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• W4246173886 abstract "When consulting a medical doctor, the most common question we all probably have heard is ‘Where does it hurt?’. Subsequently, the patient is describing the symptoms, and in some cases, various body fluids will be checked for cell numbers, hormone levels or pathogens. For the past decades, more and more molecules have been measured additionally, among them many so-called biomarkers (Nilsson et al. 2013, Syed Ikmal et al. 2013, Dai et al. 2015, Gorgens et al. 2016, Lees 2015, Simonsen & Boedtkjer 2015, Vanhoutte et al. 2015). The concept of using biomarkers is a progressive and quite young medical approach. Biomarkers can be helpful in detecting pathological changes in an early stadium of disease, before specific symptoms occur, and are therefore used as indicators for diagnosis. On the other hand, biomarkers are measured after biopsy of resected tumour tissues to predict a prognosis of the patient's outcome and tailor the medication to the individual person. Further areas of application include the stratification of prospective responders and non-responders to medication, or therapeutic monitoring to keep the effectivity of the drug under surveillance. One of the first examples of a routinely used diagnostic marker in the clinic is the prostate-specific antigen (PSA), which is measured in sera for early diagnostic screening for prostate carcinoma. PSA is specifically produced by prostate gland cells but is found to be elevated in carcinoma cells. Unfortunately, it is not as simple as it seems: PSA serum level is influenced by several factors, for example inflammation or medication, and most importantly, PSA blood levels differ interindividually. As well as an elevated PSA serum level is not always caused by prostate cancer, a low PSA serum level cannot exclude a malignant change in prostate gland. Therefore, diagnosis based on one single biomarker can lead to false-positive or false-negative results. Hence, the most important parameter for a successful biomarker is a high specificity (no false positive results) and a high sensitivity (no false negative results) to avoid overtreatment of healthy patients or overlooking a disease. In the precedent of PSA, for which measurements were established in the 1980s, further research and progress is made. For example, the determination of soluble/free PSA in ratio to total PSA (with complexed PSA) and also additional tumour marker are taken into consideration, for example PCA3, human kallikrein 2 or prostate-specific membrane antigen to obtain a precise diagnosis (Borgermann et al. 2010). As mentioned before, biomarkers are also applied to determine prognosis and suitable treatment for cancer patients. One example is the human epidermal growth factor receptor 2 (HER2) in breast cancer. Tumours with a high density of HER2 are growing more aggressively and have a higher recurrence rate, so a risk-adapted therapy should be applied. Also, a therapy targeting this growth receptor is available. Therefore, immunotherapy with specific antibody against HER2 will be used, which binds to the extracellular domain of HER2 and thereby blocks the function in signal transduction. Cells marked this way are recognized and destroyed by the immune system (Pegram et al. 1998, Eisenhauer 2001). Not only proteins are used as biomarkers, but RNA, DNA and other metabolic products. For example, microRNAs are under investigation to be used as markers in diagnosis and prognosis for diverse cardiovascular diseases. In comparison with mRNAs, circulating miRNAs are quite stable. The research on miRNAs as biomarkers is still in its early stages, so the triggers that release miRNAs into circulation remain to be elucidated. Also, it is unclear why, for example, multiple miRNAs in abdominal aortic aneurism were downregulated in the circulation but upregulated in the aneurismatic tissue. Sometimes, different studies show non-overlapping or even contradicting results; this shows that more studies are needed before new candidates can go on to clinical application. The big advantage of miRNAs as biomarkers over currently used protein markers is the detection and quantification method qRT-PCR, which is easy to handle. As for all biomarkers, it seems probable that a set of dysregulated molecules rather than one single marker will be used for diagnosis or prognosis (Wronska et al. 2015). One attempt to look for candidate biomarkers is the investigation of molecules which are spatiotemporal not typical for the target tissue. For instance, homeobox genes are found in tumour tissue of adults although normally expressed during development. Or globins, such as myoglobin, haemoglobin and cytoglobin, which have been solely considered as oxygen transport or storage proteins, were analysed in breast carcinoma. The low overall expression level of globins in tumour tissue suggests that a contribution to tumour oxygenation is unlikely, but potential functions as tumour suppressor or involvement in carcinogenesis have been assumed (Gorr et al. 2011). The systematic approach to look for a new protein-based biomarker is more challenging. Human plasma is carrying the most comprehensive human proteome, reflects many physiological processes and is therefore widely used as an analyte for protein biomarker discovery. The methodical approach is mass spectrometry. Because of this combination of the highly complex and dynamic analyte with low abundance of possible biomarkers, and the dynamic range limitations and low data sampling rates of the analysis method, previous searches for protein biomarker have failed. The suggestion is to use body fluids close to the site of disease to facilitate the detection of new biomarker candidates. Six essential process steps are proposed: