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PubMed2005

Development, validation, and implementation of a multiplex immunoassay for the simultaneous determination of five cytokines in human serum.

Quantification of biomarkers can provide important information about the safety and efficacy of candidate drugs. Unfortunately, limited sample volume and excess costs often limit analysis of multiple biomarkers. We developed, optimized, validated, and implemented a multiplex immunoassay for simultaneous measurement of multiple circulating cytokines: IL-1beta, TNFalpha, IL-6, IL-8, and IL-10. Multiplex immuoassays were performed using the Luminex LabMAP instrument. Capture antibodies for each cytokine were covalently bound to distinct microsphere subsets distinguished by differing dye ratios. The concentration of each individual cytokine determined by measuring orange fluorescence produced by a complex of a biotinylated cytokine-specific antibody and streptavidin-phycoerythrin. The lower limit of quantification for all assays was 20 pg/mL with the exception of IL-8 which was 100 pg/mL. The inter-assay precision was less than 25%CV for all analytes at all control levels both pre-study and in-study. The percent recovery ranged from 83 to 108% pre-study and 90 to 125% in-study. In a linearity assessment, a 15,000 pg/mL multi-analyte control could be diluted 1:50 and maintain expected accuracy. We measured the cytokine concentrations in more than 2000 serum samples from patients with sepsis. Multiplex results for IL-6 were compared to a conventional commercially available ELISA kit. The degree of agreement between the two methods as measured by the concordance correlation coefficient was 84.5%. Multiplex results were 2.36-fold higher than ELISA values on the average. After adjusting for this mean difference, the 95% empirical limits of agreement for the ratio of individual sample values were 0.33, 2.65. This multiplex immunoassay provided simultaneous measurement of circulating cytokines using 80% less patient specimen compared to traditional approaches and at a significantly decreased cost. Efficient use of this platform requires process improvements to fully maximize the positive impact of multiplex assays in clinical drug development.

Cytokines↗
PubMed2001

Effect of diazinon on behavior of Japanese medaka (Oryzias latipes) and gene expression of tyrosine hydroxylase as a biomarker.

This paper reports on the development of a biomarker used to monitor abnormal behaviors caused by diazinon in Japanese medaka (Oryzias latipes) as a model organism. Tyrosine hydroxylase (TH) activity in tissues was measured and the TH enzyme production in specific organs using a in situ cytochemical technique was monitored. These data were comparatively analyzed with those from semi-quantitative RT-PCR utilizing medaka TH gene that could be a potential biomarker for neuronal modulations and behaviors. For monitoring experiments at behavioral and molecular biological levels, the fish were treated under different sublethal conditions of diazinon (O, O-diethyl O-[6-methyl-2-(1-methylethyl)-4-pyrimidinyl] phosphorothioate) and their behavioral responses were observed. There were no significant differences in activity of TH head and body portions when the fish were exposed to lower concentrations (0.5-10 ppb) of diazinon including control treatment (0 ppb) for 24 hr. In temporal change of TH activity at 100 ppb diazinon treatment, however, the activity of body portion appeared to be inhibited during the first 30 min exposure but later seemed to recover slightly after 1 hr. TH appeared to be expressed mainly in the olfactory bulb, midbrain and brain stem regions as assessed by in situ immunohistochemistry. The treatment (1000 ppb) significantly suppressed TH protein production in the olfactory bulb, midbrain and brain stem regions. In kidney from the body portion the higher concentration treatment (1000 ppb) caused little suppression compared with the control. The RT-PCR showed that a production of TH mRNA transcript was significantly inhibited at 5 ppm diazinon treatment in the body portion. It was concluded that a suppression of TH activity would be one of the causes for the abnormal behaviors of the medaka that could be quantitatively monitored using an image processing system. This study provides molecular and neurobehavioral bases of a biomonitoring system for toxic chemicals using a model organism such as fish.

Animals↗
PubMed2005

Pharmacogenomics and clinical biomarkers in drug discovery and development.

