1. Medicine

2. Regulatory validation

3. Cell biology

4. Geology and astrobiology

5. Traumatic Brain Injury biomarkers
     The need for traumatic brain injury (TBI) biomarkers    TBI biomarker attributes       Current biomarker candidates    Temporal protein biomarkers in tracking different phases of TBI  

6. Ecotoxicology

7. History

8. See also

9. References

A biomarker, or biological marker is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated to examine normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.^[1] Biomarkers are used in many scientific fields.

Medicine

In medicine, a biomarker can be a traceable substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride is used as a radioactive isotope to evaluate perfusion of heart muscle.

It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody may indicate an infection. More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment.

One example of a commonly used biomarker in medicine is prostate-specific antigen (PSA). This marker can be measured as a proxy of prostate size with rapid changes potentially indicating cancer. The most extreme case would be to detect mutant proteins as cancer specific biomarkers through Selected reaction monitoring (SRM), since mutant proteins can only come from an existing tumor, thus providing ultimately the best specificity for medical purposes.^[2]

Biomarkers used for personalized medicine are typically categorized as either prognostic or predictive. An example is KRAS, an oncogene that encodes a GTPase involved in several signal transduction pathways. Prognostic biomarkers indicate the likelihood of patient outcome regardless of a specific treatment. Predictive biomarkers are used to help optimize ideal treatments, and indicates the likelihood of benefiting from a specific therapy. Biomarkers for precision oncology are typically utilized in the molecular diagnostics of chronic myeloid leukemia, colon, breast, and lung cancer, and in melanoma.^[3]

Regulatory validation

Previously used to identify the specific characteristics of the biomarker, this step is essential for doing an in situ validation of these benefits. A large number of candidates must be tested to select the most relevant ones.^[4]

This step allows the development of the most adapted protocol for routine use of the biomarker. Simultaneously, it is possible to confirm the relevance of the protocol with various methods (histology, PCR, ELISA, ...) and to define strata based on the results.

One of the most important steps, it serves to identify specific characteristics of the candidate biomarker before developing a routine test. Several parameters are considered including:

• sensitivity
• specificity
• robustness
• accuracy
• reproducibility

This optimizes the validated protocol for routine use, including analysis of the critical points by scanning the entire procedure to identify and control the potential risks.

Cell biology

In cell biology, a biomarker is a molecule that allows the detection and isolation of a particular cell type (for example, the protein Oct-4 is used as a biomarker to identify embryonic stem cells).^[6]

In genetics, a biomarker (identified as genetic marker) is a DNA sequence that causes disease or is associated with susceptibility to disease. They can be used to create genetic maps of whatever organism is being studied.

Geology and astrobiology

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, versus geomarkers, are also known as biosignatures. The term biomarker is also used to describe biological involvement in the generation of petroleum.

Traumatic Brain Injury biomarkers

 The need for traumatic brain injury (TBI) biomarkers

Significant scientific advances in the last decade have increased our understanding of the complex and heterogeneous pathophysiological processes associated with traumatic brain injury ^[7]. During the same period, numerous experimental drugs have been shown to be neuroprotective in animal models of brain injury. Unfortunately, none of these strategies have proven to be efficacious in TBI clinical trials [13–15]. The failure of clinical therapy trials has been attributed to the lack of therapeutic intervention-tracking CNS biomarkers complicated by the heterogeneity of TBI and poor translatability of preclinical TBI models. For example, it is now recognized that the pathophysiology of TBI is not only acute event, but is also a progressive and delayed neurodegenerative process made up of multiple, parallel, interacting, and interdependent cascades of biological reactions at the tissue, cellular, and subcellular levels. Due to the extended length of axonal fiber tracks, axons are particularly vulnerable to physical trauma to the brain. Thus, axonal injury is a common occurrence in both focal as well as diffuse brain trauma and can be found in TBI of all severities [16,17]. But in addition, neuronal body, dendrites, and synapses are also subjected to TBI-induced damage [18,19]. Similarly, not only are neurons at risk for injury, but also astroglia cells and the myelin-forming oligodendrocytes. For these reasons, a comprehensive understanding of these pathobiological processes at every cellular and subcellular level in greater detail is critical to bridging the knowledge gap that will allow new therapy development. Many agree that there is an unmet medical need for a rapid, simple biofluid-based diagnostic testing for the management of TBI patients, whether it is for monitoring severe TBI patients in the intensive care unit, or triaging mild and moderate TBI patients in the emergency room. Due to the multicomponent pathobiology in brain injury, it would be ideal to have a panel of neuroinjury biomarkers that closely match with the various pathological processes we described above. There are emerging data from many recent studies from multiple research teams showing that biofluid-based TBI biomarker tests have the potential to assess the extent of TBI severity and determine a patient prognosis even at times when correlation with other neurological measures (neuroimaging) may not always be informative such as for mild TBI.^[8]

