatgt gtcacccctt tggcctccag 
               
               
                   
               
               
                 cttgtccctc tctcactttc tatagctttg ttggaccaga 
               
               
                   
               
               
                 tggtgaggaa aggaatggcc tcttcccttc tagagggggc  
               
               
                   
               
               
                 tggctggagt gagacctggg gcttggcctg gaacccacca 
               
               
                   
               
               
                 cacagcccca aagtcaggaa gcctggggaa accagagctg 
               
               
                   
               
               
                 agacctcttc aacagggttt ctttgagatc ctacacctcc 
               
               
                   
               
               
                 attgggccct ttttcagtct tcaatggggg cccagttggc 
               
               
                   
               
               
                 tctagaagga gaagaggtga agcaggatcc tttgccctgg 
               
               
                   
               
               
                 gggagtctga gggcgcggtc cttggactca ttcaggccgt 
               
               
                   
               
               
                 ctttgtagtt gggggagttc cactgggcga tcccagcccc 
               
               
                   
               
               
                 tccccaccca ccctctaatg gacctcctca tagaagcccc 
               
               
                   
               
               
                 atttcacttt tgttttatct acctcttagc aaaacaatag 
               
               
                   
               
               
                 ataaattagg tagtggcagc tccacttgct taggttaggg 
               
               
                   
               
               
                 ggggaaaaag atttcttttt ccaaaggaaa aaaatattac 
               
               
                   
               
               
                 cttgagaata ctttccaaaa aataaaatta aaaaaaaaaa 
               
               
                   
               
               
                 aaccaaaaaa aaaaattttt ttttaaaagg gagacatttt 
               
               
                   
               
               
                 ccagtgacca ctggattgtt ttaatttccc aagctttttt 
               
               
                   
               
               
                 ttcccccata aataagtttc actctttggc gattttcttc 
               
               
                   
               
               
                 acttgtttaa gataacgtgc tagctattcc aacaggtaac 
               
               
                   
               
               
                 agctttcaca gtctgcccct ggcctgtctc accccatccc 
               
               
                   
               
               
                 ccaccctatt cctgccagtg agtccttcct gtgcttact 
               
               
                   
               
               
                 cccttaccc ctcccagcca gctgacttca gtcacccctg 
               
               
                   
               
               
                 tcccccctcc cctgccaata agctccccca ggaataaagg 
               
               
                   
               
               
                 ctttgttttg gggatgctta aatcttgact ggcacttccc  
               
               
                   
               
               
                 ggctgtgggg gctggggagc cacttgtaac atttctgtgc 
               
               
                   
               
               
                 agattttatg ttagccactg ctatgtaaaa gcacgttcaa  
               
               
                   
               
               
                 aatgaatttc agcagattat gtgttaccat aatgaataaa 
               
               
                   
               
               
                 cgtcctctat caccatttgg agtctccctt ttctccagga  
               
               
                   
               
               
                 tcttgatcct ggtccccaaa accagagtga atcaaaagag 
               
               
                   
               
               
                 cttcctcccc tgaggcaaag tggatttgta agcagttctg 
               
               
                   
               
               
                 aaacatcact tactcagaag agggaacgat gtattttgat 
               
               
                   
               
               
                 gagtgcaaat tgggaagagc tggaggccta ctgcttggga 
               
               
                   
               
               
                 cagttttttt tttttttttt tttttaaata tgagtgctag 
               
               
                   
               
               
                 cttattctgt aattgcggca actttgaaaa ttgtatttta 
               
               
                   
               
               
                 ctggaaatct gccagccatc accacccgat tttgattgta 
               
               
                   
               
               
                 tccttcctcc catcctttaa tctgttcatt gctttggggg 
               
               
                   
               
               
                 aggtggggca gctggctcac acgttggagt ttgttctttg 
               
               
                   
               
               
                 atggatgaac gaacactcca gttttctttc ccgtgaaggt 
               
               
                   
               
               
                 tgtttcagcc acaaaccact tcattttgct gtttcaattt 
               
               
                   
