Biomarkers disambiguation; classified by scientific field:

Geology, astrobiology, and biochemistry-

A biomarker can be any kind of molecule indicating the existence, past or present, of living organisms. In the fields of geology and astrobiology, biomarkers are also known as biosignatures. The term biomarker is also used to describe biological involvement in the generation of petroleum. A biosignature, or biomarker, is any phenomenon produced by life, either modern or ancient. In astrobiology, a biosignature is a sign of the presence of extraterrestrial life. Observation of possible biosignatures are normally made by relatively simple observations (e.g. geological, textural, geochemical).

Biosignatures need not be chemical, however. The shape and size of certain objects may potentially indicate the presence of life. For example, tiny magnetite crystals in the Martian meteorite ALH84001 were the longest-debated of several potential biosignatures in that specimen because it was believed until recently that only bacteria could create crystals of their specific shape. However, anomalous features discovered that are "possible biosignatures" for life forms would be investigated as well. Such features constitute a working hypothesis, not confirmation that life exists and has been detected. Concluding that evidence of an extraterrestrial life form (past or present) has been discovered requires proving that a possible biosignature was produced by the activities or remains of life.¹ For example, the possible biomineral studied in the Martiam ALH84001 meteorite includes putative microbial fossils, tiny rock-like structures whose shape was a potential biosignature because it resembled known bacteria. Most scientists ultimately concluded that these were far too small to be fossilized cells. A consensus that has emerged from these discussions, and is now seen as a critical requirement, is the demand for further lines of evidence in addition to any morphological data that supports such extraordinary claims.

From this point of view, even the hypothetical radio signatures that SETI scans for would be an electromagnetic biosignature, since a message from intelligent aliens would certainly demonstrate the existence of extraterrestrial life.

Biomarker (medicine):

In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or prescence of some disease state. More generally a biomarker is an indicator of a particular disease state or some other 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 gene² and MMPs³ for cancer etc. Gene based biomarker is found to be an effective and acceptable marker in the present scientific world.

Psychiatry:

In psychiatric research, a fruitful way of finding genetic causes for diseases such as schizophrenia has been the use of a special kind of biomarker called an endophenotype.

Biomarker (cell):

A biomarker can be understood as a molecule that is present (or absent) from a particular cellular type. This facilitates the characterization of a cell type, their identification, and eventually their isolation. Cell sorting techniques are based on cellular biomarkers (for example, Fluorescent-activated cell sorting). A biomarker can be used to measure the progress of disease or the effects of treatment.⁴ One example of cellular biomarker is the protein Oct-4 that is found in embryonic stem cells.

Biomarkers of exposure assessment:

Biomarkers are very useful in the world of exposure assessment when dealing with direct measurement methods. The use of biomarkers in exposure studies is also referred to as biomonitoring. They are chemicals, metabolites, susceptibility characteristics, or changes in the body that relate to the exposure of an organism to a chemical. Biomarkers have the ability to identify if an exposure has occurred, the route of exposure, the pathway of exposure, or the resulting effects of the exposure. When dealing with exposure assessment, there are three types of biomarkers that can be useful, biomarkers of susceptibility, biomarkers of exposure, and biomarkers of effect.

Biomarkers of susceptibility are indicators of the natural characteristics of an organism that make it more susceptible to the effects of an exposure to a chemical. They can help define what sensitivities are more susceptible as well as critical times when exposures can be most detrimental. For example, the exhalation strength of an asthmatic will indicate how susceptible that person would be to the respiratory effects of exposure to brevetoxin, the toxic compound produced during a red tide.

Biomarkers of exposure are the actual chemicals, or chemical metabolites, that can be measured in the body or after excretion from the body to determine different characteristics of a person’s exposure. For example a person’s blood can be tested to see the levels of lead and therefore determine the exposure.

Biomarkers of effect are the quantifiable changes that an individual endures, which indicates an exposure to a compound and may indicate a resulting health effect. For example, after exposure to DDT, an organophosphate pesticide known to cause problems in the reproductive system and woman may experience miscarriages, which can be linked to her previous exposure.

