Enhancing pathways to therapeutic development with clinical biomarkers.
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Studies on the development of potential biomarkers for rapid assessment of copper toxicity to freshwater fish using Esomus danricus as model.
Living in an environment that has been altered considerably by anthropogenic activities, fish are often exposed to a multitude of stressors including heavy metals. Copper ions are quite toxic to fish when concentrations are increased in environmental exposures often resulting in physiological, histological, biochemical and enzymatic alterations in fish, which have a great potential to serve as biomarkers. Esomus danricus was chosen as model in the present study and the metabolic rate, gill morphology, total glycogen, total protein, superoxide dismutase and catalase were critically evaluated. The 96h LC50 value was found to be 5.5mg/L (Cu as 1.402 mg/L). Fish groups were separately exposed to lethal (5.5 mg/L) and sub lethal concentrations (0.55 mg/L) of copper sulphate over a period of 96h to examine the subtle effects caused at various functional levels. Controls were also maintained simultaneously. Significant decrease in the metabolic rate (p<0.001) of the fish was observed in both the concentrations studied. Studies employing Automated Video Tracking System revealed gross changes in the architecture of gill morphology like loss, fusion, clubbing of secondary gill lamellae, and detachment of gill rakers following softening of gill shaft in fish under lethal exposures indicating reduced respiratory surface area. Biochemical profiles like total glycogen and total protein in gills and muscle of fish exposed to 5.5 mg/L showed appreciable decrease (p<0.05 to 0.001) from control. Significant inhibition of superoxide dismutase (60.83%), catalase (71.57%) from control was observed in fish exposed to 5.5 mg/L at the end of 96h exposure only. Interestingly, in fish exposed to 0.55 mg/L enzyme activity is not affected except for catalase. Toxic responses evaluated at various functional levels are more pronounced in fish exposed to 5.5 mg/L and these can serve as potential biomarkers for rapid assessment of acute copper toxicity in environmental biomonitoring.
Animals↗
[Molecular cytopathology of lung cancer--prevalence of genetic alterations and their role in the development of molecular biomarkers].
Carcinogenesis of lung cancer proceeds via a complex process that involves multiple genetic abnormalities, which do not necessarily have a linear progression. Genetic alterations include aneuploidy, deletions and amplifications of chromosomal regions, loss of heterozygosity (LOH), microsatellite alterations, point mutations and aberrant promoter methylation. There is considerable effort to use these genetic alterations as molecular biomarkers for early cancer diagnosis applying different approaches. An ideal tumor marker should be highly sensitive, tumor specific, easily to handle and non-cost intensive. While previous studies used screening for mutations, LOH and microsatellite alterations, more recent strategies concentrate on multicolor fluorescence in situ hybridization (FISH) and aberrant promoter methylation. Since in general the genetic alterations are prone to be more extensive in tumor cells as compared to non-tumor cells, methods that provide quantitative data (e.g., methylation specific real-time PCR) are likely to improve specificity. Consequently, molecular biomarkers could constribute to a more accurate risk assessment in carcinogen exposed individuals and early molecular cytologic diagnosis of precancerous lesions and cancers of the lung.
Allelic Imbalance↗
Fit-for-purpose method development and validation for successful biomarker measurement.
Despite major advances in modern drug discovery and development, the number of new drug approvals has not kept pace with the increased cost of their development. Increasingly, innovative uses of biomarkers are employed in an attempt to speed new drugs to market. Still, widespread adoption of biomarkers is impeded by limited experience interpreting biomarker data and an unclear regulatory climate. Key differences preclude the direct application of existing validation paradigms for drug analysis to biomarker research. Following the AAPS 2003 Biomarker Workshop (J. W. Lee, R. S. Weiner, J. M. Sailstad, et al. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development. A conference report. Pharm Res 22:499-511, 2005), these and other critical issues were addressed. A practical, iterative, "fit-for-purpose" approach to biomarker method development and validation is proposed, keeping in mind the intended use of the data and the attendant regulatory requirements associated with that use. Sample analysis within this context of fit-for-purpose method development and validation are well suited for successful biomarker implementation, allowing increased use of biomarkers in drug development.
Biomarkers↗
Assessing the health of grass shrimp (Palaeomonetes pugio) exposed to natural and anthropogenic stressors: a molecular biomarker system.
