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Results for “Biomarker variability”

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PubMed2002

Respiratory hypersensitivity to trimellitic anhydride in Brown Norway rats: evidence for different activation pattern of immune cells following topical and respiratory induction.

The elicitation of respiratory allergy in animal models is exquisitely complex and interpretation of results from different laboratories cannot readily be compared due to variability in testing protocols, biomarkers and techniques used to identify 'positive' responses. On the one hand, guinea-pigs have been proposed as a good model with which to study allergic and irritant bronchial hyperresponsiveness. On the other hand, considerable efforts have been made to develop animal models that take the immunological mechanisms into account to reduce the complexity as well as duration of the guinea-pig assays. In principle, local skin reactions can easily be determined by the local lymph node assay (LLNA) introduced by Kimber and Weisenberger. In contrast to lung sensitization there are already simplified and reliable models available to test for and discriminate contact sensitizers from skin irritants, i.e. the modified local lymph node assay IMDS (integrated model for the differentiation of skin reactions). Modifications of this assay verified that methods other than radioactive labelling may be comparably sensitive, and that it is possible to eliminate 'false positive' results induced by irritants (IMDS). Thus, we asked whether there could be a similar simplified model like the modified LLNA or IMDS for investigations of respiratory allergens. Therefore, we analysed immune reactions induced by the dermal and respiratory route, respectively. Analyses of the draining lymph nodes of the lung and the ear were carried out before and after challenge via the pulmonary tract. The results clearly support that (1) the reactions in the lung draining lymph nodes could be used as early indicators of respiratory sensitization, and (2) the specificity of the immune competent cells seem to be dependent of the route of administration during induction.

Administration, Inhalation↗

PubMed2005

Seasonal variability of metallothioneins, cytochrome P450, Bile metabolites and oxyradical metabolism in the European eel Anguilla anguilla L. (Anguillidae) and striped mullet Mugil cephalus L. (Mugilidae).

The European eel Anguilla anguilla (Anguillidae) and the striped mullet Mugil cephalus (Mugilidae) are typical inhabitants of Mediterranean brackish lagoons, and their utility as bioindicator organisms has already been suggested. The seasonal variability of several potential biomarkers was investigated during a field study carried out in the Orbetello lagoon (Tuscany, Italy). Organisms were sampled on a seasonal basis, and analyzed parameters included the levels of hepatic metallothioneins, the activity of cytochrome P450 1A (EROD), and the presence of biliary PAH metabolites. Special attention was also paid to antioxidant defenses, including catalase, glutathione peroxidases, glutathione reductase, glutathione S-transferases, and total glutathione concentration. Total Oxyradical Scavenging Capacity (TOSC-assay) was measured as an indication of the overall biological resistance to toxicity of different forms of oxyradicals (peroxynitrite, peroxyl and hydroxyl radicals). Obtained results suggest that natural variations of analyzed responses are associated with seasonality of both environmental and biological factors, mainly temperature and reproductive cycle which, however, have a different influence in these two species. Striped mullets exhibited the strongest variations in October when spawning occurs; eels are not influenced by a seasonal sexual maturation and showed more marked changes during the summer, likely related to the elevated seawater temperature and light irradiance in the lagoon. This study confirms the importance of characterizing seasonal variations and the influence of different factors on biological responses that can be used as biomarkers in monitoring programs.

Anguilla↗

PubMed2006

Toxicity of complex cyanobacterial samples and their fractions in Xenopus laevis embryos and the role of microcystins.

