Beyond prostate-specific antigen: new serologic biomarkers for improved diagnosis and management of prostate cancer

The use of total prostate-specific antigen (tPSA) measurement has dramatically improved the ability to detect prostate cancer at earlier stages. However, as the number of men presenting with advanced disease (and high tPSA levels) has decreased, and given the fact that tPSA is highly reflective of benign prostatic hyperplasia, the need has emerged for novel biomarkers specifically associated with prostate cancer in order to improve predictive models. Several new biomarkers have shown promise, and studies continue to investigate the role of these markers in the detection, staging, and prognosis of prostate cancer. As new useful biomarkers continue to emerge, guidelines for their employment, as well as coordination of further research studies, are needed; a systematic, phased, nomogram-based model is a rational way to manage these efforts.     

Insights into predicting diabetic nephropathy using urinary biomarkers

Diabetic nephropathy (DN) is a serious complication of diabetes caused by changes in the structure and function of the kidneys. It is important to detect diagnostic biomarkers of DN at an early stage, in which the drug can slow the loss of kidney function and prevent disease progression. In recent years, a variety of biological markers related to DN have been discovered, which is of great significance for predicting the occurrence and development of diseases. Due to the simplicity of non-invasive collection, urine is an ideal biological sample for the discovery of new biomarkers of kidney disease. We reviewed some new urinary biomarkers related to early DN patients, including urinary proteins, peptides, and exosomes biomarkers. We also highlight the proteins associated with tubular damage, glomerular damage, inflammation and oxidative stress marker. Despite the promise of these new urinary biomarkers, we next proposed a review of the most recent publications reporting on larger cohorts, focusing on those that aim at qualification or validation. This review provides important data to better understand biomarkers related to the pathophysiology of DN, and these markers have been increasingly studied for disease progression to provide effective human treatment.     

Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives

The definition of a biomarker provided by the World Health Organization is any substance, structure, or process that can be measured in the body, or its products and influence, or predict the incidence or outcome of disease. Currently, the lack of prognosis and progression markers for chronic Chagas disease has posed limitations for testing new drugs to treat this neglected disease. Several molecules and techniques to detect biomarkers in Trypanosoma cruzi-infected patients have been proposed to assess whether specific treatment with benznidazole or nifurtimox is effective. Isolated proteins or protein groups from different T. cruzi stages and parasite-derived glycoproteins and synthetic neoglycoconjugates have been demonstrated to be useful for this purpose, as have nucleic acid amplification techniques. The amplification of T. cruzi DNA using the real-time polymerase chain reaction method is the leading test for assessing responses to treatment in a short period of time. Biochemical biomarkers have been tested early after specific treatment. Cytokines and surface markers represent promising molecules for the characterisation of host cellular responses, but need to be further assessed.     

Biomarkers for prostate cancer

The detection of prostate cancer using a blood test has by many standards changed the face of the disease. Despite this tremendous success, there are limitations attributed to the use of prostate specific antigen (PSA) as a means to screen and detect prostate cancer. PSA, as its name implies, is not specific for prostate cancer and as such is often found elevated in other prostatic diseases/symptoms associated with the aging male. Clearly, more specific marker(s) that could identify which individuals actually have prostate cancer and differentiate them from those without the disease would be of tremendous value. The search for more accurate and clinically useful biomarkers of prostate cancer has been extensive. This has focused on individual markers, as well as groups of markers. Included among these are PSA isoforms, pathological indicators and stains, nucleic acids and others. This article highlights the discovery of PSA as a first blood‐based biomarker for prostate cancer detection, as well as other molecular biomarkers and their potential application in detection of the disease. J. Cell. Biochem. 108: 3–9, 2009. © 2009 Wiley‐Liss, Inc.     

Advances in ovarian cancer proteomics: the quest for biomarkers and improved therapeutic interventions

Epithelial ovarian cancer is the leading cause of cancer-related death among gynecological cancers due to the asymptomatic nature of the disease, a lack of early detection markers and the development of resistance to current chemotherapeutic agents. Currently available tests (CA-125, transvaginal ultrasound or combination of both) lack the sensitivity and specificity to be useful as an efficient screening tool for surveillance of the general population. Thus, there is an urgent need for the development and validation of new molecular markers that would be both specific and sensitive indicators of disease onset, as well as progression. Proteomic profiling has emerged as a powerful tool to study ovarian cancer in an unbiased way at the molecular level, to monitor the effects of given treatment options and for the discovery of biomarkers. In this review we discuss the challenges associated with proteomics-based biomarker discovery and some recent concepts to potentially overcome these hurdles. Recent proteomics work on ovarian cancer cells and tissues will be discussed in light of obtaining new insights into fundamental biological processes, as well as their potential integration with ongoing biomarker discovery pipelines.     

