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PubMed1996

Human biomonitoring: research goals and needs.

Epidemiological studies have taken advantage of a number of strategies to monitor human populations for mortality, incidence, and exposure to hazardous environmental agents. These studies have been compromised by the lack of individual exposure assessment data that precisely quantified internal dose. As methods improve in analytical chemistry and molecular biology, direct biological monitoring of exposed populations is possible. Biomarkers have been developed and validated in exposed populations that quantify individual exposure, susceptibility, and early markers of health effects and can be used to study relationships between exposures and environmentally induced diseases. This paper provides background on the state of the art of human populations monitoring and, through a series of case studies, provides examples of novel biomarkers of exposure, susceptibility, and effect that highlight new opportunities for biomonitoring. Prevention of human disease due to environmental contaminants can be accomplished by implementing strategies such as those discussed to monitor exposure and early health effects in human populations.

Air Pollutants↗

PubMed2005

Proteomic analysis of sera from hepatocellular carcinoma patients after radiofrequency ablation treatment.

Comparative proteomic analysis was used to search for characteristic alterations in the sera of hepatocellular carcinoma (HCC) patients who had undergone curative radiofrequency ablation treatment. Serum samples collected from eight patients before and after treatment were subjected to 2-DE. Eighty-eight protein spots differentially expressed with the treatment were selected by clustering analysis, and the proteins were identified by MS based on MALDI-TOF/TOF analysis and public database searches. The statistical analysis suggested that four proteins decreased after treatment (pro-apolipoprotein, alpha2-HS glycoprotein, apolipoprotein A-IV precursor, and PRO1708/PRO2044, which is the carboxy terminal fragment of albumin) and that seven proteins were increased after treatment, including leucine-rich alpha2-glycoprotein and alpha1-antitrypsin. These data facilitate the identification of differentially expressed proteins that are involved in HCC carcinogenesis and provide candidate biomarkers for the development of diagnostic and therapeutic tools.

Apolipoproteins A↗

PubMed2003

Early biomarkers of stroke.

BACKGROUND: The diagnosis and management of acute ischemic stroke are limited by the lack of rapid diagnostic assays for use in an emergency setting. Computed tomography (CT) scanning is used to diagnose hemorrhagic stroke but is relatively ineffective (<33% sensitive) in detecting ischemic stroke. The ability to correlate blood-borne protein biomarkers with stroke phenotypes would aid in the development of such rapid tests. METHODS: ELISAs for >50 protein biomarkers were developed for use on a high-throughput robotic workstation. These assays were used to screen plasma samples from 214 healthy donors and 223 patients diagnosed with stroke, including 82 patients diagnosed with acute ischemic stroke. Marker assay values were first compared by univariate analysis, and then the top markers were subjected to multivariate analysis to derive a marker panel algorithm for the prediction of stroke. RESULTS: The top markers from this analysis were S-100b (a marker of astrocytic activation), B-type neurotrophic growth factor, von Willebrand factor, matrix metalloproteinase-9, and monocyte chemotactic protein-1. In a panel algorithm in which three or more marker values above their respective cutoffs were scored as positive, these five markers provided a sensitivity of 92% at 93% specificity for ischemic stroke samples taken within 6 h from symptom onset. CONCLUSION: A marker panel approach to the diagnosis of stroke may provide a useful adjunct to CT scanning in the emergency setting.

Acute Disease↗

PubMed2025

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

Humans↗

PubMed2006

Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis.

Blood-brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS). It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS). The presence of gadolinium enhancing (Gd+) lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1) improve the monitoring of disease activity; 2) improve the monitoring of response to MS therapies which target BBB disruption; and 3) advance our understanding of dynamic MS processes participating in BBB disruption.

Biomarkers↗

PubMed1996

Inhibitor sensitivity of respiratory complex I in human platelets: a possible biomarker of ageing.