Biomarkers of exposure are the most widely used because they can provide information on the route, pathway, and sometime, even the source of exposure. These indicators also allow researchers to work forward in time to determine an exposure, and prevent it from causing further damage. This is unlike biomarkers of effect, in which a scientist may work backwards to determine if and what kind of exposure took place, but may be too late to change anything. However, biomarkers of effect are useful for future studies on the chemical(s) of interest and the results may aid in stricter laws or guidelines regarding the chemical(s).

Biomarkers must be evaluated in terms of their ability to predict and quantify exposure and dose. There are certain properties that are desirable when linking a biomarker with an exposure. These include high specificity (one exposure to one biomarker), linear relationship across time, strong correlation with a health effect, inexpensive study, and consistency (the same exposure will produce the same concentration of the biomarker every time). Without these ideal characteristics, the use of biomarkers as a strong predictor of exposure has limitations.

Many different classes of compounds can be measured in different tissues and parts of the body. From breath to hair to saliva, almost every tissue in the body has been tested as a biomarker of exposure and almost every major environmental pollutant can be identified by biomarkers, including volatile organic chemicals (VOCs) and metals like arsenic or lead. It all depends on the chemical structures and reactivity of the compound with the makeup of its storage space. The following table identifies major environmental pollutants and their biomarker tissue or organ.⁵

Genetic marker:

A genetic marker is a gene or DNA sequence with a known location on a chromosome and associated with a particular gene or trait. It can be described as a variation, which may arise due to mutation or alteration in the genomic loci, that can be observed. A genetic marker may be a short DNA sequence, such as a sequence surrounding a single base-pair change (single nucleotide polymorphism, SNP), or a long one, like minisatellites.⁶

Applications of Biomarkers:-

1. Biomarkers of cerebrovascular disease in dementia:

It is increasingly clear that, although dementing illnesses can arise as a result of a single pathogenetic process, they more commonly occur in the presence of multiple aetiological insults. Neurodegenerative processes including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and dementia with Lewy bodies can each cause severe dementing syndromes. It is common for these disorders to coexist with significant cerebral vascular pathology. However, in patients with a combination of neurodegenerative and vascular abnormalities, the relative significance of the separate pathological processes to the clinical features of the disease remains unclear. It has long been known that AD is more severe in the presence of established cerebral infarction^7,8, and autopsy studies show 70% of patients with definite AD to have evidence of coexistent cerebrovascular disease and 35% to have had a cerebral infarction.^9-12

Imaging biomarkers of cerebrovascular disease biomarkers:

have been identified as potentially useful in other diseases of the ageing brain that are associated with vascular pathology, such as late-onset depression, but they are described here because they have potential direct relevance to dementing disease.

1a.White matter lesions (leukoaraiosis):

The presence of white matter abnormalities in the brains of elderly subjects has been recognized for many years. The ability of CT and MRI to identify and localize these lesions has caused these techniques to be widely used as potential biomarkers of ischaemic cerebral injury. These lesions are best seen on heavily T2 weighted MRI sequences, consist of areas of high signal and most frequently occur in the deep parts of the corona radiata and centrum semiovale, giving rise to the commonly used term ‘‘deep white matter hyperintensities’’ (DWMH). Periventricular hyperintensity (PVH) around the margins of the lateral ventricles also occurs with ageing, and in most forms of cerebral disease is usually seen in association with DWMH.

PVH may simply be due to increased interstitial fluid secondary to an increased passage of CSF from the lateral ventricle into the interstitial space¹³, which can be associated with a wide range of pathologies that alter the hydrodynamics of CSF absorption and transfer.

Pathological studies have shown that DWMH are seen in approximately 60% of patients with AD, and their presence is strongly correlated with the presence of arteriosclerotic changes in small cerebral arterial vessels.¹⁴

In the early 1990s, Fazekas et al¹⁵and other groups demonstrated that the severity of DWMH was related to other evidence of ischaemic cerebrovascular disease. This led to the development of a number of semiquantitative classification systems based on the anatomical location, number and size of DWMH.^16,17 More recently automated image analysis techniques have been widely used for quantitative assessment, and DWMH are commonly used as surrogate imaging markers of vascular damage.^18,19

1b. Biomarkers of microvascular angiopathy:

Ageing is associated with evidence of cerebral arteriosclerotic microvascular disease, often referred to as MVA.^20,21,22 MVA forms a spectrum of severity, with lowgrade changes characterized by increased tortuosity and irregularity in small arteries and arterioles (Grade 1)²³ ,As these changes progress to Grade 2, there is sclerosis of vessel walls, in which hyalinosis and lipid deposits are seen, along with regional loss of smooth muscle.