This work evaluated the effects of various cyanobacterial fractions in Frog Embryo Teratogenesis Assay Xenopus (FETAX) with African clawed frog embryos. Fractions were prepared from five biomasses with different dominant genera (Microcystis, Aphanizomenon, Anabaena, Planktothrix) and different microcystin content. Effects of following fractions were investigated: (I) homogenate of complex cyanobacterial biomass, (II) cell debris (pellet) after centrifugation of complex biomass, (III) supernatant after centrifugation of complex biomass (= crude aqueous extract), (IV) permeate after passing of crude extract through C-18 column (fraction devoid of microcystins), and (V) eluate from C-18 column (containing microcystins, if present). Besides classical parameters evaluated in 96 h FETAX (mortality, growth inhibition, malformations), we have also assessed the effects on biochemical markers of oxidative stress and detoxification (glutathione pool, GSH; activity of glutathione peroxidase, GPx; glutathione reductase, GR; activity of glutathione-S-transferase, GST). Complex biomass (I) and aqueous extract (III) were generally the most toxic fractions in terms of mortality and growth inhibition, whereas eluates containing microcystins (V) were generally less toxic. On the other hand, the same fraction (eluates) induced significant malformations in low concentrations but the effects were not related to the content of microcystins. Biomarkers were affected in variable manner but no significant effect or clear relation to microcystin content was observed. Our data support the hypothesis that microcystins are not the only or major toxic compounds in the complex cyanobacterial samples (at least for some species) and that more attention should be paid to other components of complex cyanobacterial biomass including non-specific parameters such as oxygen content or toxic ammonia released during bacterial decay of organic material.

Animals↗

PubMed2024

Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

Humans↗

PubMed2001

Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers.

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assessed by anti-Xa and anti-IIa activity was studied in a two-way crossover trial. In this trial, 30 healthy volunteers received a single 175 IU/kg subcutaneous administration of tinzaparin containing approximately 3.5% of the < 2000 Da fraction and a tinzaparin-like LMWH containing 18.3% of the < 2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparable at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-Xa activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzaparin injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (< 18% for both anti-Xa and anti-IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained with tinzaparin. Based on average equivalence criteria, the two LMWH preparations were determined to be bioequivalent using either anti-Xa or anti-IIa activity as biomarkers. The calculated intrasubject variabilities were low (< 14% for anti-Xa activity and < 18% for anti-IIa activity) yielding little evidence for a significant Subject x Formulation interaction. In summary, anti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent with targeted therapeutic levels derived from previous trials in adult DVT patients. Weight-based dosing for the treatment of DVT appears rational based on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Furthermore, differences in the percentage of molecules in the < 2000 Da molecular weight fraction of tinzaparin do not translate into differences in anti-Xa and anti-IIa activity in vivo.

Adult↗

PubMed2006

Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles.

There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease.

Adult↗

PubMed2006

Reduced heart rate variability: an indicator of cardiac uncoupling and diminished physiologic reserve in 1,425 trauma patients.

BACKGROUND: Measurements of a patient's physiologic reserve (age, injury severity, admission lactic acidosis, transfusion requirements, and coagulopathy) reflect robustness of response to surgical insult. We have previously shown that cardiac uncoupling (reduced heart rate variability, HRV) in the first 24 hours after injury correlates with mortality and autonomic nervous system failure. We hypothesized: Deteriorating physiologic reserve correlates with reduced HRV and cardiac uncoupling. METHODS: There were 1,425 trauma ICU patients that satisfied the inclusion criteria. Differences in mortality across categorical measurements of the domains of physiologic reserve were assessed using the chi test. The relationship of cardiac uncoupling and physiologic reserve was examined using multivariate logistic regression models for various levels of cardiac uncoupling (>0 through 28% reduced HRV in the first 24 hours). RESULTS: Of these, 797 (55.9%) patients exhibited cardiac uncoupling. Deteriorating measures of physiologic reserve reflected increased risk of death. Measures of acidosis (admission lactate, time to lactate normalization, and lactate deterioration over the first 24 hours), coagulopathy, age, and injury severity contributed significantly to the risk of cardiac uncoupling (area under receiver operator curve, ROC=0.73). The association between deteriorating reserve and cardiac uncoupling increases with the threshold for uncoupling (ROC=0.78). CONCLUSIONS: Reduced heart rate variability is a new biomarker reflecting the loss of command and control of the heart (cardiac uncoupling). Risk of cardiac uncoupling increases significantly as a patient's physiologic reserve deteriorates and physiologic exhaustion approaches. Cardiac uncoupling provides a noninvasive, overall measure of a patient's clinical trajectory over the first 24 hours of ICU stay.

