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PubMed2005

The role of neuroimaging in the early diagnosis and evaluation of Parkinson's disease.

The development of imaging biomarkers which target specific sites in the brain represents a significant advance in neurodegenerative diseases and Parkinson's disease with the promise of new and improved approaches for the early and accurate diagnosis of disease as well as novel ways to monitor patients and assess treatment. The 3 major applications of imaging may play a role in Parkinson's disease include: 1) the use of neuroimaging as a biomarker of disease in order to improve the accuracy, timeliness, and reliability of diagnosis; 2) objective monitoring of the progression of disease to provide a molecular phenotype of Parkinson's disease which may illuminate some of the sources of clinical variability; 3) the evaluation of so-called ''disease-modifying'' treatments designed to retard the progression of disease by interfering with pathways thought implicated in the ongoing neuronal loss or replace dopamine-producing cells. Each of these areas has shown a numbers of critical clinical investigations which have better defined the utility of the imaging tools to these tasks. Nonetheless, current unresolved issues around the clinical role of neuroimaging in monitoring patients over time and validation of quantitative imaging measures of dopaminergic function are immediate issues for the field and the subject of current research efforts and the extension of the lessons learned in Parkinson's to other neurodegenerative diseases including Alzheimer's dementia.

Diagnostic Errors↗
PubMed2006

Clinically relevant oral cancer model for serum proteomic eavesdropping on the tumour microenvironment.

BACKGROUND: Serum proteomics has enormous potential in the identification of biomarkers and the development of new therapies for oral cancer. Current efforts are limited by the lack of a control subject. The human-mouse chimeric model offers a solution. OBJECTIVES: To develop and test two orthotopic xenograft mouse models of human oral squamous cell carcinoma for research in serum proteomics. METHODS: Advanced human oral cancer from three patients was implanted orthotopically into the tongues of 19 SCID and 4 RAG2/gamma(c) knockout (KO) mice. Adjacent normal tissue from each patient was also implanted into nine SCID and 4 RAG2/gamma(c) KO mice. The models were compared for tissue take, the presence of metastasis, and histologic invasiveness. Mouse serum was preserved for studies in serum proteomics. RESULTS: Tumour tissue was successfully implanted into SCID and RAG2/gamma(c) mice, and the invasiveness was confirmed pathologically. Three of the control mice demonstrated the persistence of normal tissue more than 1 month after implantation. This is the first time that this has been reported. The larger size of the RAG2/gamma(c) KO mouse facilitated serum collection for serum proteomics. CONCLUSIONS: Both RAG2/gamma(c) KO and SCID mouse are able to reliably engraft human oral cancer. Engraftment of normal oral tissue was less reliable. This is the first in vivo model allowing identification of proteins released from the tumour microenvironment.

Aged↗
PubMed1998

Mycotoxins in foods--occurrence, health & economic significance & food control measures.

Mycotoxins of importance in India include aflatoxin, fumonisins, trichothecenes, ergot alkaloids and ochratoxins. The ICMR multicentric study on the occurrence of aflatoxin contamination in risk commodities namely, maize and groundnut showed that 21 per cent of groundnut samples and 26 per cent of maize samples analysed exceeded Indian tolerance limits of 30 micrograms/kg. A study on the aflatoxin intake from maize-based diets in a rural region of Andhra Pradesh showed the intakes to be in the range of 4-100 ng/kg body wt/day. Studies on the occurrence of aflatoxin M1 in milk in the southern and western regions of India indicated levels in the range of 0.05-3.0 micrograms/l. Analysis of feed samples indicated high incidence of aflatoxin B1 contamination in the groundnut cake component. Fumonisins have been shown to occur in Indian maize and sorghum. Studies showed high levels of fumonisins in rain-affected maize and sorghum consumption of which resulted in an outbreak of fumonisin mycotoxicosis in rural regions of the Deccan Plateau. A similar disease outbreak occurred in poultry due to consumption of fumonisin contaminated feed containing rain damaged maize. Biomarkers have been developed for assessing the risk of exposure for two mycotoxins viz., aflatoxin by measurement by ELISA of aflatoxin B1 N7-guanine adduct which has a detection limit of 15.6 pmol aflatoxin B1 N7 guanine; and fumonisin B1 by measurement in urine using HPLC with a detection limit of 8 ng/ml urine. Assessment of the economic implications of aflatoxin contamination showed economic losses resulting in rejection of export consignment of hand-picked-selected (HPS) groundnut and losses in the poultry industry. Approaches for prevention and control of mycotoxin contamination in foods have shown that methods involving the segregation of contaminated or mouldy grains by hand picking and density segregation resulted in a reduction of 70-90 per cent of aflatoxin and fumonisin present in the grains. While harmonization of international regulatory limits, the requirements of food producing countries needs to be recognized and realistic but not idealistic safe limits, need to be proposed.