These features are commonly associated with lacunes thathistologically consist of three distinct types: Type 1 are small old cystic infarcts, Type 2 are scars of small haematomas and Type 3 are dilated Virchow–Robin spaces (VRS).²⁴ Grade 3 microangiopathy is especially related to severe chronic hypertension and demonstrates fibrotic wall thickening.

In depressive disorder, there is a higher rate of T2 weighted hyperintensities within the deep white matter and basal ganglia among older depressed patients compared to control subjects,^25,26 especially when the initial onset of depression occurs later in life (typically after 55 years).²⁷

1b (i). Lacunar infarction:

Pathological studies suggest that there are actually two types of lacunar infarction with different clinical manifestations.²⁸ Lacunar infarcts that result in clinical stroke syndromes (Type 1a lacunae) seem to be due mainly to obstruction of the trunk of a perforating artery by atherosclerosis. Silent lacunar infarcts (Type 1b lacunae) result from obstruction of small ramifications of the perforating arteries by microvascular angio( MVA).

These lacunes are typically distributed along the path of the strio-thalamic arteries, which penetrate the perforator substance passing upwards through the globus pallidus, putamen and caudate nucleus and into the adjacent white matter pathways.

1b (ii). Virchow–Robin spaces:

Virchow–Robin spaces are virtual perivascular spaces that surround the perforating arteries entering the brain. Dilated VRS appear as small linear structures perpendicular to the brain surface and with signal intensity equal to that of CSF on all pulse sequences.^29-31

Several mechanisms for the formation of dilated VRS have been proposed.^32,33 These include mechanical trauma due to CSF pulsation or vascular ectasia ^,29,34 fluid exudation due to abnormalities of the vessel wall permeability,^35,36 and ischaemic injury to perivascular tissue causing a secondary ex-vacuo effect.³⁷

2.Biomarkers in Pulmonary Hypertension:

Pulmonary hypertension can develop suddenly but usually develops over months and years, depending on the underlying etiology. It follows that as pulmonary artery pressure rises gradually, the right ventricle has more time to adapt and compensate and symptoms may be slow to emerge. The identification of mutations in bone morphogenetic protein receptor type 2 (BMPR2)^38-43 and the ALK1 receptor^44-46opened up new avenues for understanding the pathogenesis of pulmonary arterial hypertension (PAH).

One biomarker that has attracted interest in this regard is B-type natriuretic peptide (BNP).^47-57BNP is synthesized and released by the myocardium and its levels are affected by the degree of myocardial stretch, damage, and ischemia in the ventricle.^58-60 It is cleaved at the time of release into NT-proBNP and a C-terminal fragment, BNP32. The latter possesses vasorelaxant and natriuretic properties, is cleared by neutral endopeptidase and the clearance natriuretic peptide receptor (NPR-C), and has a relatively short plasma half-life (20 minutes)^.61 The N-terminal fragment is biologically inactive, is cleared by the kidney, has a longer plasma half-life, and is more stable in plasma samples ex vivo.⁶² NT-proBNP levels may be more useful than measurements of BNP32.^47-49,51,53

A number of biochemical measurements have been reported to correlate with prognosis. NT-proBNP,⁵⁷ BNP32,⁵⁷ ANP,⁵⁷ troponin,⁶³ uric acid,⁶⁴ and growth differentiation factor- 15 (GDF15)⁶⁵ and serum creatinine⁶⁶, recognized recently are examples. The first three reflect cardiac work and, in the case of troponin, myocardial damage. Raised serum creatinine reflects renal dysfunction.

A recent study has suggested the combination of NT-proBNP and GDF15 measurements offer a better prognostic score⁶⁵ but this has not been demonstrated prospectively.