Adult↗

PubMed1999

A clinical trial to selectively change dietary fat and/or energy intake in women: the Women's Diet Study.

Dietary fat and energy intake have been implicated in breast cancer etiology. To examine the relative importance of these dietary factors on markers of cancer risk in women, we designed an intervention trial to selectively decrease fat and/or energy intake in free-living, premenopausal women who were somewhat overweight. The study used a 2 x 2 factorial design to evaluate the independent and interactive effects of dietary fat and energy. The diets were nonintervention, low fat (15% of energy from fat, maintenance of energy intake), low energy (25% energy reduction), and combination low fat and low energy. We utilized an individualized counseling approach with self-selection of foods. Women on the low-fat and combination diets were asked to meet given daily goals for fat grams and food group exchanges, while women on the low-energy diet used only food group exchanges. Of the 113 premenopausal women randomized who were eligible for analysis, 43% were African-American. A total of 88 women completed the 12-week program, and adherence to the dietary goals was similar in both racial groups. Women on the low-fat diet were able to reduce dietary fat intake to 19% of energy by 4 weeks and to 17% by 12 weeks with a slight decrease in energy intake. Women on the low-energy diet met their energy reduction goals by four weeks while maintaining percentage of energy from fat. Women on the combination diet largely met their goals by four weeks as well. These data indicate that it is possible to selectively manipulate dietary fat and energy intake in women over a short period of time, which makes clinical studies on the relative effects of these two dietary variables on cancer risk biomarkers readily feasible.

Adult↗

PubMed2006

Analytical performance and clinical utility of the INNOTEST PHOSPHO-TAU181P assay for discrimination between Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. METHODS: The analytical performance of the INNOTEST PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Abeta(1-42), for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. RESULTS: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.

Aged↗

PubMed1999

Rising PSA after local therapy failure: immediate vs deferred treatment.

Patients whose only sign of recurrence after local therapy for prostate cancer is a rising prostate-specific antigen level (PSA-only recurrence) have become more common. We have developed two models to predict PSA-only recurrence after radical prostatectomy, one using traditional factors (race, sigmoidal transformation of PSA, postoperative Gleason sum, and organ confinement) and a second using traditional clinical and pathologic variables combined with molecular biomarker levels. Treatment options for patients with PSA-only recurrence include observation, radiation therapy for patients who have undergone surgery, salvage surgery or cryotherapy for patients who have received radiotherapy, and traditional or nontraditional hormonal therapy. Radiation for PSA-only recurrence is likely to benefit men who have no adverse pathology, a low PSA level at recurrence, and PSA recurrence after the first year. Salvage radical prostatectomy and cryotherapy pose a relatively high risk of incontinence and other morbidity and should be reserved for carefully selected patients with a high likelihood of organ-confined disease. Hormonal therapy is probably the single most beneficial treatment for PSA-only recurrence. Nontraditional low-dose oral hormonal therapy and intermittent hormonal therapy are gaining in popularity, although their long-term efficacy is unknown. More clinical trials are needed to fine-tune prognostic models and to determine the best treatments, alone or in combination, for PSA-only recurrence.

Biomarkers, Tumor↗

PubMed1991

Biomarkers of aging: changes in circadian rhythms related to the modulation of metabolic output.