Animal Diseases↗
PubMed2005

Mechanism-based pharmacokinetic-pharmacodynamic modeling-a new classification of biomarkers.

In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.

Biomarkers↗
PubMed1998

Development of new cancer chemoprevention agents: role of pharmacokinetic/pharmacodynamic and intermediate endpoint biomarker monitoring.

Recently, several promising strategies have been advanced for improving the efficiency of new agent development. These include pharmacokinetic/pharmacodynamic (PK/PD) and intermediate endpoint biomarker (IEB) monitoring. Here, we review their essential role as practical tools for guiding the evaluation of agents for cancer chemoprevention (CP) and provide examples of CP agents that utilize these approaches. Several important categories of IEBs are delineated, including histologically based (intraepithelial neoplasias and nuclear morphometry). The use of select IEBs combined with a Bayesian method for clinical trial monitoring for rapid identification of ineffective or promising agents is discussed. The similarities between IEB and TDM are described. Finally, we present future tools for enhanced monitoring of CP agents that will impact on laboratory medicine and are also applicable to many other drug classes, e.g., laser capture microdissection and cDNA chip microarrays that assess gene expression patterns of precancerous and cancerous lesions.

Anti-Inflammatory Agents↗
PubMed2026

Targeting cancer stem cells predicts response and reverses chemoresistance in ascites-derived ovarian cancer organoids.

BACKGROUND: Ovarian cancer (OC) is frequently diagnosed at an advanced stage, where tumor heterogeneity and rapid development of chemoresistance contribute to a poor prognosis. The lack of reliable predictive biomarkers further hinders the development of effective treatment strategies. Patient-derived organoids (PDOs) have recently emerged as promising preclinical models with the potential to predict therapeutic responses. METHODS: OC PDOs were generated from ascites samples representing diverse histological subtypes. Histological and genomic fidelity to parental tumors was confirmed through histopathological analysis and whole-exome sequencing. Drug sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors was evaluated and correlated with 1-year clinical outcomes. We also investigated the therapeutic efficacy of oncolytic herpes simplex virus 2 (OH2) both as a single agent and in combination with cisplatin. The expression of cancer stem cell (CSC) markers CD44 and ALDH1A1 under treatment conditions was analyzed using immunohistochemistry and flow cytometry. RESULTS: PDOs were successfully established with an 86.2% success rate. These PDOs faithfully recapitulated the histopathological and genomic features of their corresponding tumors, maintaining intratumoral heterogeneity, and were amenable to xenotransplantation. Drug sensitivity assays demonstrated that PDOs accurately predicted patient-specific responses to cisplatin and PARP inhibitors. OH2 exhibited direct cytotoxicity in both cisplatin-sensitive and cisplatin-resistant PDOs, reducing cell viability by 20-60%. Notably, the combination treatment with OH2 and cisplatin enhanced antitumor efficacy, resulting in a significant reduction of the CD44+CSC subpopulation. CONCLUSIONS: Ascites-derived OC PDOs represent a robust platform for individualized drug testing. The combination of OH2 and cisplatin offers a novel and effective strategy for circumventing chemoresistance in OC.

Female↗
PubMed2005

Molecular approaches to the identification of biomarkers of exposure and effect--report of an expert meeting organized by COST Action B15. November 28, 2003.

In the past, the term biomarker has been used with several meanings when used in human and environmental toxicology as compared to pharmaceutical development. However, with the advent of molecular approaches and their application in the field of drug development and toxicology, the concept of biomarkers has to be newly defined. In the meeting, the experts found consent in defining the term and described the application of biomarkers in toxicology, drug development and clinical diagnostics. Molecular approaches to biomarker identification and selection lead to a large amount of data. Hence, the statistical analysis is challenging and special statistical problems have to be solved in biomarker characterization, of particular interest are attempts aiming at class discovery and prediction. Reliability and biological relevance are to be demonstrated for biomarkers of exposure and effect which is also true for biomarkers of susceptibility. It is envisaged that the application of biomarkers will expand from current use in pre-clinical toxicology to the risk characterization and risk assessment of chemicals and from early clinical phases of drug development to later phases and even into daily clinical use in diagnostics and disease classification.

Biomarkers↗
PubMed2005

New science-based endpoints to accelerate oncology drug development.