Advances in ovarian cancer proteomics: the quest for biomarkers and improved therapeutic interventions

Epithelial ovarian cancer is the leading cause of cancer-related death among gynecological cancers due to the asymptomatic nature of the disease, a lack of early detection markers and the development of resistance to current chemotherapeutic agents. Currently available tests (CA-125, transvaginal ultrasound or combination of both) lack the sensitivity and specificity to be useful as an efficient screening tool for surveillance of the general population. Thus, there is an urgent need for the development and validation of new molecular markers that would be both specific and sensitive indicators of disease onset, as well as progression. Proteomic profiling has emerged as a powerful tool to study ovarian cancer in an unbiased way at the molecular level, to monitor the effects of given treatment options and for the discovery of biomarkers. In this review we discuss the challenges associated with proteomics-based biomarker discovery and some recent concepts to potentially overcome these hurdles. Recent proteomics work on ovarian cancer cells and tissues will be discussed in light of obtaining new insights into fundamental biological processes, as well as their potential integration with ongoing biomarker discovery pipelines.     

Methodological advances in the discovery of protein and peptide disease markers

The quest for biomarkers has seen a renaissance due to the application of newly developed separation methodologies and advances in biomolecular mass spectrometry. It can be argued that each disease influences the physiology of an organism and that these changes should be measurable. Many diagnostic and therapeutic decisions are supported by measurable biochemical or cellular changes in plasma, serum or urine but it is unquestionable that there is a great lack in better markers for early disease detection and prevention. In this review we cover recent developments in the areas of separation science, sample preparation and mass spectrometry as applied to biomarker discovery. We focus, in particular, on the use of LC-MS and SELDI-TOF-MS as two approaches that have seen an upswing in recent years. While validation of newly discovered biomarkers or biomarker patterns and their introduction into diagnostic practice will be a long process, it is our believe that many future diagnostic tests will be based on markers discovered through novel profiling technologies as those outlined in this article.     

A Meta Analysis of Pancreatic Microarray Datasets Yields New Targets as Cancer Genes and Biomarkers

The lack of specific symptoms at early tumor stages, together with a high biological aggressiveness of the tumor contribute to the high mortality rate for pancreatic cancer (PC), which has a five year survival rate of less than 5%. Improved screening for earlier diagnosis, through the detection of diagnostic and prognostic biomarkers provides the best hope of increasing the rate of curatively resectable carcinomas. Though many serum markers have been reported to be elevated in patients with PC, so far, most of these markers have not been implemented into clinical routine due to low sensitivity or specificity. In this study, we have identified genes that are significantly upregulated in PC, through a meta-analysis of large number of microarray datasets. We demonstrate that the biological functions ascribed to these genes are clearly associated with PC and metastasis, and that that these genes exhibit a strong link to pathways involved with inflammation and the immune response. This investigation has yielded new targets for cancer genes, and potential biomarkers for pancreatic cancer. The candidate list of cancer genes includes protein kinase genes, new members of gene families currently associated with PC, as well as genes not previously linked to PC. In this study, we are also able to move towards developing a signature for hypomethylated genes, which could be useful for early detection of PC. We also show that the significantly upregulated 800+ genes in our analysis can serve as an enriched pool for tissue and serum protein biomarkers in pancreatic cancer.     

Host biomarkers detected in saliva show promise as markers for the diagnosis of pulmonary tuberculosis disease and monitoring of the response to tuberculosis treatment

BackgroundThere is an urgent need for new tools for the rapid diagnosis of tuberculosis (TB) disease in resource-constrained settings. Tests based on host immunological biomarkers maybe useful, especially if based on easily available samples. We investigated host biomarkers detected in saliva samples from individuals with suspected pulmonary TB disease, as tools for the diagnosis of TB disease and monitoring of the response to treatment.MethodsWe collected saliva samples from 104 individuals that presented with symptoms requiring investigation for TB disease at a primary health care clinic in the outskirts of Cape Town, South Africa, prior to assessment for TB disease. We evaluated the concentrations of 33 host markers in stored saliva samples using a multiplex cytokine platform. Using a combination of clinical, radiological and laboratory results and a pre-established diagnostic algorithm, participants were later classified as having TB disease or other respiratory diseases (ORD). The diagnostic potentials of individual analytes were analysed by the receiver operator characteristics curve approach while the predictive abilities of combinations of analytes for TB disease were analysed by general discriminant analysis, with leave-one-out cross validation.ResultsOf the 104 individuals enrolled, 32 were pulmonary TB cases. There were significant differences in the levels of 10 of the markers investigated between the patients with TB disease and those with ORDs. However, the optimal diagnostic biosignature was a seven-marker combination of salivary CRP, ferritin, serum amyloid P, MCP-1, alpha-2-macroglobulin, fibrinogen and tissue plasminogen activator. This biosignature diagnosed TB disease with a sensitivity of 78.1% (95% CI, 59.6–90.1%) and specificity of 83.3% (95% CI, 72.3–90.7%) after leave-one-out cross validation. When compared to baseline levels, the concentrations of 9 markers including granzyme A, MCP-1, IL-1β, IL-9, IL-10, IL-15, MIP-1β, ferritin and serum amyloid A changed significantly by months 2 or 6 after initiation of TB treatment, thereby indicating that they might be useful in monitoring the response to TB treatment.ConclusionWe have identified candidate biomarkers in saliva, which may be useful in the diagnosis of TB disease and monitoring of the response to TB treatment. These results require further validation in larger studies.     