               
               
                 caaaataaaa ggaaacttat attgaaagac aa  
               
               
                   
               
               
                 (MDM4)(NM_002393; protein is NP_002384.1)  
               
               
                 SEQ ID NO: 8 
               
               
                 gggaggccgg aagttgcggc ttcattactc gccatttcaa 
               
               
                   
               
               
                 aatgctgccg aggccctagg atctgtgact gccacccctc 
               
               
                   
               
               
                 cccccacccg ggctcggcgg gggagcgact catggagctg 
               
               
                   
               
               
                 ccgtaagttt taccaacaga ctgcagtttc ttcactacca 
               
               
                   
               
               
                 aaatgacatc attttccacc tctgctcagt gttcaacatc 
               
               
                   
               
               
                 tgacagtgct tgcaggatct ctcctggaca aatcaatcag 
               
               
                   
               
               
                 gtacgaccaa aactgccgct tttgaagatt ttgcatgcag 
               
               
                   
               
               
                 caggtgcgca aggtgaaatg ttcactgtta aagaggtcat 
               
               
                   
               
               
                 gcactattta ggtcagtaca taatggtgaa gcaactttat 
               
               
                   
               
               
                 gatcagcagg agcagcatat ggtatattgt ggtggagatc 
               
               
                   
               
               
                 ttttgggaga actactggga cgtcagagct tctccgtgaa  
               
               
                   
               
               
                 agacccaagc cctctctatg atatgctaag aaagaatctt 
               
               
                   
               
               
                 gtcactttag ccactgctac tacagatgct gctcagactc  
               
               
                   
               
               
                 tcgctctcgc acaggatcac agtatggata ttccaagtca 
               
               
                   
               
               
                 agaccaactg aagcaaagtg cagaggaaag ttccacttcc 
               
               
                   
               
               
                 agaaaaagaa ctacagaaga cgatatcccc acactgccta 
               
               
                   
               
               
                 cctcagagca taaatgcata cattctagag aagatgaaga 
               
               
                   
               
               
                 cttaattgaa aatttagccc aagatgaaac atctaggctg 
               
               
                   
               
               
                 gaccttggat ttgaggagtg ggatgtagct ggcctgcctt 
               
               
                   
               
               
                 ggtggttat aggaaacttg agaagcaact atacacctag  
               
               
                   
               
               
                 aagtaatggc tcaactgatt tacagacaaa tcaggatgtg 
               
               
                   
               
               
                 ggtactgcca ttgtttcaga tactacagat gacttgtggt  
               
               
                   
               
               
                 attgaatga gtcagtatca gagcagttag gtgaggaat 
               
               
                   
               
               
                 aaaagttgaa gctgctgata ctgaacaaac aagtgaagaa 
               
               
                   
               
               
                 gtagggaaag taagtgacaa aaaggtgatt gaagtgggaa 
               
               
                   
               
               
                 aaaatgatga cctggaggac tctaagtcct taagtgatga 
               
               
                   
               
               
                 taccgatgta gaggttacct ctgaggatga gtggcagtgt 
               
               
                   
               
               
                 actgaatgca agaaatttaa ctctccaagc aagaggtact 
               
               
                   
               
               
                 gttttcgttg ttgggccttg aggaaggatt ggtattcaga 
               
               
                   
               
               
                 ttgttcaaag ttaacccatt ctctctccac gtctgatatc 
               
               
                   
               
               
                 actgccatac ctgaaaagga aaatgaagga aatgatgtcc 
               
               
                   
               
               
                 ctgattgtcg aagaaccatt tcggctcctg tcgttagacc 
               
               
                   
               
               
                 taaagatgcg tatataaaga aagaaaactc caaacttttt 
               
               
                   
               
               
                 gatccctgca actcagtgga attcttggat ttggctcaca 
               
               
                   
               
               
                 gttctgaaag ccaagagacc atctcaagca tgggagaaca  
               
               
                   
               
               
                 gttagataac ctttctgaac agagaacaga tacagaaaac 
               
               
                   