We developed a molecular biomarker system (MBS) to assess the physiological status of Palaomenetes pugio (grass shrimp) challenged with exposure to heat stress, cadmium, atrazine, and the water-accommodating fraction of either diesel fuel or bunker fuel No. 2. The MBS assayed 9 specific cellular parameters of shrimp that are indicative of a nonstressed or stressed condition: heat-shock protein 60, heat-shock protein 70, alpha B-crystallin homologue, lipid peroxide, total glutathione level, ubiquitin, mitochondrial manganese superoxide dismutase, metallothionein, and cytochrome P-450 2E homologue. Using these 9 parameters, the MBS can distinguish between the responses to each stressor, and to the nonstressed control conditions. The MBS was able to determine the structural integrity of the cell as defined by protein turnover, protein chaperoning, and lipid composition via lipid peroxide levels, and the status of key metabolic processes such as cytoskeletal integrity and glutathione redox potential. This technology aids in the accurate diagnosis of the health of shrimp because the physiological significance of changes of each parameter is well known. This technology is particularly relevant for environmental monitoring because grass shrimp are used as key indicator species in many estuarine ecosystems. Finally, this system is easy to implement, precise, and can be quickly adapted to an automated high-throughput system for mass sample analysis.
Journal Article↗
The applications of biomarkers in early clinical drug development to improve decision-making processes.
Selecting and evaluating biomarkers in drug discovery and early drug development can substantially shorten clinical development time or the time to reach a critical decision point in exploratory drug development. Critical decisions such as candidate selection, early proof of concept/principle, dose ranging, development risks, and patient stratification are based on the appropriate measurements of biomarkers that are biologically and/or clinically validated. The use of biomarkers helps to streamline clinical development by determining whether the drug is reaching and affecting the molecular target in humans, delivering findings that are comparable to preclinical data, and by providing a measurable endpoint that predicts desired or undesired clinical effects and will increase the success rate in the confirmatory stage of clinical development. Appropriateness of biomarkers depends on the stage of development, development strategy, and the nature of the medical indication. Even if a biomarker fails in the validation process there may be still a benefit of having used it. More knowledge about pathophysiology of the disease and the drug has been obtained. Different levels of validation exist at different development phases. Biomarkers are perhaps most useful in the early phase of clinical development when measurement of clinical endpoints may be too time-consuming or cumbersome to provide timely proof of concept or dose-ranging information. Examples of biomarkers are illustrated for the development of new drugs in variant cardiovascular, pulmonary, and CNS diseases.
Animals↗
Biomarkers in systemic lupus erythematosus.
Despite the longstanding interest and large number of publications on biomarkers in lupus, there are no validated and widely accepted biomarkers of systemic lupus erythematosus to date. To achieve the ultimate goal, to have a biomarker as a surrogate endpoint in clinical studies, candidate biomarkers have to first be validated in a statistically rigorous way. However, to qualify as a surrogate endpoint, even validated biomarkers have to go through a process that demonstrates that they accurately reflect a clinically important outcome. These goals can only be achieved in large multicenter, properly conducted studies. We reviewed the difficulties involved in developing validated biomarkers for systemic lupus erythematosus and summarized the available data on the most promising biomarker candidates of disease susceptibility and disease activity. We also report on the current status of a multicenter initiative to concentrate efforts of biomarker development.
Biomarkers↗
Antibody microarray profiling of human prostate cancer sera: antibody screening and identification of potential biomarkers.
We developed a practical strategy for serum protein profiling using antibody microarrays and applied the method to the identification of potential biomarkers in prostate cancer serum. Protein abundances from 33 prostate cancer and 20 control serum samples were compared to abundances from a common reference pool using a two-color fluorescence assay. Robotically spotted microarrays containing 184 unique antibodies were prepared on two different substrates: polyacrylamide based hydrogels on glass and poly-1-lysine coated glass with a photoreactive cross-linking layer. The hydrogel substrate yielded an average six-fold higher signal-to-noise ratio than the other substrate, and detection of protein binding was possible from a greater number of antibodies using the hydrogels. A statistical filter based on the correlation of data from "reverse-labeled" experiment sets accurately predicted the agreement between the microarray measurements and enzyme-linked immunosorbent assay measurements, showing that this parameter can serve to screen for antibodies that are functional on microarrays. Having defined a set of reliable microarray measurements, we identified five proteins (von Willebrand Factor, immunoglobulinM, Alpha1-antichymotrypsin, Villin and immunoglobulinG) that had significantly different levels between the prostate cancer samples and the controls. These developments enable the immediate use of high-density antibody and protein microarrays in biomarker discovery studies.