The fields of pathology and clinical pharmacology are in an era of rapid evolution, reflecting continuous technological advancements in molecular diagnostics focused on improving drug efficacy and reducing toxicity. The discovery and refinement of the human genome sequence, further understanding of epigenetic events, and the expansion of proteomics research combined with emerging technologies such as functional imaging, biosensors, and sophisticated computational biology are having an unprecedented impact on the pharmaceutical industry. This review focuses on the discovery and development of DNA-based gene sequence tests and RNA-based gene expression profiles as applied to the prediction of response, resistance, and toxicity of both new and existing anticancer, cardiovascular, and anti-inflammatory drugs. This review will also consider the potential of emerging biomarkers designed to assist in the clinical development of these agents.

Biomarkers↗
PubMedDate not supplied

Mechanistic data and cancer risk assessment: the need for quantitative molecular endpoints.

The cancer risk assessment process as currently proposed by the U.S. Environmental Protection Agency allows for the use of mechanistic data to inform the low-dose tumor response in humans and in laboratory animals. The aim is to reduce the reliance on defaults that introduce a relatively high level of uncertainty to the risk estimates. The types of data required for this purpose are those that help identify key events in tumor formation following exposure to environmental chemicals. Informative biomarkers of tumor responses could then be developed for describing the shape of a dose-response curve at low doses (i.e., a qualitative assessment) and for predicting tumor frequency at these low doses (i.e., a quantitative assessment). A number of recently developed molecular approaches could aid in the development of qualitatively and quantitatively informative biomarkers. An overview of these with examples of their use is presented. These methods include quantitative gene expression array techniques, quantitative proteomic assays, and the assessment of DNA alterations at the single gene level and at the genome level of detection. It is most likely that a combination of approaches at different levels of cellular organization (i.e., DNA, RNA, and protein) will be the most productive for biomarker development. The rapid progress that is being made will make this tool kit even more applicable for the cancer risk assessment process.

Biomarkers, Tumor↗
PubMed2001

Development of novel dye-doped silica nanoparticles for biomarker application.

We report the development of novel luminescent nanoparticles composed of inorganic luminescent dye, Tris(2,2'-bipyridyl) dichlororuthenium (II) hexahydrate, doped inside a silica network. These dye doped silica (DDS) nanoparticles have been synthesized using a water-in-oil microemulsion technique in which controlled hydrolysis of the tetraethyl orthosilicate leads to the formation of monodispersed nanoparticles. They are prepared with a variety of sizes: small (5+/-1 nm), medium (63+/-4 nm), and large (400+/-10 nm), which shows the efficiency of the microemulsion technique for the synthesis of uniform nanoparticles. All these nanoparticles are suitable for biomarker application since they are much smaller than cellular dimension. These nanoparticles are highly photostable in comparison to most commonly used organic dyes. These nanoparticles have been characterized by various microscopic and spectroscopic techniques. The amount of dye content in these nanoparticles has been optimized to eliminate self-quenching. It has been observed that maximum luminescence intensity is achieved when the dye content is around 20 wt%. Silica surface of DDS nanoparticles is available for surface modification and bioconjunction. For demonstration as a biomarker, the DDS nanoparticle's surface has been biochemically modified to attach membrane-anchoring groups and applied successfully to stain human leukemia cells.

2,2'-Dipyridyl↗
PubMed2002

Biomarkers and surrogate endpoints: how and when might they impact drug development?

As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs is described in this review. Additionally, the utility of pharmacokinetic data in drug development is described. Development of biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process. Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by clinicians to evaluate the potential for efficacy after start of treatment.

Biomarkers↗
PubMedDate not supplied

Total oxyradical scavenging capacity and cell membrane stability of haemocytes of the Arctic scallop, Chlamys islandicus, following benzo(a)pyrene exposure.

