In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other biological state of an organism.

An NIH study group committed to the following definition in 1998: "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." In the past, biomarkers were primarily physiological indicators such as blood pressure or heart rate. More recently, biomarker is becoming a synonym for molecular biomarker, such as elevated prostate specific antigen as a molecular biomarker for prostate cancer, or using enzyme assays as liver function tests. There has recently been heightened interest in the relevance of biomarkers in oncology, including the role of KRAS in CRC and other EGFR-associated cancers. In patients whose tumors express the mutated KRAS gene, the KRAS protein, which forms part of the EGFR signaling pathway, is always ‘turned on’. This overactive EGFR signaling means that signaling continues downstream – even when the upstream signaling is blocked by an EGFR inhibitor, such as cetuximab (Erbitux) – and results in continued cancer cell growth and proliferation. Testing a tumor for its KRAS status (wild-type vs. mutant) helps to identify those patients who will benefit most from treatment with cetuximab.

Biomarkers also cover the use of molecular indicators of environmental exposure in epidemiologic studies such as human papilloma virus or certain markers of tobacco exposure such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To date no biomarkers have been established for SCCHN.

Many fundamental risk in general medical practices are made by assessment of biomarkers. A Biomarker is a parameter that can be used to measure the progress of disease or the effects of treatment. The parameter can be chemical, physical or biological. In molecular terms biomarker is "the subset of markers that might be discovered using genomics, proteomics technologies or imaging technologies. Biomarkers plays major role in medicinal biology. Biomarker brings the future things in our hand by helping in early diagnosis, disease prevention, drug target identification, drug response etc. Several diseased based biomarker had been identified for many diseases such as serum LDL for cholesterol, blood pressure, P53 gene^[1] and MMPs ^[2] for cancer etc. Gene based biomarker is found to be an effective and acceptable marker in the present scientific world.

Contents 1 Biomarker classification and application 2 Discovery of molecular biomarker 2.1 Genomic Approach 2.2 Proteomic Approach 2.3 Metabolomics Approach 2.4 Lipidomics Approach 3 Molecular biomarker in drug development 4 Imaging biomarkers 5 Potential disadvantages 6 See also 7 References 8 External links

[edit] Biomarker classification and application

Biomarkers can be classified based on different parameters. They can be classified based on their characteristics such as imaging biomarkers (CT, PET, MRI) or molecular biomarkers. Molecular biomarkers can be used to refer to nonimaging biomarkers that have biophysical properties, which allow their measurements in biological samples (eg, plasma, serum, cerebrospinal fluid, bronchoalveolar lavage, biopsy) and include nucleic acids-based biomarkers such as gene mutations or polymorphisms and quantitative gene expression analysis, peptides, proteins, lipids metabolites, and other small molecules. Biomarkers can also be classified based on their application such as diagnostic biomarkers (ie, cardiac troponin for the diagnosis of myocardial infarction), staging of disease biomarkers (ie, brain natriuretic peptide for congestive heart failure), disease prognosis biomarkers (cancer biomarkers), and biomarkers for monitoring the clinical response to an intervention (HbAlc for antidiabetic treatment). Another category of biomarkers includes those used in decision making in early drug development. For instance, pharmacodynamic (PD) biomarkers are markers of a certain pharmacological response, which are of special interest in dose optimization studies.

[edit] Discovery of molecular biomarker

Molecular biomarkers have been defined as biomarkers that can be discovered using basic and acceptable platforms such as genomics and proteomics.Many genomic and proteomics techniques are available for biomarker discovery and few recently using techniques are given below. Apart from genomics and proteomics platforms biomarker assay techniques. Metabolomics, Lipidomics, and Glycomics are also the most commonly used as techniques in identification of biomarker.

[edit] Genomic Approach

1.Northern blot

2.Gene expression

3.SAGE

4.DNA Microarray^[3]

[edit] Proteomic Approach

1.2D-PAGE

2.LS/MS

3.SELDI-TOF

4.Ab Microarray

5.Tissue Microarray

[edit] Metabolomics Approach

The term metabolomics has been recently introduced to address the global analysis of all metabolites in a biological sample. A related term, metabonomics, was introduced to refer specifically to the analysis of metabolic responses to drugs or diseases. Metabonomics become a major area of research it is the complex system biological study,used as a to identify the biomarker for various disease. In general most of the disease case some of the metabolic pathway had been activate or deactivated,this parameter can be used as a marker for some diseases. Serotonin production pathway activated in alcoholic drinking person it can be metabolic marker of recent alcohol consumption.