Antibodies, Neoplasm↗
Abundance of macroalgal organic matter in biofilms: evidence from n-alkane biomarkers.
Biofilm development on titanium panels immersed in the surface waters of Dona Paula Bay was investigated using molecular biomarkers such as n-alkanes and other chemical and biological parameters. Biofilm biomass measured as organic carbon (OC), organic nitrogen (ON), chlorophyll a, diatoms and bacterial numbers on the titanium panels generally increased over the period of immersion. Total lipids and n-alkane concentration also showed similar trends. n-alkanes from C(12) to C(30) were detected in the biofilm samples, which showed a bimodal distribution. The first mode consisted of n-alkanes > C(23) with a strong even over odd predominance. In the second mode, the n-alkanes < C(23) were more abundant with odd carbon number maxima at C(15), C(17) and C(19) and a strong odd over even carbon number predominance (Carbon Preference Index > 2). The predominance of these odd-chain n-alkanes strongly indicates that the organic matter derived from macroalgal sources was the major contributor to the biofilm organic matter developed on the titanium panels over the 15 d period of study. The data suggest that molecular characterization is a useful tool in understanding the sources of biofilm organic matter. The observed abundance of macroalgal organic matter during the 15 d period of biofilm development may play an important role in subsequent fouling by micro- and macrofouling organisms.
Alkanes↗
P1 latency as a biomarker for central auditory development in children with hearing impairment.
We used the latency of the P1 cortical auditory-evoked potential (CAEP) as a biomarker for the development of central auditory pathways in three children who received intervention through hearing aids and/or cochlear implants. Our goal was to examine the clinical feasibility of using the latency of the P1 CAEP as an objective tool to evaluate whether acoustic amplification for hearing-impaired children has provided sufficient stimulation for normal development of central auditory pathways. If clinicians have such a marker, then they can more confidently make a decision about whether to provide a child with a cochlear implant following an appropriate hearing-aid trial. Using the same marker, clinicians will also be able to monitor the maturation of central auditory pathways once electrical stimulation is initiated.
Auditory Pathways↗
Biomarkers in psychotropic drug development: integration of data across multiple domains.
This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investigational drugs. The question remains how to verify access to the brain. Early imaging studies including micro-PET can help to overcome this. However, in case of delayed tracer development or because of no feasible application of brain imaging effects of the molecule, using CSF as a matrix could fill this gap. Proteomic research using CSF will hopefully have a major impact on the development of treatments for psychiatric disorders.
Animals↗
Changes in biomarker expression in the development of prostatic adenocarcinoma.
In spite of the prevalence of prostatic adenocarcinoma, the development and natural history of this malignancy is poorly understood. This paper reviews the current knowledge of biomarker expression during the development and progression of prostatic adenocarcinoma. Emphasis is placed on the comparison of biomarker expression in benign prostatic epithelium, intraepithelial neoplasia (PIN), a putative preinvasive lesion, and prostatic adenocarcinoma. Within the benign epithelium, the proliferative potential is restricted to the basal cells as demonstrated by the expression of proliferating cellular nuclear antigen (PCNA). The strong expression of the bcl-2 protein, an inhibitor of a apoptosis, supports the concept that the basal cells or a subpopulation of the basal cells represent the stem cell of the epithelium. In addition, the strong expression of growth factor receptors such as the epidermal growth factor receptor (EGFr), p185erbB-2, p180erbB-3, and c-met suggests that the growth of the basal cells is regulated by autocrine or paracrine factors. The luminal cells express secretory products such as prostate specific antigen and prostatic acid phosphatase, but demonstrate little expression of PCNA as well as growth factor receptors and proto-oncogene products. These observations are consistent with the theory that the luminal cell population is derived from the differentiation of the basal cells. In contrast to the normal epithelium, PCNA expression is frequently detected in the dysplastic luminal cells of the PIN lesion. Likewise, strong expression of p185erbB-2, p180erbB-3 and the c-met proto-oncogene product is also detected in the luminal cells of PIN lesions. Other factors which are strongly expressed by the dysplastic luminal cells include the nm23-H1 gene product, tumor associated glycoprotein-72 (TAG-72), fatty acid synthetase (FASE) and proteolytic enzymes. These findings suggest that PIN lesions are derived from an impairment of the differentiation of basal cells. The majority of biomarkers such as PCNA, p185erbB-2, P180erbB-3, TAG-72, nm23-H1 and FASE which are strongly expressed in PIN lesions are also expressed in prostatic adenocarcinoma supporting the concept that PIN is a preinvasive lesion. Mutations of the p53 tumor suppressor gene, as well as strong expression of transforming growth factor alpha and bcl-2 typically occur in advanced stage prostatic adenocarcinomas and therefore likely represent late events in the development of prostatic adenocarcinoma.