candidate discovery, qualification, verification, research assay optimization, biomarker validation and commercialization. After a novel biomarker is discovered, it is a long way to clinical application, and requires a huge investment of time and money for assay development, acquisition of regulatory requirements and commercialization. The high cost of this process and the relatively low profit margins compared to the ‘conservative’ drug make it a quite risky approach (Rifai et al. 2006). The altered abundance of the factors used as biomarkers are not only useable for diagnosis, prognosis or monitoring, but also as base to investigate possible targets for prevention and treatment of disease. So miRNAs are evaluated as a clinical tool in different ways, not only for diagnosis, but also as therapeutic target, for example in diabetic cardiomyopathy and nephropathy (Figueira et al. 2014). Biomarkers have been reported to correlate with acute mountain sickness, which are analysed to target the related pathways for pharmacological prophylaxis of acute mountain sickness. For example a higher level of antioxidant protein and lower concentrations of inflammatory or permeability mediators such as interleukin-1 receptor agonist (IL-1RA), heat-shock protein-70 (HSP-70) and adrenomedullin in patients with acute mountain sickness are found (Lu et al. 2015). The change in the reviewed biomarker indicates that patients have an altered oxidant/antioxidant and inflammatory/anti-inflammatory balance regulation respond to hypoxia. Acute mountain sickness patients seem to have a lower threshold to react to hypoxia with excessive responses which potentially leads to the AMS symptoms. Therefore, a set of molecules as potential targets for pharmacological acute mountain sickness prophylaxis are suggested (Lu et al. 2015). Besides the clinical application, markers are irreplaceable in research. Especially in stem cell research and immunology, cell surface molecules are used as marker to distinguish cell types and cell activation and enzyme activities are measured to follow differentiation. Just to name one of many cell surface markers, CD90 is used to evaluate the transformation of mesenchymal stem cells to hepatocytes, because it is not expressed on matured hepatocytes (Winkler et al. 2015). Except for the so far mentioned common marker molecules, also unexpected marker has a role in diagnosis of disease. Microparticles, for example, are not only biological vectors of information, but also biomarkers of cardiovascular pathologies including diabetes (Andriantsitohaina 2015). International studies with cardiovascular disease patients indicate that procoagulant microparticles provide a more effective prognostic indicator of mortality than standard biological markers (Mallat et al. 2000, Morel et al. 2004). Therefore it is suggested to consider circulating microparticles as indicators of the overall vascular status (Ishida et al. 2015). Also, several biomarkers are investigated to determine the mitochondrial content (Dahl et al. 2015). Another extraordinary example is the leucocyte telomere length (LTL) as marker for cardiovascular ageing and atheroscleoris respectively. How does it work? Leucocytes are involved in the formation of atherosclerotic plaques. The high demand of leucocytes is replenished by hematopoietic stem cells which have reduced telomerase activity. Therefore, plaque formation in atherosclerosis leads to decreased telomere length in circulating daughter cells, the leucocytes (Zietzer & Hillmeister 2014). Basically, the biomarker research and clinical application relies on the deviations in pathophysiological processes. The specific changes on molecular level are consistently overlapping in a big cohort independent of age, sex and geographical origin. But as every human being and every disease is so complex in its molecular processes (Rueth et al. 2015) and sexual dimorphisms are found (De Alencar et al. 2015), the one and only universal marker is utopian. Instead, a set of biomarkers, preferably with a look at dynamic changes for each patient to determine the basic level, should be applied to reach the highest sensitivity and specificity possible (Fisher 2015). How can biomarker determination be transferred in everyday practice? And will all the markers and new developed tests be available for the whole population? Or will the financial profit claim of the companies providing the assays limit the access to patients in conurbation and with the right amount of money? The marker troponin T, for example, measured to detect damage of the myocardium, is exclusively provided by a big company and is determined in less than 300 laboratories, while more than 2500 laboratories use troponin I, provided by eight different manufacturers in the United States (Rifai et al. 2006). Intellectual property concerning the protein or antibody can reduce the accessibility for the doctors and the patient. Another bottleneck could be the limitation of the clinical laboratories and the knowledge transfer to the medical doctors in this fast evolving field. Currently, the urologist is checking the PSA level of the patient, and the cardiologist is checking heart disease-related miRNAs, but maybe in future, many more physicians' offices will own a sequencing machine to immediately obtain a molecular profile of the patient, looking at gene mutations and biomarkers, instead of blood pressure and cholesterol level. This may lead to a medical system focusing on the molecular mechanism causing the disease and target these for treatment instead of alleviation of the symptoms. There is no conflict of interest to declare." @default.
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• W4246173886 title "Biomarkers" @default.
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