[edit] Lipidomics Approach

Lipidomics refers to the analysis of lipids. Since lipids have unique physical properties, they have been traditionally difficult to study. However, improvements in new analytical platforms have made it possible to identify and to quantify most of lipids metabolites from a single sample. Three key platforms used for lipid profiling include mass spectrometry, chromatography, and nuclear magnetic resonance. Mass spectrometry was used to delineate the relative concentration and composition of high-density lipoproteins (HDL) particles from lipid extracts isolated from coronary bypass patients and healthy volunteers. They found that HDL particles from coronary bypass patients contained significantly less sphingomyelin relative to phosphadidylcholine and higher triglycerides relative to cholesterol esters. Lipidomic profiling was also used to study the effect of rosiglitazone, a PPARγ agonist, on lipid metabolism on mice. Rosiglitazone was observed to alter lipid composition in different organs. It increased triglycérides accumulation in the liver; altered free fatty acids in the heart, in the adipose tissue, and in the heart; and reduced triglyceride levels in plasma.

[edit] Molecular biomarker in drug development

Some of the main areas in which molecular biomarkers are used in the drug development process are: Early drug development studies, Safety studies, Proof of concept studies, Molecular profiling

Molecular biomarkers are often used in early drug development studies. For instance, they are used in phase I study for establishing doses and dosing regimen for future phase II studies. PD biomarkers are commonly observed to respond (either decrease or increase) proportionally with dose. This data, in conjunction with safety data, help determine doses for phase II studies. In addition, Safety molecular biomarkers have been used for decades both in preclinical and clinical research. Since these tests have become mainstream tests, they have been fully automated for both animal and human testing. Among the most common safety tests are those of liver function(eg, transaminases, bilirubin, alkaline phosphatase) and kidney function(eg, serum creatinine, creatinine clearance, cystatin C). Others include markers of skeletal muscle(eg, myoglobin) or cardiac muscle injury(eg, CK-MB, troponin I or T), as well as bone biomarkers(eg, bone-specific alkaline phosphatase).

[edit] Imaging biomarkers

Many new biomarkers are being developed that involve imaging technology. Imaging biomarkers have many advantages. They are usually noninvasive, and they produce intuitive, multidimensional results. Yielding both qualitative and quantitative data, they are usually relatively comfortable for patients. When combined with other sources of information, they can be very useful to clinicians seeking to make a diagnosis.

Cardiac imaging is an active area of biomarker research. Coronary angiography, an invasive procedure requiring catheterization, has long been the gold standard for diagnosing arterial stenosis, but scientists and doctors hope to develop noninvasive techniques. Many believe that cardiac computed tomography (CT) has great potential in this area, but researchers are still attempting to overcome problems related to “calcium blooming,” a phenomenon in which calcium deposits interfere with image resolution. Other intravascular imaging techniques involving magnetic resonance imaging (MRI), optical coherence tomography (OCT), and near infrared spectroscopy are also being investigated.

Another new imaging biomarker involves radiolabeled fludeoxyglucose. Positron emission tomography (PET) can be used to measure where in the body cells take up glucose. By tracking glucose, doctors can find sites of inflammation because macrophages there take up glucose at high levels. Tumors also take up a lot of glucose, so the imaging strategy can be used to monitor them as well. Tracking radiolabeled glucose is a promising technique because it directly measures a step known to be crucial to inflammation and tumor growth.

[edit] Potential disadvantages

Not all biomarkers should be used as surrogate endpoints to assess clinical outcomes. Biomarkers can be difficult to validate and require different levels of validation depending on their intended use. If a biomarker is to be used to measure the success of a therapeutic intervention, the biomarker should reflect a direct effect of that intervention.

An example from the 1980s demonstrates the pitfalls of depending too heavily on biomarkers. In the mid-1980s two new drugs, flecainide and encainide, were introduced to reduce ventricular arrhythmias in patients with histories of heart disease. The drugs did indeed reduce arrhythmias. A large trial, the CAST trial, was undertaken to test the efficacy of the drugs, but the trial was stopped after a year because patients taking the drugs were found to be more than twice as likely to die as patients taking placebos. Flecainide and encainide were recalled in 1991. Their example demonstrates that improving a biomarker does not necessarily translate into increased survival.

[edit] See also

• Cardiac marker
• Molecular risk assessment

[edit] References

[edit] External links

• The latest news about oncology biomarkers
• Biomarkers Study goes on: An article
• Biomarkers Schizophrenia proteomics: biomarkers on the path to laboratory medicine?
• Environmental Biomarkers Initiative at Pacific Northwest National Laboratory
• Biomarkers in Medicine journal
• Center for Integration of Medicine and Innovative Technology
• Dmarker -- A Bio-Marker Inference System for Human Diseases

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