3.Biomarkers in Thyroid Cancer Gene Expression Profiling Studies:-

Thyroid nodules are extremely common, being palpable in 4% to7% of the North American adult population, with new nodulesdetected at a yearly rate of 0.1%.^67,68 Currently, fine-needleaspiration biopsy (FNAB) represents the most important initialtest for diagnosing malignancy. The result of the FNAB cytologycan be classified as benign (70% of cases), malignant ⁷²(5% to10%), indeterminate or suspicious (10% to 20%), or nondiagnostic(10% to 15%).^69-71Although nondiagnostic FNABs can be repeated,the indeterminate or suspicious group presents a dilemma forthe clinician. In a recent report from our center on 80 patientswho underwent thyroid resection for an indeterminate FNAB diagnosisof follicular neoplasm (FN), only 20% were confirmed as malignant.Thus, many patients undergo thyroid surgery for nodular diseasethat is eventually diagnosed as benign disease.

A vote-counting strategy based on thenumber of studies reporting a gene as differentially expressedand further ranking based on total sample size and average fold-change.Similar strategies have been used to show that gene pairs consistentlycoexpressed in multiple platforms⁷³ are morelikely to share a common biologic process.

4. Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome:-

Millions of patients with chest pain present annually to hospitals,and many more present with other symptoms potentially indicativeof ischemia.^74-77 A considerable proportion have suspectedacute coronary syndromes (ACS).⁷⁴

Recent investigations have indicated that increases in biomarkersupstream from markers of necrosis, such as inflammatory cytokines,cellular adhesion molecules, acute-phase reactants, plaque destabilizationand rupture biomarkers, biomarkers of ischemia, and biomarkersof myocardial stretch may provide an earlier assessment of overallpatient risk and aid in identifying patients with higher riskof having an adverse event.

4a. Myeloperoxidase- It is releasedinto the extracellular fluid and general circulation duringinflammatory conditions. This enzyme has been implicated inthe oxidation of lipids contained within LDL.⁷⁸

There have been a few clinical studies examining the role ofmyeloperoxidase as a marker of risk for ACS. Using an enzymeassay, Zhang et al.⁷⁹ showed that blood and leukocyte myeloperoxidaseactivities were higher in patients with coronary artery disease(CAD) than angiographicallyverified normal controls, and that these increased activitieswere significantly associated with presence of CAD [odds ratio,11.9; 95% confidence interval (CI), 5.5–2 Zhang R, Brennan ML, Fu X, Aviles RJ, Pearse GL, Penn MS, et al.

4b. Choline- It and phosphatidic acid are major products generated byphosphodiesteric cleavage of membrane phospholipids (phosphatidylcholinefor example) catalyzed by phospholipase D enzymes. Whole-bloodcholine (WBCHO) and plasma choline (PLCHO) concentrations increaserapidly after stimulation of phospholipase D (PLD) and the activationof cell surface receptors in coronary plaque destabilizationand tissue ischemia.⁸⁰

Increased WBCHO concentrations were first identified as a promisingmarker for ACS by use of high-resolution proton magnetic resonancespectroscopy. WBCHO was a significant predictor of cardiac deathor cardiac arrest, life-threatening cardiac arrhythmias, heartfailure, and coronary angioplasty when measured in the firstblood sample on admission. cTnI or cTnT and WBCHO were the mostpowerful independent predictors in multivariate analysis, andthe combination of WBCHO and cardiac troponins allowed a superiorrisk assessment compared with each test alone. WBCHO was nota marker for myocardial necrosis but indicated high-risk UAin patients without acute Myocardial infraction (sensitivity, 86.4%; specificity,86.2%).

4c. Free fatty acids (FFAs)-These are bound with albumin, withonly a small amount of the total, the unbound FFAs (FFA_u), presentas the soluble form. The mechanisms that initiate and maintain increasedFFA_u concentrations after ischemia are not clear. Increasedblood catecholamines in association with ischemia suggest thatincreased FFA_u concentrations result from increased FFA releasethrough adipose lipolysis. Although ischemia activates lipidhydrolysis within the heart, the large increases in serum FFA_uare likely attributable to FFAs originating from other tissues,such as adipose, along with a reduction of FFA use after ischemia.