NADH-Coenzyme Q reductase was assayed in platelet mitochondrial membranes obtained from 19 pools of two venous blood samples from female young (19-30 years) individuals and 18 pools from aged ones (66-107 years). The enzyme activities were not significantly changed in the two groups, but a decrease of sensitivity to the specific inhibitor, rotenone, occurred in a substantial number of aged individuals. The results are in agreement with the predictions of the mitochondrial theory of ageing and may be used to develop a sensitive biomarker of the ageing process.

Adult↗

PubMed2026

Using cancer profiles to identify synthetic lethal therapeutic targets and predictive biomarkers in cancer gene dependency data.

MOTIVATION: Large scale loss-of-function screens utilising CRISPR or siRNA can provide profound insights into the importance of individual genes for the survival of a cancer cell and can drive the identification of therapeutic targets and biomarkers, and the development of targeted drugs. However, the analysis of these data and the substantial bodies of metadata that relate to them, is technically challenging and typically requires substantial expertise in data science and computer coding. RESULTS: To facilitate the analysis of cancer gene dependency data by cancer biologists and clinical scientists, we have developed DepMine-a computational toolkit providing a powerful system for framing complex queries relating cancer gene dependency to the underlying genetic changes that occur in cancer cells. DepMine identifies synthetic lethal relationships between putative target genes and complex 'cancer profiles' built from user-specified combinations of mutations, copy-number variation, and expression levels, and can refine these to optimal biomarker definitions for target dependency. AVAILABILITY: The Python implementation of DepMine and associated data files can be obtained at https://github.com/UOSbioinformaticslab/depmine and is free to academics and Not-For-Profit organisations. The DepMine release referenced in this paper is archived as DOI: 10.5281/zenodo.19570601.

Humans↗

PubMed1991

Immunochemical techniques in biological monitoring.

Immunoassays are analytical methods that detect interactions between antibodies and antigens. Immunoassays were used originally to detect large biological molecules. The new generation of these antibody-based assays can detect small synthetic compounds. As a result, immunoassays are being developed specifically for biomarkers of exposure and effect to environmentally prevalent chemicals. Immunochemical detection of parent compounds in blood and tissues, metabolites in excreta, and adducts with DNA and protein have been successfully performed by several investigators. Although there is great potential for use of immunoassays in biological monitoring studies, the limitations of these analyses must be fully understood to prevent improper evaluation of the acquired data. This review will cover some of the background material necessary to understand how an antibody-based assay is developed. The differences between polyclonal and monoclonal antibody-based assays and the importance of antibody class, affinity, specificity, and cross-reactivity must be considered in both study design and data analysis.

Antibodies↗

PubMed1997

Developing a marker of exposure to xenoestrogen mixtures in human serum.

It has been hypothesized that environmental estrogens may play a role in the increasing incidence of breast cancer, testicular cancer, and other problems of the reproductive system. While a single causal agent can be identified in cases in which humans have had occupational exposures, wildlife showing signs of reproductive damage have usually been exposed to a combination of endocrine disruptors that may act cumulatively. The development of appropriate biomarkers of cumulative exposure, and their measurement at developmental points where exposure is critical, are required to test the environmental estrogen hypothesis. Measuring levels of each of the xenoestrogens in blood is a better approximation of real exposure at the target organ level than inferring cumulative exposure by estimating from mass balance of dietary levels. However, the cumulative estrogenicity of mixtures cannot be directly concluded from individual xenoestrogen plasma levels. Two approaches may be used to assess total load: a) the development of methods to study mixtures of these xenoestrogens, to quantify their cumulative effects, and to begin to understand their interactions (i.e., additivity, synergy, antagonism, or independent action), so that plasma concentrations may be translated into units of activity such as "estradiol equivalents"; and b) the development of methods to separate xenoestrogens from ovarian estrogens in blood and to directly measure the estrogenic activity of the xenoestrogen extract using a bioassay. The cumulative activity may be used as a marker of exposure to xenoestrogens. This article reports the development of a method to extract and separate xenoestrogens from ovarian estrogens using human serum as a source, followed by using a bioassay for determination of the cumulative xenoestrogen load as "estradiol equivalents."