               
               
                 atggaggatt gccagaatct cttgaagcca tgtagcttat 
               
               
                   
               
               
                 gtgagaaaag accacgagac gggaacatta ttcatggaag 
               
               
                   
               
               
                 gacgggccat cttgtcactt gttttcactg tgccagaaga 
               
               
                   
               
               
                 ctaaagaagg ctggggcttc atgccctatt tgcaagaaag 
               
               
                   
               
               
                 agattcagct ggttattaag gtttttatag cataatggta 
               
               
                   
               
               
                 gtacgaacat aaaaatgcat ttattccgtt cacttaccac 
               
               
                   
               
               
                 attatttgaa aatcaatcct ttatttaatt ttatttccaa 
               
               
                   
               
               
                 cctgtcagag aatgttctta ggcatcaaaa tccaaggtag 
               
               
                   
               
               
                 ctgtaagaaa aatactggag ctaacaatga agaacagaag 
               
               
                   
               
               
                 taatctgatt agtcaaatta ttaagtgcca tggattactt 
               
               
                   
               
               
                 tatgcagcag tcaggtacat agttaggtga acccaaaaga 
               
               
                   
               
               
                 aaaactcttg aaaacaagag atttcttcca tgcacattta 
               
               
                   
               
               
                 caatattgag gtataattaa catgataaag tgtttccttc 
               
               
                   
               
               
                 taacgagttg tagaaatctg agtaaccacc caaaaaagca 
               
               
                   
               
               
                 atagaatgtt tctgtcaccc caaaacactc ccttctgccc 
               
               
                   
               
               
                 ctcttcagac agtccttcag ctatttcatg gctctcaccc 
               
               
                   
               
               
                 tagttattt tttttttgca cttttttttt tccgggggta 
               
               
                   
               
               
                 taggggaggt gtggggcgac agggtctgtc ttgttctgtc 
               
               
                   
               
               
                 tcccaggctg aagtgcagtg cagtggtatg atcatggctc 
               
               
                   
               
               
                 actgcagcct tggtttcctg ggcataagtg gtatcccac 
               
               
                   
               
               
                 ttcagcctcc tgagtagctg agactataga ctagcataac 
               
               
                   
               
               
                 cacactggct aattttttgt ggagatgaag tctcactatg 
               
               
                   
               
               
                 ttgcccaggc tggtctcgaa ctcctgggct caaacaatcc 
               
               
                   
               
               
                 tcccgcctca gccttccaaa ttgctgggat tatagtcatg  
               
               
                   
               
               
                 aggcacctag tctggccctt ttgcaagact ttaatctgaa 
               
               
                   
               
               
                 atctaaattt ttaaaattta agtacttaca aaggatatac  
               
               
                   
               
               
                 tatccaacat attgcatatt atatatgtgc tttaaagttt 
               
               
                   
               
               
                 tttttttttt ttgagagacg gtctcacttt gtcatccaag  
               
               
                   
               
               
                 ctggagtgca gtggtgcaaa cacggcccac ctcctgggct 
               
               
                   
               
               
                 caagtgatcc tccagcctca gatccctca caggcattca 
               
               
                   
               
               
                 ctatcactcc cagctaatta aaataatttg tagacggtgt 
               
               
                   
               
               
                 ctcgttatgt tgcccaggct ggtctcgaac tcctgggttt 
               
               
                   
               
               
                 aagtgattcc cccgcctcag cctcccaaag tgttgggctt 
               
               
                   
               
               
                 acagccttga gccactatgc ttggctcaaa gatattttta 
               
               
                   
               
               
                 tgaaagccct gggactatag atttagctga ttaaatttat 
               
               
                   
               
               
                 agaaaaagtc ctgtcatata aactggcaaa gtctgttctt 
               
               
                   
               
               
                 aatttaatta gccaaatcag acttaacttc cgtcagaaca 
               
               
                   
               
               
                 tgtcttggtt ttaattcaga taaacacaca aacatacttc 
               
               
                   