Although several new oncology drugs have reached the market, more than 80% of drugs for all indications entering clinical development do not get marketing approval, with many failing late in development often in Phase III trials, because of unexpected safety issues or difficulty determining efficacy, including confounded outcomes. These factors contribute to the high costs of oncology drug development and clearly show the need for faster, more cost-effective strategies for evaluating oncology drugs and better definition of patients who will benefit from treatment. Remarkable advances in the understanding of neoplastic progression at the cellular and molecular levels have spurred the discovery of molecularly targeted drugs. This progress along with advances in imaging and bioassay technologies are the basis for describing and evaluating new biomarker endpoints as well as for defining other biomarkers for identifying patient populations, potential toxicity, and providing evidence of drug effect and efficacy. Definitions and classifications of these biomarkers for use in oncology drug development are presented in this paper. Science-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising tools for measuring biomarkers have also been developed and are based on genomics and proteomics, direct visualisation by microscopy (e.g., confocal microscopy and computer-assisted image analysis of cellular features), nanotechnologies, and direct and remote imaging (e.g., fluorescence endoscopy and anatomical, functional and molecular imaging techniques). The identification and evaluation of potential surrogate endpoints and other biomarkers require access to and analysis of large amounts of data, new technologies and extensive research resources. Further, there is a requirement for a convergence of research, regulatory and drug developer thinking - an effort that will not be accomplished by individual scientists or research institutions. Research collaborations are needed to foster development of these new endpoints and other biomarkers and, in the United States (US), include ongoing efforts among the Food and Drug Administration (FDA), National Cancer Institute (NCI), academia, and industry.

Antineoplastic Agents↗
PubMedDate not supplied

Biomarkers as diagnostic and prognostic tools for wildlife risk assessment: integrating endocrine-disrupting chemicals.

The state of art of the biomarker approach in ecotoxicology is reviewed with particular reference to its use in the assessment of exposure to endocrine-disrupting chemicals in wildlife. The following topics are discussed: the theoretical basis of the biomarker approach; the advantages of biomarker strategies in biomonitoring programs; application of biomarker strategies in an ecotoxicological context; the main biomarker techniques; interpretation of the results; and the development and validation of nondestructive biomarkers.

Animals↗
PubMed1996

Validation of a high-performance liquid chromatographic assay for lysylpyridinoline in urine: a potential biomarker of bone resorption.

We developed and validated a high-performance liquid chromatographic (HPLC) method for quantifying the bone-specific collagen crosslink, lysylpyridinoline (LP), in urine, LP was purified from cortical bone and characterized by spectrophotometry, HPLC, and 1H NMR spectroscopy. Our HPLC detected urinary LP independently of the sample volume and the range of quantification was between 63 nM and 1 microM. Average recovery of added LP standard to human urine samples was 106 +/- 21%. Mean inter- and intraassay CVs, respectively, for urines containing low, medium, and high concentrations of the crosslink LP were 7.4 and 6.3%. This analytical method is more efficient than previously published HPLC assays for LP because of the significant 24-h reduction in urinary sample preparation time. There was agreement between urinary LP concentrations measured with this method and the Metra Pyrilinks-D enzyme immunoassay (r2 = 0.714). These results emphasize the importance of using a thoroughly standardized HPLC assay as the "gold standard" for comparison of results with newly developed immunoassays.

Aged↗
PubMed2005

Dazl deficiency leads to embryonic arrest of germ cell development in XY C57BL/6 mice.

Genes of the DAZ family play critical roles in germ cell development in mammals and other animals. In mice, Dazl mRNA is first observed at embryonic day 11.5 (E11.5), but previous studies using Dazl-deficient mice of mixed genetic background have largely emphasized postnatal spermatogenic defects. Using an inbred C57BL/6 background, we show that Dazl is required for embryonic development and survival of XY germ cells. By E14.5, expression of germ cell markers (Mvh, Oct4, Dppa3/Stella, GCNA and MVH protein) was reduced in XY Dazl-/- gonads. By E15.5, most remaining germ cells in XY Dazl-/- embryos exhibited apoptotic morphology, and XY Dazl-/- gonads contained increased numbers of TUNEL-positive cells. The rare XY Dazl-/- germ cells that persisted until birth maintained a nuclear morphology that resembled that of wildtype germ cells at E12.5-E13.5, a critical developmental period when XY germ cells lose pluripotency and commit to a spermatogonial fate. We propose that Dazl is required as early as E12.5-E13.5, shortly after its expression is first detected, and that inbred Dazl-/- mice of C57BL/6 background provide a reproducible standard for exploring Dazl's roles in embryonic germ cell development.

Animals↗
PubMed1993

Strategies for the application of biomarkers for risk assessment and efficacy in breast cancer chemoprevention trials.