Biological Assay↗

PubMed2005

Vanadium inhibits the development of 2-acetylaminofluorene-induced premalignant phenotype in a two-stage chemical rat hepatocarcinogenesis model.

In recent years, research on the biological influence of micronutrients in cancer has grown enormously. Among these, vanadium, a dietary micronutrient present in mammalian tissues has received considerable attention as a limiting agent. In the present study, attempts have been made to investigate the in vivo antitumour potentials of this micronutrient at the 0.5 ppm dosage in drinking water in a defined model of a two-stage experimental rat hepatocarcinogenesis. The chemopreventive effect of vanadium was assessed by studying certain biomarkers, such as development of gamma-glutamyltranspeptidase (GGT)-positive foci, levels of some essential trace elements, in situ expression of proliferating cell nuclear antigen (PCNA) and chromosomal aberrations. Hepatocarcinogenesis was induced in male Sprague-Dawley rats by chronic feeding of 2-acetylaminofluorene (0.05% in basal diet) on and from week 4. Vanadium administration throughout the experiment reduced the relative liver weight, nodular incidence (66.70%), total number and multiplicity (79.93%) and restored hepatic levels of selenium (Se) and iron (Fe) (P < 0.001) when compared to the carcinogen control. Moreover, long-term vanadium treatment significantly abated the expressions of GGT (P < 0.001) and PCNA with concomitant reduction in PCNA immunolabeling index (P < 0.001; 36.62%). Finally, the anticlastogenic potential of vanadium was reflected through its ability to inhibit early chromosomal aberrations (P < 0.001; 45.17%) in 2-AAF-challenged rat hepatocytes. Our results suggest that supplementary vanadium at a dose of 0.5 ppm, when administered continuously throughout the study, than administered either in the initiation or promotion phase alone, is very much effective in suppressing neoplastic transformation in vivo. We conclude the significant role of vanadium in limiting cell proliferation and chromosomal aberrations during the preneoplastic stages of hepatocarcinogenesis in rats.

2-Acetylaminofluorene↗

PubMed2005

Stress and active oxygen species--effect of alpha-tocopherol on stress response.

Stress is implicated in the pathogenesis of numerous disorders such as cardiovascular diseases or neurodegeneration. The extensive overlap between diseases attributed to stress and oxidative damage is indicative of their potential relationship. We hereby study the influence of alpha-tocopherol (alpha-toc) on the development of stress biomarkers (morphological and biochemical), on specific biomarkers of radical insult (lipid peroxidation, oxidized proteins, or glutathione content in brain and liver), as well as on drug metabolism. In our experimental protocol two groups of female rats are exposed to stress conditions, i.e. cold plus starvation. Before stress and during its application one group is treated with alpha-toc for 20 d (0.42 mmol/kg per os, once daily). Our results indicate that oxidative damage accompanies the development of stress, while treatment with alpha-toc completely prevents stress-induced radical attack and reduces stress indices like plasma corticosterone, uropepsinogen, and morphological changes. It is found that stress increases the drug metabolic potential of the liver (total P450, CYP2E1, or CYP3A1 activity). Administration of alpha-toc, in combination with stress, further increases erythro mycin N-demethylation (CYP3A1) compared to stress control, while 4-nitrophenol hydroxylation (CYP2E1) is not affected significantly.

Administration, Oral↗

PubMed1999

Proteinchip(R) surface enhanced laser desorption/ionization (SELDI) mass spectrometry: a novel protein biochip technology for detection of prostate cancer biomarkers in complex protein mixtures.