Application of proteomics in non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease with diverse pathological features. Clinical proteomics allows the discovery of molecular markers and new therapeutic targets for this most prevalent type of lung cancer. Some of them may be used to detect early lung cancer, while others may serve as predictive markers of resistance to different therapies. Therapeutic targets and prognostic markers in NSCLC have also been discovered. These proteomics biomarkers may help to pair the individual NSCLC patient with the best treatment option. Despite the fact that implementation of these biomarkers in the clinic appears to be scarce, the recently launched Precision Medicine Initiative may encourage their translation into clinical practice.     

Soluble IL-18 receptor complex: a new star in the firmament of rheumatoid arthritis diagnosis?

It has long been recognized that laboratory tests are useful in the diagnosis of disease and to monitor treatment outcome. Their performance has become even more demanding with the development of personalized medicine. In patients with rheumatoid arthritis (RA) the standard biochemical tests measure serological markers of disease, such as C-reactive protein, and RA-associated auto-antibodies, such as rheumatoid factor and anti-citrullinated protein antibodies. The information obtained from these markers does not, however, provide a complete picture of the disease and treatment efficacy. New biomarkers based on cytokine receptor complexes are promising for RA theragnostics.     

Functional relationship and gene ontology classification of breast cancer biomarkers

Breast cancer is a complex disease that still imposes a significant healthcare burden on women worldwide. The etiology of breast cancer is not known but significant advances have been made in the area of early detection and treatment. The advent of advanced molecular biology techniques, mapping of the human genome and availability of high throughput genomic and proteomic strategies opens up new opportunities and will potentially lead to the discovery of novel biomarkers for early detection and prognostication of breast cancer. Currently, many biomarkers, particularly the hormonal and epidermal growth factor receptors, are being utilized for breast cancer prognosis. Unfortunately, none of the biomarkers in use have sufficient diagnostic, prognostic and/or predictive power across all categories and stages of breast cancer. It is recognized that more useful information can be generated if tumors are interrogated with multiple markers. But choosing the right combination of biomarkers is challenging, because 1) multiple pathways are involved, 2) up to 62 genes and their protein products are potentially involved in breast cancer-related mechanisms and 3) the more markers evaluated, the more the time and cost involved. This review summarizes the current literature on selected biomarkers for breast cancer, discusses the functional relationships, and groups the selected genes based on a Gene Ontology classification.     

Looking for Thom's biomarkers with proteomics

In recent years, large numbers of putative disease biomarkers have been identified. Combinations of protein biomarkers have been proposed to overcome the lack of single, magic-bullet identifiers of disease conditions. The number of biomarkers in a panel must be kept small to avoid the combinatorial explosion that requires very large, uneconomical sample cohorts for validation. Recent results on high sensitivity blood-based diagnostic proteomics (Godovac-Zimmermann, J et al., J. Proteome Res. 2006) suggest that the keys to identifying useful panels include judicious application of physiological knowledge to choose appropriate combinations of local, tissue/disease markers and global, systemic markers and to use very high sensitivity protein detection. Biomarkers that show non-Gaussian landscapes reminiscent of Rene Thom's multiple, stable-state landscapes seem to have the greatest predictive value for breast cancer (Godovac-Zimmermann, J. et al., J. Proteome Res. 2006).     

Biosensors for cancer markers diagnosis

Point-of-care diagnostic devices present a viable option for the rapid and sensitive detection and analysis of cancer markers. With the growing number of cancer cases being diagnosed worldwide and the increased number of fatalities due to late disease detection, biosensors can play an important role in the early diagnosis of cancer. Molecular profiles of patients are being increasingly studied using new molecular tools such as genomic and proteomic techniques. These methods combined with bioinformatics tools are generating new data which is being employed in the elucidation of new disease biomarkers. As with many disease conditions finding specific and sensitive markers that are associated with only one type of the disease can be difficult. In addition to this, the level of the biomarkers in biological fluids can vary depending on different disease conditions and stages. A number of molecular markers are therefore usually evaluated for cancer diagnosis and these can include proteins, peptides, over/under expression of gene markers and gene mutations. This review provides an overview of the biosensor technology available today, areas which are currently being developed and researched for cancer markers diagnosis—and a consideration of future prospects for the technology.     