Industrial activities, notably oil and gas industries, are expanding in the Arctic. Most of the biomarkers were developed using temperate organisms living at temperatures above 10 degrees C. Little is known about the biomarker responses of organisms living between -1.88 and 5 degrees C. Therefore, assessment of the toxicity of chemicals to cold-water adapted species is required. In this study, the Arctic scallop, Chlamys islandicus, was selected as a key species for bio-monitoring because of wide distribution in Arctic waters and its commercial value. Test animals, stored in seawater at 2 degrees C, were injected with benzo(a)pyrene (diluted in cod liver oil 5 mg ml(-1)) in the adductor muscle every 24 h for four days giving a final dose of 0, 74 and 90.6 mg kg(-1) wet weight for control, low and high dose, respectively. The biomarkers used were total oxyradical scavenging capacity (TOSC) in the digestive gland and cell membrane stability of haemocytes. TOSC values were significantly reduced (ca. 30%) in exposed groups (P < 0.05), indicating a depletion in oxyradical molecular scavengers. The antioxidant defences appeared to be overwhelmed by the reactive oxygen species as the plasma membranes of haemocytes were destabilised (P < 0.05) probably due to lipid peroxidation. These data indicate that reactive oxygen species (ROS) were produced by Arctic scallops via the metabolisation of benzo(a)pyrene at 2 degrees C.

Adaptation, Physiological↗
PubMed2006

Metabolomic approaches to phenotype characterization and applications to complex diseases.

Metabolites are the key regulators of systems homeostasis. As such, concentration changes of specific groups of metabolites may reflect systemic responses to environmental, therapeutic or genetic interventions. Thus, the study of metabolites is a powerful tool for the characterization of complex phenotypes as well as for the development of biomarkers for specific physiological responses. Therefore, metabolomics is a valuable platform for studies of complex diseases and the development of new therapies, both in nonclinical disease model characterization and clinical settings.

Animals↗
PubMed2025

Innovative strategies for mitochondrial dysfunction in myeloproliferative neoplasms a step toward precision medicine.

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells characterized by aberrant proliferation of myeloid lineages, driven primarily by mutations in JAK2, CALR, and myeloproliferative leukemia, leading to constitutive activation of the JAK-STAT pathway. Emerging evidence highlights mitochondrial dysfunction as a key factor in MPN pathogenesis, contributing to increased reactive oxygen species production, mitochondrial DNA mutations, and dysregulated mitochondrial dynamics, which collectively promote clonal expansion and apoptosis resistance. Targeting mitochondrial pathways has gained attention as a therapeutic strategy, with approaches including mitochondria-targeted antioxidants, metabolic inhibitors, and modulation of mitophagy and mitochondrial fission/fusion dynamics. However, challenges such as drug delivery specificity, therapeutic resistance, and off-target effects remain significant. Recent advances in precision medicine, incorporating genomic, transcriptomic, and proteomic profiling, offer a more personalized approach to MPN treatment by tailoring interventions to individual mutation patterns. Additionally, novel therapeutic strategies, including gene editing technologies, RNA-based therapies, and nanoparticle-mediated drug delivery systems, hold promise for overcoming current treatment limitations. The integration of artificial intelligence in drug discovery and biomarker identification further enhances the potential for targeted therapies. Future research should focus on refining these strategies, developing reliable biomarkers for patient stratification, and exploring combination therapies that enhance treatment efficacy while minimizing adverse effects. By addressing mitochondrial dysfunction as an underlying driver of MPNs, these emerging approaches have the potential to improve disease management, extend patient survival, and enhance quality of life. Also, this new approach of precision medicine allows patient stratification and ensures that treatments are formed according to the individual disease biology of each patient, which results in overall better outcomes.

combination drug therapy↗
PubMedDate not supplied

Biomarkers of human exposure to benzene.

Three biomarkers for benzene exposure were developed. The first biomarker, muconic acid in urine, results from the ring opening of a benzene metabolite. A gas chromatography/mass spectroscopy (GC/MS) assay was developed to measure urinary muconic acid, and the analyte in urine samples from workers occupationally exposed to benzene was determined. Workers exposed to benzene concentrations as low as 4.4 ppm over an 8-h day showed higher urinary muconic acid concentrations than did any control individual (p < .005). The second biomarker, S-phenylcysteine (SPC) in hemoglobin (Hb), results from the addition of benzene oxide to a cysteine sulfhydryl group. A GC/MS assay was developed to measure SPC in the blood of F344/N rats and B6C3F1 mice exposed to benzene by inhalation. The cysteine moiety on rat Hb is at a more accessible site than on Hb of mice or humans, and rats showed considerably higher levels of SPC than did mice. As yet, we have been unable to detect SPC in the globin of humans occupationally exposed to benzene. The third biomarker is SPC in albumin. In humans occupationally exposed to average concentrations of 0, 4.4, 8.4, and 23.1 ppm benzene, 8 h/d, 5 d/wk, SPC increased in the exposed groups linearly, giving a statistically significant slope (p < .001) of 0.044 +/- 0.008 pmol/mg albumin/ppm. The assay for SPC is arduous and often imprecise; assuming these difficulties can be overcome, muconic acid in urine and SPC in albumin may be useful for accurately determining benzene exposure.