               
               
                 tctggcacag ccttcagaag catcagtttt tgttttgttt 
               
               
                   
               
               
                 tgttttgat tttgagacag ggtcttgctc tgtcgcccag 
               
               
                   
               
               
                 gctggagtgc actggcacaa tcacagttca ctgcagcctc 
               
               
                   
               
               
                 gacctcccag atccaagcaa tcctcccacc taagcctccc 
               
               
                   
               
               
                 aagtagctgg gtctataggc gcgtgccacc accatgccca 
               
               
                   
               
               
                 gctgaatttt gtattttttg tacagacagc attttgccat 
               
               
                   
               
               
                 gttgcccagg ctggtcccaa acttctagcc tcaagcaacc 
               
               
                   
               
               
                 ctcctgcctc agcctctcaa agtgctagga ttgcagtcct 
               
               
                   
               
               
                 gagctactgc cccctaccct ctttgcgtct taggagtcat 
               
               
                   
               
               
                 ttagattttt tttgatcctt ttgtttagtg cctctggagc 
               
               
                   
               
               
                 tgcttacacc aaggcaatac gccttgatat actggatggt 
               
               
                   
               
               
                 tgagaggcag cctctttttt tttttttttt tttattttt 
               
               
                   
               
               
                 tttggaggat agggagtatg gctgttgtga aaagggaggt 
               
               
                   
               
               
                 aaagagaaat ggtagatctg aagaggcctc atcagagcac 
               
               
                   
               
               
                 atattttagg acaacacata tggaaattgg acatctttaa 
               
               
                   
               
               
                 gttggtttcc atagagctat gcatgtatcc ttacccccat 
               
               
                   
               
               
                 gggaaaatgt tggtgtgttc tcaagggtat gcatgtgtca 
               
               
                   
               
               
                 ttttgaagac caaggcccta gaattgtcaa acttaaggat 
               
               
                   
               
               
                 cataaaaatc atgagggttg cttgttaaaa atgtccaaac  
               
               
                   
               
               
                 gtgcagagac tgatattga gatctggacc aggaatttgc 
               
               
                   
               
               
                 atttgaacaa gtgttcctgg aatctctatg caagttttat 
               
               
                   
               
               
                 acagaacata cattggaat ccttgcccta gacaggggtg 
               
               
                   
               
               
                 tccaatcat tggcttccct ggtccacaat ggaagaagaa 
               
               
                   
               
               
                 ttgtcttgga ccacacataa aatacactaa cactaacaat 
               
               
                   
               
               
                 agctgatgag ctaaaaaaaa aaaaaaaaaa aatcgtggac 
               
               
                   
               
               
                 cgggcgtagt ggctcacgcc tgtaatccca acactttggg 
               
               
                   
               
               
                 agatcaccta ggtcgggagt ttgagaccag cctgaccgac 
               
               
                   
               
               
                 atggagaaac cccattttta ctaaaaatac aaaaaattag  
               
               
                   
               
               
                 ctgggcatgg tggtgcatgc ctgtagtccc agctactcag 
               
               
                   
               
               
                 gaggctgagg caggagaatc gcttgaacct gagaggggga 
               
               
                   
               
               
                 gattgcggtg agctgagatt gcgccattgc accccagcct 
               
               
                   
               
               
                 gggcaacaat agcgaaactg tctcagaaaa aagaaaaaaa 
               
               
                   
               
               
                 aaatcgcaaa aagaaaaatc tcataatgtc gttgttggtt 
               
               
                   
               
               
                 tttttttttt tttttgagac agtctcactc tgttgcccag 
               
               
                   
               
               
                 gctggagtgc aatggcatga tctctgctca ccgcaacctc 
               
               
                   
               
               
                 tgcctcccgg gttcaggtga ttctcctgcc tcagcctccc 
               
               
                   
               
               
                 agatagctgg gactacaggc acataccacc atgcctggct 
               
               
                   
               
               
                 aatttttgta tttttagtag agatgggggt ttcactgtgt 
               
               
                   