Twenty-four hour (circadian) rhythmicity is an important component of biological variability associated with studies relating to biomarkers of aging. Chronobiological testing techniques must be utilized because (1) many variables that are related to the modulation of metabolic output vary dramatically at different times of the day; (2) various experimental variable and treatment groups must be synchronized with environmental cues that control circadian rhythms; and (3) multiple circadian variables may interact together to modulate the rate of aging. The rhythm for physiological factors such as whole animal metabolic output, body temperature, heart rate, urine flow, potassium, etc. were found to be dissociated or altered by the senescence process; behavioral variables such as spontaneous activity, wheel running, feeding and drinking, verbal performance, as well as sleep-wakefulness rhythms, seem to be accurate predictors of biological age. Circadian rhythms for a variety of enzymes of intermediary metabolism which are directly associated with energy metabolism have been well documented. These well-defined rhythms of enzyme activity have also been shown to degenerate with aging. Rhythms tend to lose amplitude as activity falls with age and as a general loss of regulation (especially time of day where maximal activity might be found) of activity across the 24-h span occurs. As with behavioral variables, changes in enzyme rhythms appear to accurately predict aging. Generally speaking, the loss of temporal organization with age, characterized by decreased circadian amplitude, loose internal synchronization, and poor response to external environmental time queues, is associated with poor health states and decreased longevity. Temporal rhythms for whole animal parameters are highly correlated with molecular events, such as regulation of cellular metabolism. DNA repair, and gene expression. Automated data acquisition and process control systems will be required for future chronobiological studies to develop biomarkers of aging.

Aging↗

PubMed2006

Acute toxicity profile of cadmium revealed by proteomics in brain tissue of Paralichthys olivaceus: potential role of transferrin in cadmium toxicity.

An analytical approach using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) separated proteins from the brain tissue of the fish Paralichthys olivaceus. Approximately 600 protein spots were detected from the brain sample when applying 600 microg protein to a 2D-PAGE gel in the pH range 3.5-10.0. Compared to a control sample, significant changes of 24 protein spots were observed in the fish tissue exposed to acute toxicity of seawater cadmium (SCAT) at 10 ppm for 24h. Among these spots, nine were down-regulated, nine were up-regulated, two showed high expression, and four showed low expression. The collected spots were identified by peptide mass fingerprinting (PMF) and database search, and they were further classified by LOC tree, a hierarchical system of support vector machines which predict their sub-cellular localization. The amount of transferrin expression in brain cells decreased linearly with the increase of SCAT concentration in seawater. Among the 24 proteins identified on a 2D-PAGE gel, 9 demonstrated a synchronous response to acute cadmium, suggesting that they might represent a biomarker profile. Based on their variable levels and trends on the 2D-PAGE gel this protein (likely to be transferrin) suggesting they might be utilized as biomarkers to investigate cadmium pollution levels in seawater and halobios survival, as well as to evaluate the degree of risk of human fatalities. The results indicate that the application of multiple biomarkers has an advantage over a single biomarker for monitoring levels of environmental contamination.

Animals↗

PubMed2003

Comparison of plasma biomarkers with dietary assessment methods for fruit and vegetable intake.

OBJECTIVE: To assess the variability and validity of plasma-based biomarkers of antioxidant vitamin, and fruit and vegetable intake. SETTING: Leeds, Wakefield, Huddersfield and Bradford, England. SUBJECTS: A total of 54 free-living, nonsmoking women recruited from participants of the UK Women's Cohort Study (UKWCS). METHODS: Two fasting blood samples were taken at two time points, 18 months apart. A 4-day food diary was completed prior to the first blood sample and a 24-h recall was conducted at the time of the second blood collection. All blood samples were analysed for ascorbic acid and four carotenoids. Associations between antioxidant vitamin intake from all food sources and supplements, as well as fruit and vegetable intake, and plasma levels of the antioxidant vitamins were assessed. RESULTS: Using the 4-day diary, positive associations were found between micronutrient intake from all food sources and plasma concentrations of ascorbic acid (P<0.01) and beta-carotene (P<0.01). No associations were seen between plasma micronutrient levels and specifically fruit and vegetable intakes. In general, associations between plasma levels and intakes assessed by the 24-h recall were less marked than those based on the 4-day diary. CONCLUSIONS: Plasma ascorbic acid and beta-carotene are good indicators of previous vitamin C and beta-carotene intake, from all food sources. However, caution is required in extrapolating these results to include individual food groups, rich in these vitamins. The results imply that the practice of using plasma biomarkers simply as a proxy measure of dietary intake is not valid and emphasise that plasma biomarkers are not simply a reflection of dietary intake, but also of a number of physiological processes. Biomarkers in nutrition epidemiological studies are however useful to measure nutrient status at the tissue level.