4d. MMPs are a class of 24 endopeptidases that are physiologic regulatorsof the extracellular matrix.⁸¹

4e. Pregnancy-associated plasma protein A (PAPP-A)-It is a high–molecular-mass(200 kDa) glycoprotein synthesized by the syncytiotrophoblastand is typically measured during pregnancy for screening ofDown syndrome⁸². It was reported to be an insulin-like growthfactor (IGF)-dependent IGF-binding protein-4-specific metalloproteinase,thus potentially a proatherosclerotic molecule through its rolein disrupting the integrity of the atheroma’s protectivecap.⁸³

PAPP-A has also been evaluated as a marker of cardiovascular risk in asymptomatic hyperlipidemic individuals, showing a correlation with the degree of echogenicity of carotid atherosclerotic plaques84. However, PAPP-A concentrations were not influenced by statin treatment.85 These preliminary findings suggest that increases in PAPP-A concentrations may not be limited to ACS patients but could also reflect the earlier stages of atherosclerotic lesions, even in the absence of clinical signs of atherosclerosis.⁸⁶

5. Biomarkers for lung cancer:

There are several distinct types of cancer biomarkers based on different areas: genetics, epigenetics, proteomics, metabolomics, imaging technology, and general physical techniques. Genetics- based cancer biomarkers utilize DNA arrays, polymerase chain reaction (PCR), reverse transcriptase polymerase chain reaction (RT-PCR), DNA sequencing, fluorescent in situ hybridization (FISH) etc. to detect the genetic alterations occurring in the cancerous state. On the other hand, recent development of epigenetic modification analysis also provides tools as cancer biomarkers. Epigenetic modification usually occurs in CpG island of the gene regulatory regions, which results in the down-regulation of the gene expression. These alterations can evade the cells from their normal cell cycle control, and thus result in cancer cells formation.^87,88

5a. DNA-based lung cancer biomarkers-

Cancers are thought to arise by genetic alteration, environmental factors and combined both. Although fewer than 10% of cancers are considered to be linked to Mendelian inheritance of genetic traits⁸⁹, genetics are closely related to the nature of the cancer. Following the development in genomics, fundamental advances in DNA- or RNA-based cancer biomarkers have been brought into clinical uses.⁸⁹

5a(i). Chromosomal changes:

Inactivation of tumor suppressor genes during the cell division is one of the key factors that drive clonal cells of cancer into uncontrolled growth, migration and metastasis.⁹⁰ In many cases the inactivation is induced by loss of DNA or chromosomal rearrangement accidentally happening during cellular division. Most well-known frequently occurring abnormality is deletion of the short arm of chromosome 3 (3p) where several TSG are present.^91-94 Loss of chromosomal material has also been reported to be detected in metaplastic epithelium tissues of smoker or exsmokers. The loss of one allele or loss of herterozygosity (LOH) indicates predisposing potentials to lung cancers, too.^95,96

5a(ii). Gene hypermethylation:

Altered hypermethylation, methylation of the cytosine phosphate guanosine rich regions (CpG islands) of various promoter regions, is a representative epigenetic change in the cell and may cause gene silencing. As an alternative mechanism for inactivating TSGs, hypermethylation is generally discovered in most tumors, including lung cancer.^97,98-104Thus, certain methylation status in the genes can be biomakers in lung cancers especially in TSGs.

CONCLUSION:

Biomarkers can be used to follow the course of a patient's disease and monitor his/her response to therapy. At present this is done on the basis of patients' symptoms, measures of functional capacity such as 6-minute walk test, and echocardiography findings. Chromosomal changes, Gene hypermethylation are useful for lung cancer. Myeloperoxidase, Pregnancy-associated plasma protein A (PAPP-A), Choline are biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome.

B-type natriuretic peptide are helpful in Pulmonary Hypertension. The availability of new high-throughput technologies in genomics, proteomics, transcriptomics, and metabolomics has opened up approaches for novel biomarker discovery. Screening blood samples, circulating cells and tissue from well-phenotyped patient groups is an active area of research in a number of centers.

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Received on 23.11.2009

Accepted on 30.12.2009

Research J. Pharmacology and Pharmacodynamics 2(1): Jan. –Feb. 2010: 5-11

Pollutant Group	Parent Compound	Metabolite
VOCs	Breath, blood	Blood, urine
Tetrachoroethylene	Breath, blood, mothers' milk	None
SVOCs (pesticides, PCBs, PAHs, dioxins/furans	Blood, fat, mothers' milk	Blood, urine
Metals	Blood, bone, hair, cord blood, placenta, feces
Carbon monoxide	Breath, blood	Blood (carboxyhemoglobin)
Environmental Tobacco Smoke (ETS)	Breath, blood (2,5-dimethylfuran)	Saliva, blood (cotinine)