Current chemoprevention trial designs based on epidemiological risk assessment and occurrence of cancer as an endpoint are inefficient and expensive. Novel biomarkers are needed to facilitate the development of chemopreventive interventions. The following four categories of biomarkers may be useful in prevention trials: histologic and morphometric markers; phenotypic markers of dysregulated proliferation, differentiation, and cell loss; specific oncogenes and growth regulators which are qualitatively or quantitatively altered in breast cancers; and markers of genetic and epigenetic instability. Some of these markers will be generally useful regardless of the chemopreventive approach used, whereas others may be uniquely useful in trials of specific chemopreventive agents [e.g., upregulation of progesterone receptor (PR) expression in response to tamoxifen]. The development of these markers requires three phases of study: "Phase I": assessing the prevalence of the putative marker in malignant and premalignant tissue from individuals who have developed breast cancer; "Phase II": assessing in vivo modulation of the biomarker by the proposed chemopreventive agent; and "Phase III": applying the proposed biomarker in larger-scale trials of chemopreventive agent in high-risk populations, either before or after the development of a primary breast malignancy. The use of these biomarkers may also allow identification of novel targets for chemoprevention.

Biomarkers, Tumor↗
PubMed2006

Genomic approach to biomarker identification and its recent applications.

This paper discusses selected activities, issues, and challenges in recent development of analytical methods and applications in biomarker identification and validation using state-of-the-art genomic approaches. Molecular profiling via genomics, proteomics, and metabonomics has opened new windows to study disease states and biological systems. It has also provided exciting opportunities for novel applications in clinical research as well as in drug discovery and development. In the past several years, we have witnessed enormous progress resulting particularly from gene expression profiling of mRNA or transcriptomics. After a brief review on technology advances in gene expression profiling using microarrays, I mainly discuss recent developments of the genomic approaches to biomarker identification and validation in two major types of applications. The first type involves examples in cancer diagnostics and prognostics based on tumor gene expression profiling, whereas the second type involves biomarker applications in drug discovery and development. The focus will be on analytical methods and algorithms that have been developed in recent years facilitating biomarker discovery and application by leveraging genome-wide expression profiles derived from microarrays. Technical issues in experimental design, data processing, error modeling, quality control, figures of merit for performance evaluation, and meta-analysis related to biomarker discovery and application are also discussed. A case study of disease outcome prognosis for breast cancer patients based on tumor expression pattern is presented before closing remarks.

Biomarkers↗
PubMed2004

Nutrition and physical activity and chronic disease prevention: research strategies and recommendations.

A shortage of credible information exists on practical dietary and physical activity patterns that have potential to reverse the national obesity epidemic and reduce the risk of major cancers and other chronic diseases. Securing such information is a challenging task, and there is considerable diversity of opinion concerning related research designs and priorities. Here, we put forward some perspectives on useful methodology and infrastructure developments for progress in this important area, and we list high-priority research topics in the areas of 1) assessment of nutrient intake and energy expenditure; 2) development of intermediate outcome biomarkers; 3) enhancement of cohort and cross-cultural studies; and 4) criteria for and development of full-scale nutrition and physical activity intervention trials.

Biomarkers↗
PubMed2006

Classification of osteoarthritis biomarkers: a proposed approach.

OBJECTIVE: Osteoarthritis (OA) biomarkers are needed by researchers and clinicians to assist in disease diagnosis and assessment of disease severity, risk of onset, and progression. As effective agents for OA are developed and tested in clinical studies, biomarkers that reliably mirror or predict the progression or amelioration of OA will also be needed. METHODS: The NIH-funded OA Biomarkers Network is a multidisciplinary group interested in the development and validation of OA biomarkers. This review summarizes our efforts to characterize and classify OA biomarkers. RESULTS: We propose the "BIPED" biomarker classification (which stands for Burden of Disease, Investigative, Prognostic, Efficacy of Intervention and Diagnostic), and offer suggestions on optimal study design and analytic methods for use in OA investigations. CONCLUSION: The BIPED classification provides specific biomarker definitions with the goal of improving our ability to develop and analyze OA biomarkers, and to communicate these advances within a common framework.

Arthrography↗
PubMed2003

Measurement of inflammatory biomarkers in synovial tissue extracts by enzyme-linked immunosorbent assay.