               
               
                 tggccaggct ggtctcgaac tcctgacctc atgatccaca 
               
               
                   
               
               
                 cacctcggcc tcccaaagtc ctgcgattac aggcgtgagc 
               
               
                   
               
               
                 taccgcaccc agccaagttg taatttttaa taaaacttaa  
               
               
                   
               
               
                 gaagtaaaca ttttacttat gtttataggt atttgatcct 
               
               
                   
               
               
                 aaatttgaca catcattgcc catgaaagaa tcctcttagg  
               
               
                   
               
               
                 ctgctcagct tcactcttcc tgcttgccca ccggggtttt 
               
               
                   
               
               
                 tcactgcttc tgttagcact aagtacttag acgatcctaa  
               
               
                   
               
               
                 gatatgtgct tgagccgaat ttcatcttta cttgtaggaa 
               
               
                   
               
               
                 actttaaact atttcttttc ttttcttttt tttttttttt 
               
               
                   
               
               
                 tacttgagat ggagttttgc tcttgtcgcc caggctggag 
               
               
                   
               
               
                 tgcagtggag tgatctcggc tcactgcaac ctctgcctcc  
               
               
                   
               
               
                 cgggttcaaa tgattctcct gcctcagcct cccaagtagc 
               
               
                   
               
               
                 tgggattaca ggtgtgcacc accatgtctg gctaattttg  
               
               
                   
               
               
                 tatttttagt agagatggtt tcaccatgtt ggtcaggctg 
               
               
                   
               
               
                 gtctcgaact cctgacctca ggtcatccac ccacctcagc  
               
               
                   
               
               
                 ctcgcaaagt gctgagatta caggcatgag ccacagcgcc 
               
               
                   
               
               
                 cagcttaaac tattttcttg gtctgttttt gattttcttt  
               
               
                   
               
               
                 taccttgcc actgcggtac agattattt tactcactgc 
               
               
                   
               
               
                 cactaaacta aagcaaggca tagatatat gtgaagtgtt  
               
               
                   
               
               
                 cagagtttac tgctataagg aaacttccaa atactgacat 
               
               
                   
               
               
                 ttacctata gctgtagtta ttgggaccat gtgctctggt  
               
               
                   
               
               
                 tttctggaga ctgccaaatt gctcccattt ttctgcatcc 
               
               
                   
               
               
                 cacctggttt ctttctgcat gtcccctttc actttcaaac  
               
               
                   
               
               
                 ctatcattt ggatgttaaa ttatatggtc acctagttat 
               
               
                   
               
               
                 aggtaagcct tgttcgagtt gatatcttga ttgtgaggaa  
               
               
                   
               
               
                 ggatctgtgt cattggagct tgtttctgct gcaacgtgct 
               
               
                   
               
               
                 gtagactatg aataatgaaa tcacaccaca ttaccatcag  
               
               
                   
               
               
                 atttcttgtt ttagttgtca aattaatatt tatgattgtt 
               
               
                   
               
               
                 atcttgggcg aaaagttcag agcagagatg acaaatcatt  
               
               
                   
               
               
                 agaacaacga tgaatttcag tattacggct aaaaagttct 
               
               
                   
               
               
                 tctgtctgaa tattaactca ctctccttcc agtgtacttc  
               
               
                   
               
               
                 acagtaattg gtatgctttt ttatttaatg cttaaatcaa 
               
               
                   
               
               
                 actttataaa aatcttagac cagatcttta atatggtatg  
               
               
                   
               
               
                 ccatttcccc agtctaccaa tggaatagta tgggtttcta 
               
               
                   
               
               
                 atcctaggct tgtacaatgg attggagttg agccatgcca  
               
               
                   
               
               
                 gcctccacac tgccactaac ttctgtaatg taagattgag 
               
               
                   
               
               
                 tcactgccaa gcatttgaaa tatgcagttg tgttttaatt  
               
               
                   
               
               
                 ataatttatg tatagttaga tgtatgtagt gcattgtgtg 
               
               
                   