Adenocarcinoma↗
Capillary separations enabling tissue proteomics-based biomarker discovery.
Development of the capability to enable large-scale proteome studies, analogous to comprehensive gene expression analysis, will clearly have far-reaching impacts on protein biomarker investigations of human diseases such as cancer through interrogation of the archived fresh frozen and formalin-fixed and paraffin-embedded tissue collections. This review therefore focuses on the most recent advances in microdissection techniques and proteome platforms for procuring homogeneous subpopulations of tumor cells or structures and performing comprehensive analysis of protein profiles within tissue specimens, respectively. Developments in capillary separations capable of providing extremely high resolving power and selective analyte enrichment are particularly highlighted for their roles within the broader context of a state-of-the-art integrated tissue proteome effort. The capabilities of CIEF-based multidimensional separations for performing proteome analysis from minute samples create new opportunities in the pursuit of biomarker discovery using enriched and selected cell populations procured from tissue specimens. These proteome technological advances combined with recently developed tissue microdissection techniques provide powerful tools for those seeking to gain a greater understanding at the global level of the cellular machinery associated with human diseases such as cancer.
Biomarkers↗
Clinical utility of biomarkers in myocardial injury.
PURPOSE OF REVIEW: This review will focus on recent developments in biomarkers of myocardial injury. We will discuss the clinical utility of cardiac-specific troponin in the post-operative setting and highlight some of the most promising new biomarkers under development. RECENT FINDINGS: Troponin I and T, measured in the post-operative setting, have been recently shown to have strong short- and long-term prognostic information in cardiac and vascular surgery patients. This ability of troponins to risk stratify post-operative patients occurs independent of clinical factors and other biomarkers. Additionally, brain natriuretic peptide has garnered significant interest as a biomarker of neurohormonal activation and appears to yield independent prognostic information from troponins. Recent studies have introduced two new biomarkers, soluble CD40 ligand and ischemia-modified albumin, which may aid in both diagnostic and prognostic decision making. SUMMARY: The current data strongly supports the use of troponin I and T in post-operative non-cardiac and cardiac surgical patients to assist in identifying those patients at high risk for short- and long-term complications. Several promising new biomarkers are currently under development but further studies are warranted to define their role in the post-operative setting.
Journal Article↗
Proteomics in biomarker discovery and drug development.
Proteomics is a research field aiming to characterize molecular and cellular dynamics in protein expression and function on a global level. The introduction of proteomics has been greatly broadening our view and accelerating our path in various medical researches. The most significant advantage of proteomics is its ability to examine a whole proteome or sub-proteome in a single experiment so that the protein alterations corresponding to a pathological or biochemical condition at a given time can be considered in an integrated way. Proteomic technology has been extensively used to tackle a wide variety of medical subjects including biomarker discovery and drug development. By complement with other new technique advances in genomics and bioinformatics, proteomics has a great potential to make considerable contribution to biomarker identification and to revolutionize drug development process. This article provides a brief overview of the proteomic technologies and their application in biomarker discovery and drug development.
Animals↗
Localization of matrix metalloproteinases, (MMPs) their tissue inhibitors, and vascular endothelial growth factor (VEGF) in growth plates of children and adolescents indicates a role for MMPs in human postnatal growth and skeletal maturation.
