Background: Volatile organic compounds (VOCs) in urine may provide information about biomarkers of tumors in their early stages and about tumor growth. Methods: This study demonstrates that the effect of low protein diet on the pattern of VOCs in the urine of healthy and cancer bearing mice is significant. Results: Pentanal, found in nine out of the ten breast cancer-bearing mice on a high protein (HP) diet, was not found in any of the cancer bearing mice under a low protein (LP) diet, even after tumor development. In addition, the concentration of 3-heptanone, also elevated in the HP group, was not found in the LP group. Benzoic acid, 4-ethoxy-, ethyl ester, 2-pentanone, and propane, 1-isothiocyanato-3-(methylthio), all associated with anti-cancer properties or activity, were observed in the LP group, but not in the HP group. 6-methyl-3-heptanone exhibited a marked increase in concentration as a function of tumor growth when mice were maintained on an HP diet; however, its concentration exhibited no change in mice on the LP diet. The LP group showed much better survival, and even spontaneous recovery from cancer. Conclusion: Our results give an insight into the effects of an LP diet on the management of breast cancer and melanoma. While other research groups focus on improving the relative rates of efficacy and accuracy of cancer biopsy results, this study attempted to monitor the initial appearance of cancer by VOCs excreted in urine that may be associated with metabolic and other physiological changes associated with tumor development, and with a diet that inhibits such development. Keywords: mouse urine composition, breast cancer, melanoma, cancer biomarkers, low protein diet
Purpose: Neuron-specific enolase (NSE) is an isoform of the glycolytic enzyme enolase. For decades, changes in NSE levels in biofluids have been studied for their clinical value in diagnosis, prognosis and monitoring of a plethora of pathologies and conditions, including brain injuries, various kinds of cancers and tumors, and other diseases (eg, Guillain-Barré syndrome and Creutzfeldt-Jakob). However, because of its long 24–30 hours half-life, NSE’s diagnostic and prognostic power, specifically for brain injuries, was found to be limiting in respect to other biomarkers with faster dynamics (eg, S100β). Thus, we hypothesize that measuring NSEs fast decaying enzymatic activity, rather than only amounts of protein, will provide improved resolution of dynamic temporal changes. Methods: Our previously reported tethered enzyme-based biosensor was used here to provide rapid measurement of changes in NSE activity as measured in vitro following incubation in canine and human serum or plasma. NSE activity was then compared with total protein amounts to assess the relative changes of these two parameters. Results: We find that in serum, recovered plasma, and fresh plasma at 37°C, NSE protein levels (NSE P ) are highly stable, whereas the enzymatic activity (NSE A ) decays at a considerably faster rate. Conclusion: Because the decay rate of NSE A is significantly higher as measured in vitro than its reported half-life in biofluids, and taking into account physiological clearance rates, measuring its enzymatic activity can provide better assessment of dynamic changes in the levels of this biomarker. A convenient and rapid technology for measurement of NSE enzymatic activity would improve understanding of NSE temporal dynamics, in comparison to more commonly used diagnostic methods. Keywords: biomarker, enzyme activity, tethered enzymes, biosensor, brain injuries, tumor markers
Serum carcinoembryonic antigen (CEA) is widely used as a representative marker of various malignant tumors. CEA-related cell adhesion molecules (CEACAMs), including CEACAM5, are encoded in the human genome by 12 independent genes and can be potential targets for future cancer treatments. In nonsmall cell lung cancer, serum CEA levels have been reported to predict patient survival. However, associations between mRNA expression of CEACAM gene family members in tumor tissues and patient prognosis remain unclear. To clarify this point, we used the Kaplan–Meier plotter global portal site, which collects the results of Affymetrix gene expression microarray analyses from the publicly accessible Gene Expression Omnibus database and combined it with survival data of patients. A total of 1,926 nonsmall cell lung cancer patients were identified from the Gene Expression Omnibus series, Cancer Biomedical Informatics Grid, and The Cancer Genome Atlas databases. We found statistically significant associations between mRNA expression of several CEACAMs and overall survival (OS) in patients with nonsmall cell lung cancer and lung adenocarcinoma (n=720) but not squamous cell carcinoma (n=524). In adenocarcinoma, higher expression levels of CEACAM6 and CEACAM8 were significantly associated with better OS, whereas higher expression levels of CEACAM3 , CEACAM4 , CEACAM19 , and CEACAM21 were associated with worse OS. Conflicting results among multiple probe sets for the same gene were found for CEACAM1 , CEACAM5 , and CEACAM7 . The findings of this study indicated that CEACAMs play important roles in tumor progression and impact OS of patients with adenocarcinoma. As the impact on OS differed based on the gene family members or the probe set used, the individual CEACAMs seem to function through complicated mechanisms. Further studies are necessary to resolve the problems encountered in our present study. Keywords: mRNA, microarray, survival, nonsmall cell lung cancer, CEACAM, CEA