               
               
                 gtattatttg gtttgtaaga atttattttt aagggtcaag  
               
               
                   
               
               
                 gtcatttgta acattttgtg tgtgtcaatt caatgcaatg 
               
               
                   
               
               
                 ttggctgcct tttgaagtct ttgatatatt ggtgaatatt  
               
               
                   
               
               
                 cttctgatct ataatacaaa gctatgtaat gttacctctt 
               
               
                   
               
               
                 gactcgcttt tgaaaggaag acaattgtta actagatatt  
               
               
                   
               
               
                 tgagtttttt cccctcagaa ttatgtgaat ttctgatata 
               
               
                   
               
               
                 tggctttaga tactgtgaat ctgttttcca tttagtcagt  
               
               
                   
               
               
                 tatctgctta aattgttcag aactatatcc taacgagcaa 
               
               
                   
               
               
                 ttagttctga tggttctccc agtcatgagt gtgcatgtgt  
               
               
                   
               
               
                 gcaagcatgt tttgatcctg atgctacctt tgctaaaaat 
               
               
                   
               
               
                 ggccatagat taggaactag ctatgttttt agaatcaaag  
               
               
                   
               
               
                 atgaaccggt aagctgtctc atgtaccaaa cgtgaaattt 
               
               
                   
               
               
                 acagtgttta caaatgtctg gaattttgca ctgccatagg  
               
               
                   
               
               
                 gaatgttaag gttacttggc tggaatttat cagacttgtg 
               
               
                   
               
               
                 agtaaacaag ttgaagttta gcagatgagg gggaatattg  
               
               
                   
               
               
                 aggcccctaa ggctaaacaa aataatcagt atctgagata 
               
               
                   
               
               
                 gtggctaatg tggctcccca ggcctaattt gggaacagtt  
               
               
                   
               
               
                 tttcctgatt gctttgagaa gtactttctt 
               
               
                   
               
               
                 ttgacagaaa ttttcattct gcttgccatt gctatattct  
               
               
                   
               
               
                 ccattatag gagccattgg atttattcc ttttgtggga 
               
               
                   
               
               
                 aatgtcccat tagcattttc agatatttg atgtgcacta  
               
               
                   
               
               
                 atgccattat tggtaatgcc gttattggtg aatacagcat 
               
               
                   
               
               
                 agttaaataa actgttacag taaatctaca cttggatttg  
               
               
                   
               
               
                 ctgcacctct accaatagcc ttttgaatga ctgaaagtgt 
               
               
                   
               
               
                 taacagagaa agaggcatgt ctgcagaaag agatagctaa 
               
               
                   
               
               
                 tattttttgg tactttatct gaaatccaag atgctgcttc 
               
               
                   
               
               
                 ccctgcaggt tgttttcctt cttacgatcc tcattgaatc 
               
               
                   
               
               
                 ccctctggga gcacaggaca gttagtagaa ctctccattt 
               
               
                   
               
               
                 cttttttttt ttttttagac ggagtctctc tctgtcgccc 
               
               
                   
               
               
                 cggctggagt gcagtggcgc gatctcggct cactgcaacc 
               
               
                   
               
               
                 tccgcctccc gggttcaccc cattctcctg cctcagcctc 
               
               
                   
               
               
                 cctagtagct gggactatag gcgcccgcca ccacgcctgg 
               
               
                   
               
               
                 ctaatttttg tatttttatt ggagacgggg tttcaccgtc 
               
               
                   
               
               
                 ttagccagga tggtatgat ctcctgacct cgtgatctgc 
               
               
                   
               
               
                 ccacctcagc ctcccaaagt actgggatta caggcgtgag 
               
               
                   
               
               
                 ccaccgcgcc cggccggaac tctccatttc ttaaggtaaa  
               
               
                   
               
               
                 gagggtcaag gatacctaaa aagggtcaaa taatgctaga 
               
               
                   
               
               
                 agagcaattc ctctttcaga gcagttgctg taatttggca 
               
               
                   
               
               
                 aatgctttat cgaagattga tattaggcta ggggcggtgg 
               
               
                   