Numerous studies have focused on the expression, regulation, and biological significance of matrix metalloproteinases (MMPs) in the growth plate. Findings in mouse knockout models and in vitro data from various species indicate that MMPs not only degrade extracellular matrix components but may regulate the activity of local growth factors. In this study we investigated the presence, distribution, and activity of various MMPs and inhibitors, tissue transglutaminase (tTG or TG2) and vascular endothelial growth factor (VEGF) in the human child and adolescent growth plates by means of immunohistochemistry and gelatin zymography. Tissue was derived during orthopedic surgery (epiphysiodesis) in two prepubertal and four pubertal patients.MMP-2 and MMP-14 were present in reserve cell chondrocytes. MMP-14 was the most prominent MMP within all zones of the growth plate including proliferating chondrocytes. MMP-1 and MMP-13 (collagenases 1 and 3), MMP-9 (gelatinases B), MMP-10, and MMP-11 (stromelysins) and VEGF were positive in hypertrophic chondrocytes and osteoblasts. MMP-2 showed the same expression pattern but was negative in osteoblasts. Osteoclasts stained positive for MMP-9, MMP-2, and TG2. Tissue inhibitor of MMP (TIMP)-1 was present in all zones of the growth plate, osteoblasts, and osteoclasts; TIMP-2 was found in hypertrophic chondrocytes and osteoblasts. In summary, the presence of MMPs, TIMPs, TG2, and VEGF in our study indicated that the MMPs are relevant in growth plate physiology during the postnatal period in humans. The specific location of MMP expression within the growth plate may be the basis for further studies on the role of MMPs in the local regulation of chondrocyte differentiation, proliferation, and ossification at the chondroosseus junction.
Adolescent↗
Establishing a cancer center data bank and biorepository for multidisciplinary research.
The establishment of a biorepository with linkage to clinical and epidemiologic data will provide an invaluable resource for cancer research, including studies of cancer etiology, progression, and prognosis, as well as development of biomarkers for early detection. Developing an infrastructure for a biorepository linked to clinical, pathologic, and epidemiologic data requires significant efforts in strategic planning for efficient means to ascertain, identify, and consent participants, as well as guidelines for blood collection, processing, and storage while maintaining participant privacy rights. In this report, we present an approach to developing a Data Bank and Biorepository at our own institution, with discussion of elements to be considered when establishing such a bank.
Biological Specimen Banks↗
Development of surrogate endpoint biomarkers for clinical trials of cancer chemopreventive agents: relationships to fundamental properties of preinvasive (intraepithelial) neoplasia.
The tissue changes offering the greatest immediate potential for development as surrogate endpoint biomarkers (SEBs) to be used in Phase II trials of cancer chemopreventive agents are those derived from the microscopic tissue changes pathologists use to make the diagnosis of preinvasive (intraepithelial) neoplasia. These changes comprise four categories: proliferative index, ploidy, nuclear morphometry (size, shape, texture, and pleomorphism), and nucleolar morphometry (number, size, shape, position, and pleomorphism). Computer-assisted image analysis (CIA) permits dozens of additional morphometric parameters to be developed. Other categories of candidate SEBs are: DNA and chromosomal structural changes associated with genomic instability, activation of oncogenes and inactivation of tumor suppressor genes, structural changes in differentiated molecules, and aberrations of growth factor/receptor structure and function. Self-perpetuating DNA breakage with secondary mutator mutations in genomic stability genes is a major mechanism by which the genomic instability characteristic of neoplasia occurs, and from which stem other basic neoplastic properties, including clonal evolution, along multiple pathways of genetic variation that are stochastically determined, continuously increasing proliferation, rate and extent of phenotypic heterogeneity. SEBs resulting from genomic instability include homogeneously staining regions, double minute chromosomes, micronuclei, dicentrics, gene amplification, loss of heterozygosity, and alterations in chromosome number. Newly developed assays for detecting genomic instability include comparative genomic hybridization using fluorescence in situ hybridization on > 20 micron-thick sections monitored by confocal laser scanning microscopy, assays for microsatellite instability, and restriction landmark genomic scanning. These assays offer promise for detecting the earliest molecular changes of neoplasia in normal-appearing epithelium prior to the onset of the dysplastic phase of intraepithelial neoplasia.
Anticarcinogenic Agents↗