We developed methods for measuring inflammatory biomarkers (cytokines, chemokines, and metalloproteinases) in synovial biopsy specimens from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Soluble extracts of synovial fragments were prepared with mild detergent and analyzed by enzyme-linked immunosorbent assay (ELISA) for interleukin 1beta (IL-1beta), IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and matrix metalloproteinase 3. The optimal detergent was 0.1% Igepal CA-630, which interfered minimally with ELISA detection but extracted 80% of IL-6 from synovial tissue. Upon spiking, 81 to 107% of added biomarkers could be recovered. To determine within-tissue variability, multiple biopsy specimens from each RA synovial extract were analyzed individually. A resulting coefficient of variation of 35 to 62% indicated that six biopsy specimens per synovial extract would result in a sampling error of < or = 25%. Preliminary power analysis suggested that 8 to 15 patients per group would suffice to observe a threefold difference before and after treatment in a serial biopsy clinical study. The previously described significant differences in IL-1beta, IL-6, IL-8, and TNF-alpha levels between RA and OA could be detected, thereby validating the use of synovial extracts for biomarker analysis in arthritis. These methods allow monitoring of biomarker protein levels in synovial tissue and could potentially be applied to early-phase clinical trials to provide a preliminary estimate of drug efficacy.

Arthritis, Rheumatoid↗
PubMed2003

Biomarkers, validation and pharmacokinetic-pharmacodynamic modelling.

Four elements are crucial to successful pharmacokinetic-pharmacodynamic (PK/PD) modelling and simulation for efficient and effective rational drug development: (i) mechanism-based biomarker selection and correlation to clinical endpoints; (ii) quantification of drug and/or metabolites in biological fluids under good laboratory practices (GLP); (iii) GLP-like biomarker method validation and measurements and; (iv) mechanism-based PK/PD modelling and validation. Biomarkers can provide great predictive value in early drug development if they reflect the mechanism of action for the intervention even if they do not become surrogate endpoints. PK/PD modelling and simulation can play a critical role in this process. Data from genomic and proteomics differentiating healthy versus disease states lead to biomarker discovery and identification. Multiple genes control complex diseases via hosts of gene products in biometabolic pathways and cell/organ signal transduction. Pilot exploratory studies should be conducted to identify pivotal biomarkers to be used for predictive clinical assessment of disease progression and the effect of drug intervention. Most biomarkers are endogenous macromolecules, which could be measured in biological fluids. Many exist in heterogeneous forms with varying activity and immunoreactivity, posting challenges for bioanalysis. Reliable and selective assays could be validated under a GLP-like environment for quantitative methods. While the need for consistent reference standards and quality control monitoring during sample analysis for biomarker assays are similar to that of drug molecules, many biomarkers have special requirements for sample collection that demand a well coordinated team management. Bioanalytical methods should be validated to meet study objectives at various drug development stages, and possess adequate performance to quantify biochemical responses specific to the target disease progression and drug intervention. Protocol design to produce sufficient data for PK/PD modelling would be more complex than that of PK. Knowledge of mechanism from discovery and preclinical studies are helpful for planning clinical study designs in cascade, sequential, crossover or replicate mode. The appropriate combination of biomarker identification and selection, bioanalytical methods development and validation for drugs and biomarkers, and mechanism-based PK/PD models for fitting data and predicting future clinical endpoints/outcomes provide powerful insights and guidance for effective and efficient rational drug development, toward safe and efficacious medicine for individual patients.

Biomarkers↗
PubMed2007

Pharmacodynamic biomarkers for molecular cancer therapeutics.

Rational and efficient development of new molecular cancer therapeutics requires discovery, validation, and implementation of informative biomarkers. Measurement of molecular target status, pharmacokinetic (PK) parameters of drug exposure, and pharmacodynamic (PD) endpoints of drug effects on target, pathway, and downstream biological processes are extremely important. These can be linked to therapeutic effects in what we term a "pharmacological audit trail." Using biomarkers in preclinical drug discovery and development facilitates optimization of PK, PD, and therapeutic properties so that the best agent is selected for clinical evaluation. Applying biomarkers in early clinical trials helps identify the most appropriate patients; provides proof of concept for target modulation; helps test the underlying hypothesis; informs the rational selection of dose and schedule; aids decision making, including key go/no go questions; and may explain or predict clinical outcomes. Despite many successes such as trastuzumab and imatinib, exemplifying the value of targeting specific cancer defects, only 5% of oncology drugs that enter the clinic make it to marketing approval. Use of biomarkers should reduce this high level of attrition and bring forward key decisions (e.g., "fail fast"), thereby reducing the spiraling costs of drug development and increasing the likelihood of getting innovative and active drugs to cancer patients. In this chapter, we focus primarily on PD endpoints that demonstrate target modulation, including both invasive molecular assays and functional imaging technology. We also discuss related clinical trial design issues. Implementation of biomarkers in trials remains disappointingly low and we emphasize the need for greater cooperation between various stakeholders to improve this.

Animals↗