Administration, Inhalation↗
PubMed2005

A biomarker model of sublethal genotoxicity (DNA single-strand breaks and adducts) using the sentinel organism Aporrectodea longa in spiked soil.

There is a need to develop risk biomarkers during the remediation of contaminated land. We employed the earthworm, Aporrectodea longa (Ude), to determine whether genotoxicity measures could be applied to this organism's intestinal tissues. Earthworms were added, for 24h or 7 days, to soil samples spiked with benzo[a]pyrene (B[a]P) and/or lindane. After exposure, intestinal tissues (crop/gizzard or intestine) were removed prior to the measurement in disaggregated cells of DNA single-strand breaks (SSBs) by the alkaline comet assay. Damage was quantified by comet tail length (CTL, microm). B[a]P 24-h exposure induced dose-related increases (P<0.0001) in SSBs. Earthworm intestine was significantly (P<0.0001) more susceptible than crop/gizzard to B[a]P and/or lindane. However, both tissues appeared to acquire resistance following 7-day exposure. B[a]P-DNA adducts, measured by (32)P-postlabelling, showed a two-adduct-spot pattern. This preliminary investigation suggests that earthworm tissues may be incorporated into genotoxicity assays to facilitate hazard identification within terrestrial ecosystems.

Animals↗
PubMed1998

Uncertainty analysis methods for comparing predictive models and biomarkers: A case study of dietary methyl mercury exposure.

Biologically based markers (biomarkers) are currently used to provide information on exposure, health effects, and individual susceptibility to chemical and radiological wastes. However, the development and validation of biomarkers are expensive and time consuming. To determine whether biomarker development and use offer potential improvements to risk models based on predictive relationships or assumed values, we explore the use of uncertainty analysis applied to exposure models for dietary methyl mercury intake. We compare exposure estimates based on self-reported fish intake and measured fish mercury concentrations with biomarker-based exposure estimates (i.e., hair or blood mercury concentrations) using a published data set covering 1 month of exposure. Such a comparison of exposure model predictions allowed estimation of bias and random error associated with each exposure model. From these analyses, both bias and random error were found to be important components of uncertainty regarding biomarker-based exposure estimates, while the diary-based exposure estimate was susceptible to bias. Application of the proposed methods to a simple case study demonstrates their utility in estimating the contribution of population variability and measurement error in specific applications of biomarkers to environmental exposure and risk assessment. Such analyses can guide risk analysts and managers in the appropriate validation, use, and interpretation of exposure biomarker information.

Animals↗
PubMed1999

Progress in cancer chemoprevention.

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).

Animals↗
PubMed2004

Obesity as a risk factor for osteoarthritis: mechanical versus metabolic.

Obesity is a risk factor for the development and progression of radiograhic OA and probably works through both mechanical as well as metabolic pathways. We are just beginning to unravel these associations. By better understanding these associations, improved biomarkers for development and progression of OA and new novel therapies for the prevention and treatment of OA may be developed. The Osteoarthritis Initiative will help us understand these associations and allow us to evaluate new biomarkers for symptomatic incident and progression of established knee OA as well as the relationship of obesity and generalized OA.

Humans↗
PubMed1996

Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental compounds: biological markers of exposure and effects.

Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups.

Biomarkers↗
PubMed2006

Effects of paraquat on the freshwater fish Channa punctata (Bloch): non-enzymatic antioxidants as biomarkers of exposure.