TBI biomarker attributes   

In order for a biofluid-based TBI protein biomarker to be clinically useful, ideally it should have as many of the following attributes as possible (Table 2): (1) The protein biomarker levels should be readily measured in accessible biofluid such as cerebrospinal fluid (CSF), serum, plasma, and/or whole blood in TBI patients. [For severe TBI (i.e. those TBI patients in neurointensive care unit), the biofluid type where the biomarker can be detected should be biofluids such as CSF, serum, plasma, and/or whole blood. For moderate and mild TBI (e.g. those patients managed in Emergency Departments or admitted to non-ICU settings), the biofluid type should be serum, plasma, and/or whole blood for rapid accessibility and convenience. (2) The biomarker levels must be elevated in various forms and/or severities of human TBI in the acute phase (3–24 h post-injury), when compared to normal control counterparts. (3) The biomarker must have low background or basal biofluid levels in general noninjured healthy control population. (4) The biomarker detected in biofluid after TBI should be derived from or originated from the injured brain as the major source. (5) The biomarker levels in the above stated biofluids should be readily determined and quantified using sandwich ELISA or similar immunoassays with at least two assay formats or platforms. (6) There should be one or more available assay platform for such biomarker with test-retest reliability and reproducibility assay that meet assay analytical performance requirements acceptable to FDA. (7) The biomarker should be translational in nature with demonstrated evidence that there are similar to biofluid profiles in at least two different animal models of TBI (e.g. rodent control cortical impact [CCI], fluid percussion injury [FPI], close head injury [CHI], penetrating ballistic brain injury [PBBI], or blast overpressure wave brain injury [OBI]). (8) The biomarker should be sensitive to severity of TBI as defined by GCS, CT abnormality. (9) The biomarker should allow for repeated detections in one of the above-mentioned biofluids within a 48 h window following brain injury. (10) The biomarker should have initial acute levels (within first 48 h post-injury) that correlate with currently available and commonly accepted TBI patient outcome indices (such as Glasgow Outcome Scale [GOS] or GOS-extended [GOS-E]). (11) The post-TBI biofluid levels of the biomarker are responsive to therapeutic treatments.Based on cumulative evidence on a number of existing neuroinjury biomarkers and the discovery of additional biomarkers, we derived a TBI biofluid-based biomarker panel .

Current biomarker candidates

Mirroring the different pathophysiologic processes occurring in TBI, a panel of TBI biofluid-based protein biomarkers has now been identified. The processes covered by these biomarkers thus far include axonal injury, dendritic injury, neuronal cell body injury, demyelination, synaptic injury and astroglia injury, and microglia responses. Neuronal cell body injury markers include Neuron-specific enolase (NSE), Ubiquitin C-terminal hydrolase-L1 (UCH-L1), Astroglial biomarkers include S100B protein and glial fibrillary acidic protein (GFAP), There are also αII-spectrin breakdown products/fragments as cell death markers. Delayed axonal injury and demyelination markers include Neurofilament proteins (NF) – heavy, medium and light and Myelin basic protein (MBP).  Subacute, chronic TBI biomarkers can include neuroinflammatory markers. Post-injury neurodegeneration/tauopathy such as Tau protein and phospho-tau protein. There are also autoantibodies as autoimmune response. They can target brain protein such as GFAP.  Other biomarker candidates with biofluid evidence from animal models of TBI from severe to mTBI in human. These include dendritic protein microtubule-associated protein-2 (MAP-2) [137,138], brain-derived nerve growth factor (BDNF) [139], and postsynaptic protein neurogranin. Other  emerging biomarkers include MicroRNA (miRNA), Circulating nucleic acids, and Exosome/micro-vesicles biomarkers.

Temporal protein biomarkers in tracking different phases of TBI

TBI biomarkers might be detected in biofluid (such as blood or CSF) in different post-injury time. See graph.

Ecotoxicology

Biomarkers are used to indicate an exposure to or the effect of xenobiotics which are present in the environment and in organisms. The biomarker may be an external substance itself (e.g. asbestos particles or NNK from tobacco), or a variant of the external substance processed by the body (a metabolite) that usually can be quantified.

History

The widespread use of the term "biomarker" dates back to as early as 1980.^[9] The term "biological marker" was introduced in 1950s.^[10][11] In 1998, the National Institutes of Health Biomarkers Definitions Working Group defined a biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention."^[12][13]

See also

• Bioindicator
• Biomarker discovery
• Biomarkers (journal)
• Biomarker Insights – a journal
• Imaging biomarker
• Endophenotype
• Molecular marker
• Saliva testing
• Sponge biomarkers

References

• Luca Ferrari (writer)
• Luca Ferri
• Luca Filippi
• Luca Forte
• Luca Franchini
• Luca Garri
• Luca gaurico
• Luca Giammarco
• Luca, Giovanni Battista de
• Luca Gusella
• Lucainena de Las Torres
• Lucainena de las Torres, Almería
• Lucainena de las Torres, Spain
• Luca Lacrimini
• Luca La Notte
• Luca Lanotte
• Luca Lionello
• Luca Lombardi
• Luca Longhi
• Lucalox
• Lucama
• Luca Marchegiani
• Luca Maria Gambardella
• Luca Marin
• Luca Marmorini