Improving early detection, diagnosis, treatment monitoring and prognosis of cancer will require rapid and high throughput detection, identification, and measurement of multiple biomarkers. In this study, we demonstrate the versatility of the innovative SELDI ProteinChip(R) MS technology for the rapid, reproducible and simultaneous identification of four well-characterized prostate cancer-associated (PCA) biomarkers, prostate specific antigen (free and complexed forms), prostate specific peptide, prostate acid phophatase and prostate specific membrane antigen in cell lysates, serum and seminal plasma. Proteins corresponding to the mass of these biomarkers could readily be captured and detected using either chemically defined or antibody coated ProteinChip(R) arrays. Several (yet to be identified) proteins were found upregulated in cell lysates of pure populations of PCA cells procured by laser capture microdissection (LCM) when compared with mass spectra of normal cell lysates. Coupling LCM with SELDI provides tremendous opportunities to discover and identify the signature proteins associated with each stage of tumor development. Collectively, these observations demonstrate the potential of SELDI for the discovery and simultaneous detection of and clinical assay development for PCA biomarkers in complex biological mixtures.

Journal Article↗

PubMed2006

Dependence network modeling for biomarker identification.

MOTIVATION: Our purpose is to develop a statistical modeling approach for cancer biomarker discovery and provide new insights into early cancer detection. We propose the concept of dependence network, apply it for identifying cancer biomarkers, and study the difference between the protein or gene samples from cancer and non-cancer subjects based on mass-spectrometry (MS) and microarray data. RESULTS: Three MS and two gene microarray datasets are studied. Clear differences are observed in the dependence networks for cancer and non-cancer samples. Protein/gene features are examined three at one time through an exhaustive search. Dependence networks are constructed by binding triples identified by the eigenvalue pattern of the dependence model, and are further compared to identify cancer biomarkers. Such dependence-network-based biomarkers show much greater consistency under 10-fold cross-validation than the classification-performance-based biomarkers. Furthermore, the biological relevance of the dependence-network-based biomarkers using microarray data is discussed. The proposed scheme is shown promising for cancer diagnosis and prediction. AVAILABILITY: See supplements: http://dsplab.eng.umd.edu/~genomics/dependencenetwork/

Algorithms↗

PubMed2006

Protein expression profiling of the shrimp cellular response to white spot syndrome virus infection.

To better understand the pathogenesis of white spot syndrome virus (WSSV) and to determine which cell pathways might be affected after WSSV infection, two-dimensional gel electrophoresis (2-DE) was used to produce protein expression profiles from samples taken at 48 h post-infection (hpi) from the stomachs of Litopenaeus vannamei (also called Penaeus vannamei) that were either specific pathogen free or else infected with WSSV. Seventy-five protein spots that consistently showed either a marked change (>50%) in accumulated levels or else were highly expressed throughout the course of WSSV infection were selected for further study. After in-gel trypsin digestion followed by LC-nanoESI-MS/MS, bioinformatics databases were searched for matches. A total of 53 proteins were identified, with functions that included energy production, calcium homeostasis, nucleic acid synthesis, signaling/communication, oxygen carrier/transportation, and SUMO-related modification. 2-DE results were shown to be consistent with relative EST database data from a previously developed EST database of two Penaeus monodon cDNA libraries. For seven selected genes, 2-DE and EST data were also compared with transcriptional time-course RT-PCR data. This study is the first global analysis of differentially expressed proteins in WSSV-infected shrimp, and in addition to increasing our understanding of the molecular pathogenesis of this virus-associated shrimp disease, the results presented here should be useful both for identifying potential biomarkers and for developing antiviral measures.

Animals↗

PubMedDate not supplied

Serum biomarkers for heart failure.

The incidence of heart failure has been steadily increasing over the past several decades. High readmission rates in patients with acute decompensated heart failure led to the search for biomarkers that could predict future clinical course and would, in an ideal case, enable monitoring of patients with heart failure and guidance of their therapy. From among several promising markers, the B-type natriuretic peptide and the biologically inactive N-terminal portion of its pro-hormone, NT-proBNP, have become the most frequently used analytes. Other known markers, such as atrial natriuretic peptide and endothelin-1, are currently used for research purposes. The development of additional biomarkers will be an important step from improving diagnosis and treatment of patients with chronic and acute decompensated heart failure.