Currently, there exists a lack of definitive diagnostic tools for neuropsychiatric disorders, particularly molecular markers that could help assess the illness and develop more personalized treatments for different disorders. Understanding of the neurobiology and potential novel treatments for bipolar disorder (BD), one of the most complex psychiatric illnesses, remains poor. This review aims to compile the most reproducible findings regarding the molecular, genetic, and structural changes that occur in BD. Neuroimaging studies have indicated alterations in neural circuits, disrupted white matter integrity, alterations in reward activation, and decreased gray matter (GM) volume. Genetic studies have identified variations in a number of genes that confer risk for BD development. Studies involving peripheral biomarkers include alterations in the levels of oxidative stress, inflammation, and neurotrophins. These potential molecular markers could be used as tools for diagnosis, to assess illness progression, and to help with the improvement of more specific and personalized treatments for patients with BD. Identification of biologically relevant markers could improve the quality of life of patients with BD and revolutionize public health. Keywords: biomarkers, neuroimaging, neural activation, gene regulation, microRNAs, oxidative stress, inflammation
Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dys- function and by abnormalities of the microvasculature with vascular obliteration, eventually leading to fibrosis of the skin, gastrointestinal tract, lungs, heart, and kidney. The etiology and pathogenesis of SSc remain unclear, despite recent significant progress in the field. Immune activation and microangiopathy are followed by widespread organ fibrosis, leading to organ failure and increased mortality. The production of inflammatory cytokines and growth factors after tissue injury, as well as the presence of circulating autoantibodies, provide a source of bio- markers with potential diagnostic and prognostic applications in the clinical routine. Two prin- cipal approaches exist to discover and characterize biomarkers. The proof-of-concept approach verifies the ability of known proteins, generally involved in the pathogenesis, to correlate with disease phenotype and outcome. A proteomic approach does not need prior knowledge of the proteins or of their function, but it requires high-performance and time-consuming techniques. In this review, we highlight the most recent findings in biomarkers used to characterize SSc organ involvement, to stratify the patients, and to assess the response to treatment.
Although many laboratory methods have been developed to expedite the diagnosis of active tuberculosis (TB) and Mycobacterium tuberculosis (Mtb) infection, delays in diagnosis remain a major problem in clinical practice. Biomarkers may contribute favorably or unfavorably to TB diagnosis in a clinical suspect TB case with inconclusive diagnostic findings. A good understanding of the effectiveness and practical limitations of these biomarkers is important to improve diagnosis. This review summarizes currently used biomarkers, mainly as validation, and focuses on latent TB infection, active pulmonary TB, and tuberculous pleural effusion. Keywords: tuberculosis, biomarker, diagnosis, latent tuberculosis infection, pleural effusion
Idiopathic pulmonary fibrosis (IPF) is a typically fatal disease that remains incompletely understood despite intense study and the arrival of drugs that may alter the natural history of the disease. Rendering an accurate diagnosis and predicting prognosis remain challenging problems to clinicians. One potential solution to these clinical problems is the identification of IPF biomarkers, easily measured factors that can be employed to predict clinical behavior. Candidate biomarkers have been identified by research in the laboratory on potential culprit cells or genes that may contribute to the pathogenesis of IPF. In this review, we present the current data on a number of well-studied IPF biomarker candidates and their potential role in the pathogenesis of disease. We also establish a framework for evaluating utility of incorporating these IPF biomarkers into clinical practice. Keywords: idiopathic pulmonary fibrosis, usual interstitial pneumonia, biomarker, matrix metalloproteinases