Biomarkers for atherosclerosis: pathophysiological role and pharmacological modulation

PURPOSE OF REVIEW: The aim of this article is to discuss the potential value of biomarkers for atherosclerosis in the assessment of risk for cardiovascular disease, in the pathogenesis of atherosclerosis, and in the monitoring of pharmacological treatment. RECENT FINDINGS: In an attempt to improve global cardiovascular risk prediction, considerable effort has been made in the discovery and characterization of soluble biomarkers which can go beyond the measure of total and LDL cholesterol levels. In particular, circulating molecules related to chronic inflammation have emerged as potential biomarkers for atherosclerosis. Evidence, obtained from in-vitro and in-vivo experimental models, has also documented that the majority of biomarkers play a pathological role in atherogenesis. Multiple screening of different biomarkers may therefore improve the assessment of risk, diagnosis, and prognosis for cardiovascular disease. In addition, soluble biomarkers have been shown to be modulated by hypolipidemic drugs and to be potentially useful in determining the clinical benefits of pharmacological therapies that do not alter serum lipid levels. SUMMARY: Altered levels of soluble biomarkers are associated with cardiovascular disease, and profiling of multiple biomarkers for atherosclerosis will be a useful indicator for better risk assessment, diagnosis, and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.     

Biomarkers for susceptibility to infection and disease severity in human malaria

Malaria remains a major infectious disease that affects millions of people. Once infected with Plasmodium parasites, a host can develop a broad range of clinical presentations, which result from complex interactions between factors derived from the host, the parasite and the environment. Intense research has focused on the identification of reliable predictors for exposure, susceptibility to infection and the development of severe complications during malaria. Although most promising markers are based on the current understanding of malaria immunopathogenesis, some are also focused more broadly on mechanisms of tissue damage and inflammation. Taken together, these markers can help optimise therapeutic strategies and reduce disease burden. Here, we review the recent advances in the identification of malarial biomarkers, focusing on those related to parasite exposure and disease susceptibility. We also discuss priorities for research in biomarkers for severe malaria.     

Biomarkers of intake for coffee,tea, and sweetened beverages

Non-alcoholic beverages are important sources of nutrients and bioactive compounds that may influence human health and increase or decrease the risk of chronic diseases. A wide variety of beverage constituents are absorbed in the gut, found in the systemic circulation and excreted in urine. They may be used as compliance markers in intervention studies or as biomarkers of intake to improve measurements of beverage consumption in cohort studies and reveal new associations with disease outcomes that may have been overlooked when using dietary questionnaires. Here, biomarkers of intake of some major non-alcoholic beverages—coffee, tea, sugar-sweetened beverages, and low-calorie-sweetened beverages—are reviewed. Results from dietary intervention studies and observational studies are reviewed and analyzed, and respective strengths and weaknesses of the various identified biomarkers discussed. A variety of compounds derived from phenolic acids, alkaloids, and terpenes were shown to be associated with coffee intake and trigonelline and cyclo(isoleucylprolyl) showed a particularly high specificity for coffee intake. Epigallocatechin and 4′-O-methylepigallocatechin appear to be the most sensitive and specific biomarkers for green or black tea, while 4-O-methylgallic acid may be used to assess black tea consumption. Intake of sugar-sweetened beverages has been assessed through the measurement of carbon-13 enrichment of whole blood or of blood alanine in North America where sugar from sugarcane or corn is used as a main ingredient. The most useful biomarkers for low-calorie-sweetened beverages are the low-calorie sweeteners themselves. Further studies are needed to validate these biomarkers in larger and independent populations and to further evaluate their specificity, reproducibility over time, and fields of application.     

Compositional and genetic alterations in Graves’ disease gut microbiome reveal specific diagnostic biomarkers

Graves’ Disease is the most common organ-specific autoimmune disease and has been linked in small pilot studies to taxonomic markers within the gut microbiome. Important limitations of this work include small sample sizes and low-resolution taxonomic markers. Accordingly, we studied 162 gut microbiomes of mild and severe Graves’ disease (GD) patients and healthy controls. Taxonomic and functional analyses based on metagenome-assembled genomes (MAGs) and MAG-annotated genes, together with predicted metabolic functions and metabolite profiles, revealed a well-defined network of MAGs, genes and clinical indexes separating healthy from GD subjects. A supervised classification model identified a combination of biomarkers including microbial species, MAGs, genes and SNPs, with predictive power superior to models from any single biomarker type (AUC = 0.98). Global, cross-disease multi-cohort analysis of gut microbiomes revealed high specificity of these GD biomarkers, notably discriminating against Parkinson’s Disease, and suggesting that non-invasive stool-based diagnostics will be useful for these diseases.Subject terms: Microbiome, Biomarkers, Population genetics