Paraquat is a quaternary herbicide widely used for broadleaf weed control, which has been known to be a highly toxic compound for humans and animals. Therefore, analysis and development of biomarkers of exposure are undoubtedly valuable in evaluating the toxicity of paraquat contaminated water bodies. The effect of a single exposure of paraquat (1 ppm) for 24 h on various non-enzymatic antioxidants was studied in freshwater fish Channa punctata (Bloch). The levels of the reduced glutathione were significantly reduced in the liver and gill of exposed fish. The total and protein thiol levels were increased in all the tissues of the exposed fish. The non-protein thiol levels were reduced in liver and gill. The levels of ascorbic acid increased in liver. The uric acid level increased significantly in kidney and decreased significantly in gill of the exposed fish. The findings of the present investigation demonstrate the oxidative-stress-inducing potential of the herbicide paraquat in fish. This work indicated the possibility of using non-enzymatic antioxidants as biomarkers of exposure to environmental contamination and subsequent validation as a sensitive system for biomonitoring and ecotoxicological risk assessment.

Animals↗
PubMed1991

Cancer prevention: recent progress and future opportunities.

Knowledge gathered during the past few decades from the fields of cancer epidemiology, carcinogenesis, biochemistry, and molecular biology, much of which was communicated through the pages of the journal Cancer Research, provides powerful new strategies for cancer prevention. Indeed, I believe that it is possible to draft a blueprint for a comprehensive approach to cancer prevention, to be used as we approach the 21st century. This plan includes: (a) expanded epidemiological and laboratory studies to identify the specific causes of human cancers; (b) intervention studies, such as risk reduction by the cessation of cigarette smoking, dietary modifications, chemoprevention, and the development of vaccines for viral agents implicated in human cancer (i.e., hepatitis B, human papilloma virus, Epstein-Barr virus, and certain retroviruses), and (c) early detection and screening. Concepts and methods that have developed in the field of cellular and molecular biology will accelerate this progress. Indeed, we are currently in a very exciting phase of cancer research that brings together fields of cancer research which in the past were often disparate and disconnected, i.e., basic laboratory studies, epidemiology, prevention, and treatment. Thus, the astounding advances in our understanding of the molecular biology of cancer provide a unified concept of the nature of the cancer cell and also suggest new clinical approaches to cancer etiology, prevention, and treatment. Many of the biomarkers being developed for etiological studies, using the approach of molecular epidemiology, can also serve as biomarkers or intermediate end points to evaluate the efficacy of dietary intervention and chemoprevention studies. Some of these biomarkers will also be useful for evaluating the efficacy of cancer therapy. Furthermore, certain compounds being developed for cancer chemoprevention, e.g., the retinoids, may also be useful in the therapy of fully established neoplasms. It seems likely, therefore, that even before the year 2000 these powerful and unifying themes will accelerate advances in both cancer prevention and treatment, thus leading to major reductions in both the incidence and mortality of human cancer.

Humans↗
PubMed2002

Consensus statements from the Second International Lung Cancer Molecular Biomarkers Workshop: a European strategy for developing lung cancer molecular diagnostics in high risk populations.

The Second Molecular Biomarkers Workshop was held at the Roy Castle International Centre for Lung Cancer Research in Liverpool, in June 2001 and it brought together experts in the clinical, epidemiological and molecular-pathology of lung cancer from Europe and the USA, to address issues surrounding the development of a European strategy for early lung cancer detection. The 2001 Workshop Breakout Groups concentrated on the current challenges in the early detection of lung cancer which need to be addressed in the light of the recent surge in interest in many countries for mounting new clinical trials to evaluate the utility of Spiral CT in early lung cancer detection. If population-based trials of CT screening are mounted it will also be a favorable clinical environment in which to evaluate efficiently recent advances in molecular screening and genotyping. The Workshop focused specifically on: a) clinical and molecular biomarkers, b) sputum as an early detection and diagnostic tool, c) validation of molecular markers prior to their use in early detection trials and d) ethical issues that have to be considered in early lung cancer detection trials. A distillation of the Workshop discussions is given in this article.

Biomarkers, Tumor↗