Even if early lung cancer detection has been recently significantly improved, the invasive nature of current diagnostic procedures, and a relatively high percentage of false positives, is limiting the application of modern detection tools. The discovery and clinical evaluation of novel specific and robust non-invasive biomarkers for diagnosis of lung cancer at an early stage, as well as for better prognosis and prediction of therapy response, is very challenging. MicroRNAs (miRNAs) can play an important role in the diagnosis and management of lung cancer patients, as important and reliable biomarkers for cancer detection and prognostic prediction, and even as promising as novel targets for cancer therapy. miRNAs are important in cancer pathogenesis, and deregulation of their expression levels has been detected not only in lung cancer but in many other human tumor types. Numerous studies strongly support the potential of miRNAs as biomarkers in non-small-cell lung cancer, and there is increasing evidence that altered miRNA expression is associated with tumor progression and survival. It is worth mentioning also that detection of miRNAs circulating in plasma or serum has enormous potential, because miRNAs serve as non-invasive biomarkers not only for the diagnosis and prognosis of the disease, but also as novel response and sensitivity predictors for cancer treatment. In this review, we summarize the current findings on the critical role of miRNAs in lung cancer tumorigenesis and highlight their potential as circulating biomarkers in lung cancer. Our review is based on papers that have been published after 2011, and includes the key words “miRNAs” and “lung cancer”. Keywords: non-small-cell lung carcinoma, miRNAs, tumor biomarkers, circulating miRNAs, liquid biopsy, exosomes
Malignant pleural mesothelioma (MPM), a highly lethal cancer strictly related to asbestos exposure, is usually characterized by delayed diagnosis, resistance to current therapies, and dismal prognosis. MPM is difficult to distinguish histologically from nonmalignant reactive mesothelial proliferations (RMPs) as there are no clinically validated immunohistochemical markers yet and the main diagnostic criterion remains deep invasion into the pleura and underlying fat tissue, which is often not appreciable in small pleural biopsies. In this regard, microRNAs (miRNAs), given their size and stability, are particularly attractive biomarkers in formalin-fixed paraffin-embedded tissue specimens for routine pathology. Moreover, circulating miRNAs appear to be promising biomarkers for early detection and monitoring of patients with MPM. Here, we review the studies mostly performed by miRNA arrays and reverse transcription-quantitative polymerase chain reaction in formalin-fixed paraffin-embedded or frozen tissue samples, MPM cell lines, and blood/plasma/serum samples that have highlighted the potential of miRNAs as biomarkers in MPM. Certain studies have pointed to the ability of miRNAs to distinguish the different histological MPM subtypes or separate MPM from lung adenocarcinoma, and other investigations have revealed that miRNAs can aid in differentiating MPM from RMP or have prognostic value in predicting the patient outcome. Mechanistic aspects of the involvement of miRNAs in mesothelioma genesis and possible use of miRNAs as future therapeutic targets in MPM are also emphasized. Finally, limitations of the data currently obtained due to the drawbacks of reverse transcription-quantitative polymerase chain reaction, heterogeneity of MPM tissue samples, and differences in methodological platforms as well as in types of specimens utilized in different studies are discussed. Because of these inherent weaknesses of collected data, further studies assessing the expression and distribution of miRNAs by in situ hybridization in combination with the codetection of their respective targets by immunohistochemistry and further validation of miRNAs’ targets in vitro are warranted to fully reveal the potential clinical utility of miRNAs in MPM. Keywords: malignant pleural mesothelioma, miRNAs, cancer biomarkers, diagnosis, prognosis, future therapy
Objective. To evaluate a multi-biomarker disease activity (MBDA) score, a novel index based on 12 serum proteins, as a tool to guide management of RA patients. Methods. A total of 125 patients with RA from the Behandel Strategieën study were studied. Clinical data and serum samples were available from 179 visits, 91 at baseline and 88 at year 1. In each serum sample, 12 biomarkers were measured by quantitative multiplex immunoassays and the concentrations were used as input to a pre-specified algorithm to calculate MBDA scores. Results. MBDA scores had significant correlation with DAS28-ESR (Spearman’s ρ = 0.66, P < 0.0001) and also correlated with simplified disease activity index, clinical disease activity index and HAQ Disability Index (all P < 0.0001). Changes in MBDA between baseline and year 1 were also correlated with changes in DAS28-ESR (ρ = 0.55, P < 0.0001). Groups stratified by European League Against Rheumatism disease activity (DAS28-ESR ≤ 3.2, 3.2–5.1 and > 5.1) had significantly different MBDA scores (P < 0.0001) and MBDA score could discriminate ACR/EULAR Boolean remission with an area under the receiver operating characteristic curve of 0.83 (P < 0.0001). Conclusion: The MBDA score reflects current clinical disease activity and can track changes in disease activity over time.