Amino Acid Sequence↗

PubMed2004

Research issues and strategies for genomic and proteomic biomarker discovery and validation: a statistical perspective.

The development and validation of clinically useful biomarkers from high-dimensional genomic and proteomic information pose great research challenges. Present bottlenecks include: that few of the biomarkers showing promise in initial discovery were found to warrant subsequent validation; and biomarker validation is expensive and time consuming. Biomarker evaluation should proceed in an orderly fashion to enhance rigor and efficiency. A molecular profiling approach, although promising, has a high chance of yielding biased results and overfitted models. Specimens from cohorts or intervention trials are essential to eliminate biases. The high cost for biomarker validation motivates some novel study design features, including sequential filtering and DNA pooling. For data analysis, logistic regression (in particular, boosting logistic regression) has features of robustness against model misspecification, and has resistance to model overfitting. Model assessment and cross-validation are critical components of data analysis. Having an independent test set is a vital feature of study design.

Biomarkers, Tumor↗

PubMed2001

Altered gene expression profile in chemically induced rat mammary adenocarcinomas and its modulation by an aromatase inhibitor.

In the present study, competitive cDNA library screening (CCLS) and cDNA microarray analyses were employed to identify differentially expressed genes in methylnitrosourea-induced rat mammary adenocarcinomas. The preliminary screening of 100 000 plaques by CCLS identified 1217 clones with differential expression. Dot-blot analysis of the isolated clones verified differential expression in 471 distinct genes. Confirmation of these 471 genes was conducted by performing reverse transcription-polymerase chain reactions, and a total of 160 genes were confirmed after comparing six rat mammary adenocarcinomas and three normal rat mammary glands. Fifty-nine of these showed lower expression in the adenocarcinomas while the remaining 101 were overexpressed in the tumors. Employing a cDNA microarray containing 588 known genes revealed an additional 33 differentially expressed genes in these tumors. Importantly, most of the identified genes demonstrated relatively reproducible overexpression or underexpression in individual tumors. Many of the altered genes determined by cDNA microarray analysis were oncogenes, tumor suppressor genes, or genes involved in cell cycle control and apoptosis. CCLS identified many others not previously associated with mammary carcinogenesis, including a novel gene named RMT-7. Preliminary studies to determine the applicability of this gene expression approach for detecting potential biomarkers for cancer chemoprevention was evaluated in rat mammary tumors obtained from animals treated with vorozole, a potent aromatase inhibitor. When genes exhibiting differential expression as determined by CCLS or cDNA microarray analysis were examined in control and vorozole-treated tumors, expression of 19 genes was found to be modulated significantly in tumors treated with vorozole. Further investigations into these identified genes should contribute significantly to our understanding of the molecular mechanisms of rat mammary tumorigenesis. In addition, the identified genes may become useful targets for drug development and potential biomarkers for monitoring treatment and prevention of breast cancer in humans.

Adenocarcinoma↗

PubMed2002

Biomarkers, yesterday, today and tomorrow: the basis for health claims.

The development of useful and accurate biomarkers for predicting outcomes of food based interventions is becoming more and more important, given the emphasis being placed on ingredients in foods contributing to disease risk reduction and optimal health promotion. With the human genome now laid bare, opportunities abound to barcode individuals with their risk profiles. The massive increase in DNA sequence information together with the development of new technologies such as genomics, proteomics and bioinformatics, has resulted in a much greater capacity to determine individual risk profiles. Screening for biomarkers at the gene or protein expression level using microarray technology has the potential to identify new biomarkers for disease diagnosis. Whether these techniques will enable a better understanding of food-gene interactions to permit health claims rather than better therapeutic treatment (at high economic cost) remains to be demonstrated.

Biomarkers↗