               
               
                 cttacgcctg taatcccagc actttgggag gccgaggtgg 
               
               
                   
               
               
                 gtggattgcc tgagctcagg agttcgagac cagtctgacc 
               
               
                   
               
               
                 agtatggtga aaccctgtct ctactaaaaa tacaaaaatt 
               
               
                   
               
               
                 agccggtcgt ggtggcgtgc acctgtagtc ccagctactt 
               
               
                   
               
               
                 ggcaggttga gacaggagaa tcgcttgaac ctgggaggtg 
               
               
                   
               
               
                 gaggttgcag tgagccgaga ctgcaccact gcgctcccac  
               
               
                   
               
               
                 ctgggtgaca gagactctgt ctcaaaaaaa aggacattta 
               
               
                   
               
               
                 tcattataac atcttattag agcccctaat ttcttatctg 
               
               
                   
               
               
                 aaggcactgt tttttttttt aaacagttaa gtactgatgt 
               
               
                   
               
               
                 caacagacaa atatttctga tcagatagtc ccctgtcaac  
               
               
                   
               
               
                 agtagcaaat gtggtttcat aaagtgggaa gaaaacagca 
               
               
                   
               
               
                 ttttaaagta actttttggg agactgattt gagtaataat  
               
               
                   
               
               
                 aaaactctgg tctcccttaa gaaaaaaaaa cccttccacc 
               
               
                   
               
               
                 tttactgtgt catttatatc cccttagttc caaagttaat  
               
               
                   
               
               
                 tatatattt ctggatang atttatacc aaagaccat 
               
               
                   
               
               
                 atcagccat gtaactacag tatattaga taagattcct  
               
               
                   
               
               
                 ctttccagtc agtcctggga aatgtttctg ttgcagagtt 
               
               
                   
               
               
                 aggcggtaga tgggaagctg tgatggcaga  
               
               
                   
               
               
                 gctactatct aataaagtaa caactcgtag ttgaggcttc 
               
               
                   
               
               
                 ctttctgtgt gtgatggggg atagggagtt agctcccctg  
               
               
                   
               
               
                 ttgtctcagc actaagaaat tgaggtcagg ccaggcgcgg 
               
               
                   
               
               
                 tggttcactc ctgttattcc agcactgggg  
               
               
                   
               
               
                 tggccaaagt gggcagattg cttgcgctct ggagctcgag 
               
               
                   
               
               
                 accagcctgg gcaacatggt gaaaccctgt  
               
               
                   
               
               
                 ctctaccaaa aatacaaaaa aaaagctggg catggtgggt 
               
               
                   
               
               
                 gcatgcttgt cccagctact gaggaggctg  
               
               
                   
               
               
                 aggtgggagg atcgcttgag cctgggaggt ggaggttgca 
               
               
                   
               
               
                 gtgagctgag atggcaccac tgcaatccaa  
               
               
                   
               
               
                 ggtgggtgac agagacgctg tctcaaagaa attgaggtca 
               
               
                   
               
               
                 ggcttccttc ttacagaatt atttttttct ctgtagtttg  
               
               
                   
               
               
                 cctcattftt tcactttctt ttcaatgaga atcgaagtgt 
               
               
                   
               
               
                 ttcttttggg tttttttttc ccccttttaa aatcaacagg  
               
               
                   
               
               
                 aaatgtttca aaggagggat gaaatgcttc ttggatcct 
               
               
                   
               
               
                 cagcacttgg caaggtagac ctcatagcaa ccttgaatat  
               
               
                   
               
               
                 gactttcttt agtctctagc tatgcactat taagtgcctc 
               
               
                   
               
               
                 ttgggtagag gtagagttaa gtattgagtg ccagtcttga  
               
               
                   
               
               
                 cgtccgtatg cctcagtttt tctcatatat aaaaagcagt 
               
               
                   
               
               
                 atacatacct acccttttct acctcatcat ttgttgtagg  
               
               
                   