Adult↗

PubMed2005

Evaluation of the Mytilus galloprovincialis Lam. digestive gland metallothionein as a biomarker in a long-term field study: seasonal and spatial variability.

A study was made of seasonal and spatial variability of metallothionein (MT) concentrations, determined spectrophotometrically in the soluble fraction of the digestive gland of mussels Mytilus galloprovincialis, collected between 1999 and 2001 from several coastal and estuarine locations along the central Eastern Adriatic coast (Croatia). The seasonal influence on the MT and metal concentrations (higher values in winter-spring season, than in summer-autumn season) is more pronounced than the local site-specific influence. Furthermore, within each season a significant site-specific dependence on the MT and trace metal variations can be detected. An inverse relationship of mussel condition index (CI) and temperature with MT and trace metals levels indicates the influence of food abundance and mussel annual reproductive cycle. Substantially higher concentrations of both MT and Cd were recorded in mussels inhabiting estuarine locations, possibly indicating a markedly higher Cd bioavailability at these locations. The positive correlations obtained between MT and Cd in all seasons except autumn support an argument for application of digestive gland MT as a biomarker of Cd exposure, providing evidence for assessing the most appropriate season for mussel sampling.

Analysis of Variance↗

PubMed2003

Natriuretic peptide hormone measurement in acute coronary syndromes.

Cardiac Ischemia is an important trigger for the release of B-type natriuretic peptide (BNP). BNP and N-terminal pro-BNP (N-proBNP) are emerging as important biomarkers for risk stratification in patients with acute coronary syndromes. Higher levels of BNP and pro-BNP are associated with a greater risk for death and heart failure, independent of traditional clinical variables and levels of other biomarkers such as troponins and C-reactive protein. The therapeutic implications of these findings are not yet known.

Acute Disease↗

PubMed2006

Functional genomics and proteomics in the clinical neurosciences: data mining and bioinformatics.

The goal of this chapter is to introduce some of the available computational methods for expression analysis. Genomic and proteomic experimental techniques are briefly discussed to help the reader understand these methods and results better in context with the biological significance. Furthermore, a case study is presented that will illustrate the use of these analytical methods to extract significant biomarkers from high-throughput microarray data. Genomic and proteomic data analysis is essential for understanding the underlying factors that are involved in human disease. Currently, such experimental data are generally obtained by high-throughput microarray or mass spectrometry technologies among others. The sheer amount of raw data obtained using these methods warrants specialized computational methods for data analysis. Biomarker discovery for neurological diagnosis and prognosis is one such example. By extracting significant genomic and proteomic biomarkers in controlled experiments, we come closer to understanding how biological mechanisms contribute to neural degenerative diseases such as Alzheimers' and how drug treatments interact with the nervous system. In the biomarker discovery process, there are several computational methods that must be carefully considered to accurately analyze genomic or proteomic data. These methods include quality control, clustering, classification, feature ranking, and validation. Data quality control and normalization methods reduce technical variability and ensure that discovered biomarkers are statistically significant. Preprocessing steps must be carefully selected since they may adversely affect the results of the following expression analysis steps, which generally fall into two categories: unsupervised and supervised. Unsupervised or clustering methods can be used to group similar genomic or proteomic profiles and therefore can elucidate relationships within sample groups. These methods can also assign biomarkers to sub-groups based on their expression profiles across patient samples. Although clustering is useful for exploratory analysis, it is limited due to its inability to incorporate expert knowledge. On the other hand, classification and feature ranking are supervised, knowledge-based machine learning methods that estimate the distribution of biological expression data and, in doing so, can extract important information about these experiments. Classification is closely coupled with feature ranking, which is essentially a data reduction method that uses classification error estimation or other statistical tests to score features. Biomarkers can subsequently be extracted by eliminating insignificantly ranked features. These analytical methods may be equally applied to genetic and proteomic data. However, because of both biological differences between the data sources and technical differences between the experimental methods used to obtain these data, it is important to have a firm understanding of the data sources and experimental methods. At the same time, regardless of the data quality, it is inevitable that some discovered biomarkers are false positives. Thus, it is important to validate discovered biomarkers. The validation process may be slow; yet, the overall biomarker discovery process is significantly accelerated due to initial feature ranking and data reduction steps. Information obtained from the validation process may also be used to refine data analysis procedures for future iteration. Biomarker validation may be performed in a number of ways - bench-side in traditional labs, web-based electronic resources such as gene ontology and literature databases, and clinical trials.