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 53–59 Current Biomarker Findings Dovepress
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 61–68 Current Biomarker Findings Dovepress
Messenger RNA (mRNA) processing is an essential step for the expression of most eukaryote genes. Ion channels are critical for proper electrical activity in the heart, and perturbations of these channels are known to cause arrhythmia. Recently, mRNA processing defects have been shown to contribute to altered ion channel activity and arrhythmogenesis. Abnormal pre-mRNA splicing of cardiac ion channels, including the cardiac sodium channel, potassium channels, and calcium channels, because of mutations of the cis -elements within the RNA or abnormal expression of splicing factors, has been documented to contribute to arrhythmic risk. In addition to pre-mRNA splicing, other mRNA processing events, such as 3'-end formation and mRNA turnover, are also disrupted in cardiac diseases, such as congenital heart disease caused by mutation at the 3'-untranslated region of GATA4. mRNA stability is also dysregulated by altered expression of microRNAs in atrial fibrillation. In this review, we discuss our current understanding of how mRNA processing defects contribute to the risk of arrhythmias and how monitoring the products of abnormal processing may lead to diagnostic tests for arrhythmic risk. Keywords: messenger RNA, arrhythmia, sudden death, ion channels, biomarkers
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 81–92 Current Biomarker Findings Dovepress
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 93–106 Current Biomarker Findings Dovepress
Serum tumor markers have an important role in the management of patients with testicular cancer. They are useful for diagnosis, staging and risk assessment, follow-up, evaluation of response, and early detection of relapse. Alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase are established serum markers in testicular cancer, but they have a limited sensitivity. Ongoing research may lead to the identification of novel biomarkers. Therefore, we review the experimental analyses for nucleic acids, circulating tumor cells, and proteins as potential biomarkers in the serum of testicular germ cell cancer patients. Keywords: biomarker, serum, testicular germ cell cancer
: Alzheimer’s disease (AD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD) are three major types of neurodegenerative dementia. Intervention and treatment differ significantly among these major dementias, necessitating early and accurate diagnosis. Patients with AD, LBD, and FTLD exhibit specific patterns of visual dysfunction as early behavioral signs. These visual impairments are the manifestations of topographic patterns of neuropathology specific to each type of dementia. Electrophysiological measurements, such as visual evoked potentials and event-related potentials, are objective and noninvasive tools that can detect subtle functional changes in human brain. Therefore, with the use of visual evoked potentials and event-related potentials, early detection of specific patterns of visual dysfunction may be useful for differential diagnosis of dementia. In this review, we first summarize current knowledge about the relevant aspects of the human visual system. Second, we outline clinical characteristics, including visual perceptual abnormalities, of each type of degenerative dementia. Finally, we describe the application of visual evoked potential and event-related potential recording techniques to study visual perception in patients with mild cognitive impairment (prodromal stage of dementia). We stress that electrophysiological signals have potential as reliable biomarkers in the diagnosis of different types of dementia, especially in the case of overlapping phenotypes.
Biological markers of chronic alcoholism can be divided into two groups: direct and indirect markers. Direct markers (mainly blood or serum and urine ethanol, ethylglucuronide, ethyl sulfate, and phosphatidylethanol) directly track the intake of alcohol and vary in their sensitivity and kinetics of appearance and clearance. Indirect markers (mean corpuscular volume,γ-glutamyl transferase, alanine aminotransferase and aspartate aminotransferase, and carbohydrate-deficient transferrin) are biological parameters that are influenced by a steady and significant alcohol intake. We discuss the values of these tests and the relevance of their prescriptions for the clinical evaluation of heavy drinking. We indicate, when known, the pathophysiological mechanism of their elevations. We also discuss the amount and time of alcohol consumption required to give a positive result and the duration of abstinence required for the return to normal values. The forensic use of these biomarkers will not be considered in this review. Keywords: alcoholism, biomarker, CDT, relapse, alcohol-induced liver disease
Polyclonal free light chains: promising new biomarkers in inflammatory disease Judith A Hampson,1 Alice M Turner,1 Robert A Stockley2 1Department of Clinical and Experimental Medicine, University of Birmingham, 2ADAPT (Antitrypsin Deficiency Assessment and Programme for Treatment), Lung Function and Sleep Department, Queen Elizabeth Hospital, Birmingham, UK Abstract: In this review, we explore potential novel roles of polyclonal free light chains (FLCs) as a biomarker of disease processes and predictor of mortality in different patient populations. In recent years, there have been many publications demonstrating raised polyclonal FLCs in several inflammatory and infective diseases. However, the potential utility of FLCs as a clinical biomarker remains an area of debate. We review the current evidence, and establish whether certain key criteria to fulfill the role of a useful biomarker have been satisfied. In addition, we also consider the potential role of FLCs in the pathophysiology of inflammatory disease and address the concepts of FLCs as both a therapeutic target and potential therapeutic agent. Keywords: biomarker, free light chains, autoimmune disease, inflammation
Fibromyalgia is a common syndrome diagnosed by clinical criteria. The main symptom of fibromyalgia is pain, but patients frequently also complain about other nonspecific symptoms, such as headache, sleep disturbance, mood disorder, and cognitive impairment. In the light of the multifactorial origin of the disease and of the lack of objective diagnostic findings, several attempts have been made to find a reliable biomarker. For this reason, over the years, a number of patients and various biological samples have been studied, using many different approaches and techniques. Despite this, none of these studies has been able to find the proper biomarker. The aim of this review is to provide a critical overview of the current environment characterizing the search for fibromyalgia biomarkers. Keywords: genetics, proteomics, oxidative stress, fibromyalgia