               
               
                 gattaaatcc gggagagcaa ttctgaagcc tataaatttc 
               
               
                   
               
               
                 cttgaagaga tctaagaacc tattatgctc ttggtgtacc  
               
               
                   
               
               
                 aagctctggg gtatatattc agaatacctc atgttctgga 
               
               
                   
               
               
                 agctgagcac tagctcccct ttattgcctg cctggcagag  
               
               
                   
               
               
                 cctgtttgat tactgcaggc ccttttaccc atgcttctag 
               
               
                   
               
               
                 tttaggtatt attattga tatgaggctc ttgaccagaa  
               
               
                   
               
               
                 aagagttctt tctctaggtg ttctgagaga agtttgtaaa 
               
               
                   
               
               
                 tttggatagt acattctatc ctgataaaac caccttgctg  
               
               
                   
               
               
                 tggtatgat gtacaaaaaa aaattttttt tttgagacag 
               
               
                   
               
               
                 agtatactc tgtcacccag gctggaatgc agtggcgcaa  
               
               
                   
               
               
                 tcttggttca ctgcaacccc cgcctcctgg gttcaagcga 
               
               
                   
               
               
                 tcctcctgcc tcaacctctc aagtagctgg  
               
               
                   
               
               
                 gactacaggc gtgcaccacc acacctggct aattttgta 
               
               
                   
               
               
                 ttttagtaga gacagggttt caccatgttg  
               
               
                   
               
               
                 gccaggctgg tcttgaactc ctgacctcag gcgatctgcc 
               
               
                   
               
               
                 cgccttggcc tcccaaagta ctgggattac  
               
               
                   
               
               
                 aggcgtgagc aactgctcct ggcccaaaac atctctact  
               
               
                   
               
               
                 acatacactt gagtaggtgg cataaaatgc  
               
               
                   
               
               
                 actgtcaata tatagaaaac atgaaatttt ccaaatattt 
               
               
                   
               
               
                 ccgatcagag aatcacaaga gcagcaaatg tggtttcat  
               
               
                   
               
               
                 aagtgggaag aaagcagcaa tttaaaataa ctttttggga 
               
               
                   
               
               
                 gactgaattg agtaataata aaacttcagt ctttcgctaa  
               
               
                   
               
               
                 taataataat aataataata ataacaacaa cttattgaat 
               
               
                   
               
               
                 gtggccagct cactagatga ggaaagagga aggcattttc  
               
               
                   
               
               
                 tgcattcttg cctagttttc cttataagca ccactaagtt 
               
               
                   
               
               
                 aatagctctg tctttttggt gtttgcacta tgtaatgctt  
               
               
                   
               
               
                 ttaatacttt ttaattgtgc ttttttatgt attaaatgtt 
               
               
                   
               
               
                 tttccttttg cca  
               
               
                   
               
               
                 (CA VI)(NM_001215)  
               
               
                 SEQ ID NO: 9 
               
               
                 MRALVLLLSLELLGGQAQHVSDWTYSEGALDEAHWPQHYPACGGQRQSP  
               
               
                   
               
               
                 INLQRTKVRYNPSLKGLNMTGYETQAGEFPMVNNGHTVQISLPSTMRMT  
               
               
                   
               
               
                 VADGTVYIAQQMHFHWGGASSEISGSEHTVDGIRHVIEIHIVHYNSKYK  
               
               
                   
               
               
                 SYDIAQDAPDGLAVLAAFVEVKNYPENTYYSNFISHLANIKYPGQRTTL  
               
               
                   
               
               
                 TGLDVQDMLPRNLQHYYTYHGSLTTPPCTENVHWFVLADFVKLSRTQVW  
               
               
                   
               
               
                 KLENSLLDHRNKTIHNDYRRTQPLNHRVVESNFPNQEYTLGSEFQFYLH 
               
               
                   
               
               
                 KIEEILDYLRRALN  
               
             
          
         
       
     
         [0162]    All references, publications, patent applications, issued patents, accession records and databases cited herein, including in any appendices, are incorporated by reference in their entirety for all purposes.