A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Luminally expressed gastrointestinal biomarkers

Introduction: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility

Blood Cytokines as Biomarkers of In Vivo Toxicity in Preclinical Safety Assessment: Considerations for Their Use

In the drive to develop drugs with well-characterized and clinically monitorable safety profiles, there is incentive to expand the repertoire of safety biomarkers for toxicities without routine markers or premonitory detection. Biomarkers in blood are pursued because of specimen accessibility, opportunity for serial monitoring, quantitative measurement, and the availability of assay platforms. Cytokines, chemokines, and growth factors (here referred to collectively as cytokines) show robust modulation in proximal events of inflammation, immune response, and repair. These are key general processes in many toxicities; therefore, cytokines are commonly identified during biomarker discovery studies. In addition, multiplexed cytokine immunoassays are easily applied to biomarker discovery and routine toxicity studies to measure blood cytokines. However, cytokines pose several challenges as safety biomarkers because of a short serum half-life; low to undetectable baseline levels; lack of tissue-specific or toxicity-specific expression; complexities related to cytokine expression with multiorgan involvement; and species, strain, and interindividual differences. Additional challenges to their application are caused by analytical, methodological, and study design–related variables. A final consideration is the strength of the relationship between changes in cytokine levels and the development of phenotypic or functional manifestations of toxicity. These factors should inform the integrated judgment-based qualification of novel biomarkers in preclinical, and potentially clinical, risk assessment. The dearth of robust, predictive cytokine biomarkers for specific toxicities is an indication of the significant complexity of these challenges. This review will consider the current state of the science and recommendations for appropriate application of cytokines in preclinical safety assessment

High serum Aspartate Transaminase (AST) levels on day 3 post liver transplantation correlates with graft and patient survival and would be a valid surrogate for outcome in liver transplantation clinical trials

Aspartate transaminase, a liver specific enzyme released into serum following acute liver injury is used in experimental organ preservation studies as a measure of liver IR injury. Whether post-operative serum transaminases are a good indicator of IR injury and subsequent graft and patient survival in human liver transplantation remains controversial.METHODS: A single centre prospectively collected liver transplant database was analysed for the period 1988-2012. All patients were followed up for 5 years or until graft failure. Transaminase levels on the 1(st) , 3(rd) and 7(th) post-operative days were correlated with the patient demographics, operative outcomes, post-operative complications and both graft and patient survival via a binary logistic regression analysis.RESULTS: Graft and patient survival at 3 months was 80.3% and 87.5%. AST levels on the 3(rd) (p=0.005) and 7(th) (p=0.001) post-operative days correlated with early graft loss. Patients were grouped by their AST level (day 3): &lt;107iU, 107-1213iU, 1213-2744iU and &gt;2744iU. The incidence of graft loss at 3 months was 10%, 12%. 27% and 59% and 1 year patient mortality was 12%, 14%, 27% and 62%.CONCLUSIONS: Day 3 AST levels correlate with patient and graft outcome post liver transplantation and would be a suitable surrogate end-point for clinical trials in liver transplantation. This article is protected by copyright. All rights reserved.</p

Salivary cytokines as biomarkers of periodontal diseases

Periodontal disease is time consuming and expensive to treat and therefore its prevention, early detection and management are issues which, if effectively addressed, are likely to yield considerable health-care benefit (97). However, despite numerous advances in our understanding of the pathogenesis of chronic inflammatory diseases, periodontitis is still only diagnosed once connective tissue and bone destruction has occurred. Furthermore, monitoring disease progression is a highly skilled and technically demanding process, involving measurement of bleeding on probing, probing depth and attachment loss coupled with radiographic assessment and (subjective) visual observations (76). It would be highly desirable to develop biomarkers for early detection of periodontal disease and to identify progression because current diagnostic approaches do not reflect current disease activity but simply assess the cumulative effects of historical tissue destruction (53). Rational diagnosis would also have concomitant patient benefit because the paucity of evidence-based knowledge of disease progression in individual patients may lead to unintentional clinical mismanagement (97). In addition, studies of the salivary mediators associated with disease may help in the development of novel therapies aimed at controlling cytokine bioavailability (e.g. through anti-cytokine antibodies, antagonists or soluble receptors) or by targeting the intracellular signaling pathways they activate, approaches which have been successful in the treatment of other chronic inflammatory diseases, such as rheumatoid arthritis (60, 91, 95). Cytokines have been defined as soluble factors produced by one (immune) cell that act on another cell within the same milieu (26). However, it is now recognized that the range of molecules with cytokine-like activity can be extended to include, for example, growth factors and adipokines, which also have immunoregulatory functions. Importantly, cytokine functions often overlap or merge, building a complex immunoregulatory network in the immune system that is often perturbed in disease. It is increasingly appreciated that cytokines have vital roles in the development and homeostasis of numerous cell types and, in a wide range of tissues, have roles in resolution of inflammation, wound healing, repair and regeneration. In the following review, the term ‘cytokine’ will be used in this broad context. In addition to direct analysis of cytokines, the levels of molecules such as matrix metalloproteinases and tissue inhibitors of metalloproteinases, which are regulated by cytokines, have also been given considerable attention as potential periodontitis biomarkers, as reviewed elsewhere in this volume of Periodontology 2000

Peripheral blood biomarkers in multiple sclerosis.

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heteroge-neity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpre-dictable response to therapies. The major focus of the research on MS is the identification of biomarkers inbiologicalfluids, such as cerebrospinalfluid or blood, to guide patient management reliably. Because of the diffi-culties in obtaining spinalfluid samples and the necessity for lumbar puncture to make a diagnosis has reduced,the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However,currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkerscould radically alter the management of MS at critical phases of the disease spectrum, allowing for interventionstrategies that may prevent evolution to long-term neurological disability. This article provides an overview ofthis researchfield and focuses on recent advances in blood-based biomarker researc

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown

Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box

A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges

Personalization of prostate cancer prevention and therapy: are clinically qualified biomarkers in the horizon?

Prostate cancer remains the most common malignancy among men and the second leading cause of male cancer-related mortality. Death from this disease is invariably due to resistance to androgen deprivation therapy. Our improved understanding of the biology of prostate cancer has heralded a new era in molecular anticancer drug development, with multiple novel anticancer drugs for castration resistant prostate cancer now entering the clinic. These include the taxane cabazitaxel, the vaccine sipuleucel-T, the CYP17 inhibitor abiraterone, the novel androgen receptor antagonist MDV-3100 and the radionuclide alpharadin. The management and therapeutic landscape of prostate cancer has now been transformed with this growing armamentarium of effective antitumor agents. This review discusses strategies for the prevention and personalization of prostate cancer therapy, with a focus on the development of predictive and intermediate endpoint biomarkers, as well as novel clinical trial designs that will be crucial for the optimal development of such anticancer therapeutics