Animals↗

PubMed2005

Serum levels of insulin-like growth factor I, II, and binding protein 3, transforming growth factor beta-1, soluble fas ligand and superoxide dismutase activity in stomach cancer cases and their controls in the JACC Study.

BACKGROUND: The prognosis of stomach cancer with advanced stage remains poor. New biomarkers of the disease that may contribute to establish the potential screening strategy would be of value for the early detection of individuals at high risk of the disease. METHODS: We conducted a prospective, nested case-control analysis among apparently healthy men and women who were followed for up to 8 years in the Japan Collaborative Cohort (JACC) Study, to evaluate serum levels of insulin-like growth factor I, II, and binding protein 3 (IFG-I, IGF-II, and IGFBP-3), transforming growth factorbeta-1 (TGFbeta1), soluble fas (sFas) and superoxide dismutase activity (SOD) in 210 stomach cancer cases diagnosed in the JACC Study in relation to those levels in their 410 controls. RESULTS: Among 6 serum biomarkers tested for case-control differences, only sFas level in female stomach cancer cases was significantly higher than that of controls (2.22 pg/ml vs. 2.04 pg/mL, respectively; P=0.013 by two-way analysis of covariance controlling for matching variable). CONCLUSION: None of the biomarkers consistently predicted future risk of stomach cancer in both men and women in the present analysis. Serum sFas level in women, however, should be studied much more thoroughly whether it provides meaningful refinement of risk stratification, or it elucidate the mechanisms of tumorigenesis in women.

Adult↗

PubMed2003

Desmosterol: a biomarker for the efficient development of 20,25-diazacholesterol as a contraceptive for pest wildlife.

20,25-Diazacholesterol is being evaluated as a contraceptive for the nonlethal control of avian and mammalian wildlife pests. The identification of an analyte in blood which was highly correlated with absorbed dose and efficacy is valuable for determining effective formulations and dosing variables. Such an analyte or biomarker is also valuable for determining the percentage of pest populations that consume an effective dose of the active ingredient in the field. HPLC analyses of blood collected from dosed animals failed to detect 20,25-diazacholesterol but indicated that levels of free cholesterol and related compounds were affected by 20,25-diazacholesterol absorption. The greatest percent change in chromatographic peak area associated with 20,25-diazacholesterol administration was observed for desmosterol, a cholesterol precursor. 20,25-Diazacholesterol appeared to block the conversion of desmosterol to cholesterol, resulting in an elevated concentration of the precursor. The elevation of blood desmosterol levels is being used as an indicator of 20,25-diazacholesterol absorption and to facilitate the development of a 20,25-diazacholesterol-based contraceptive for pest wildlife.

Animals↗