Showing papers on "Biomarker (medicine) published in 2002"

Clinical potential of proteomics in the diagnosis of ovarian cancer.

Abstract: The need for specific and sensitive markers of ovarian cancer is critical. Finding a sensitive and specific test for its detection has an important public health impact. Currently, there are no effective screening options available for patients with ovarian cancer. CA-125, the most widely used biomarker for ovarian cancer, does not have a high positive predictive value and it is only effective when used in combination with other diagnostic tests. However, pathologic changes taking place within the ovary may be reflected in biomarker patterns in the serum. Combination of mass spectra generated by new proteomic technologies, such as surface-enhanced laser desorption ionization time-of-flight (SELDI-TOF) and artificial-intelligence-based informatic algorithms, have been used to discover a small set of key protein values and discriminate normal from ovarian cancer patients. Serum proteomic pattern analysis might be applied ultimately in medical screening clinics, as a supplement to the diagnostic work-up and evaluation.

Overview of biomarkers and surrogate endpoints in drug development

Abstract: There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker for in vivo activation of peroxisome proliferator-activated receptors (PPAR) γ activity.

Application of a novel protein biochip technology for detection and identification of rheumatoid arthritis biomarkers in synovial fluid.

Abstract: We compared protein profiles of the synovial fluid of patients with rheumatoid arthritis and osteoarthritis by using surface-enhanced laser desorption/ionization mass spectrometry technology. With this approach, we identified a protein expressed specifically in the synovial fluid of the patients with rheumatoid arthritis. During the investigation, we found several reproducible and discriminatory biomarker candidates for distinction between rheumatoid arthritis and osteoarthritis. Among these candidates, a 10 850 Da protein peak was the clearest example of a single signal found specifically in the rheumatoid arthritis samples. This candidate was purified using a size-exclusion spin column followed by gel electrophoresis and subsequently identified by peptide mapping and post-source decay (PSD) analysis. The results clearly indicate that the protein is myeloid-related protein 8, which was verified by the enzyme immunoassay. It is known that the myeloid-related protein 8 level in serum and synovial fluid is related to disease activity in juvenile rheumatoid arthritis. The results suggest that the ProteinChip platform is useful to detect and identify protein biomarkers expressed specifically in diseases or in some stage of diseases.

Cardiac markers for myocardial infarction. A brief review

Abstract: Blood testing for biomarkers of myocardial injury plays an increasingly important role for the evaluation, diagnosis, and triage of patients with chest pain. The guidelines for the diagnosis of myocardial infarction (MI) have recently changed and prominently incorporate the results of cardiac marker testing in the clinical definition of MI. We review these updated guidelines for MI definition as it pertains to cardiac biomarker testing and further compare the differing biology and release kinetics of clinically relevant biomarkers. Finally, we define the contemporary use of cardiac biomarker testing for patients with chest pain, including appropriate integration of point-of-care testing into day-to-day clinical use.

Lp-PLA2: an emerging biomarker of coronary heart disease.

Abstract: Cardiovascular disease is the leading cause of death in most industrialized countries. However, the diagnosis and management of coronary heart disease is far from optimal. Lipoprotein-associated phospholipase A2 (Lp-PLA2), also known as platelet-activating factor acetylhydrolase, is an enzyme that hydrolyses oxidized phospholipids and is primarily associated with low-density lipoprotein. Discussed in this review is the accumulating evidence supporting the view that Lp-PLA2 is a potential biomarker of coronary heart disease and plays and an important proinflammatory role in the progression of atherosclerosis. A new ELISA method for the quantitative measurement of Lp-PLA2 mass in human plasma developed by diaDexus, Inc. is presented. Furthermore, potential clinical applications of Lp-PLA2 mass measurements are proposed.

Identification and efficacy of longitudinal markers for survival

Abstract: Methods for the combined analysis of survival time and longitudinal biomarker data have been developed in recent years, with most emphasis on modelling and estimation. This paper focuses on the use of longitudinal marker trajectories as individual-level surrogates for survival. A score test for association which requires only standard methods for implementation is derived for the initial identification of candidate biomarkers. Methods for assessing efficacy of markers are discussed and a measure contrasting conditional and marginal distributions is proposed. An application using prothrombin index as biomarker for survival of liver cirrhosis patients is included.

Molecular and biologic markers of premalignant lesions of human breast.

Abstract: Summary: There is currently great interest in the detection and characterization of putative precursor breast cancer lesions because of the possibility of chemoprevention. Knowledge of the biologic features of premalignant lesions, although limited, is rapidly evolving. Premalignant breast lesions have been examined for the presence of genetic alterations and for the expression of biomarkers such as the estrogen receptor (ER), Ki67, p53, and HER2/neu. Data obtained from genetic studies of precursor breast lesions clearly support the contention that genetic alterations begin quite early in selected subsets of histologically benign lesions. Although the results of biomarker expression profiles have been contradictory, most studies agree that precursor lesions significantly overexpress ER and that progressive alterations in ER expression accompany the transition of normal cells to hyperplastic lesions and carcinoma in situ. So far, the collected evidence indicates that precursor lesions in the breast demonstrate biomarker expression profiles and genetic abnormalities that are distinct from those of terminal ductal lobular units but share some of these features with invasive tumors. Future research in this field is urgently needed to identify specific biomarkers of prognostic and predictive value, which can help not only in the selection of patients for chemopreventive therapy but in monitoring the progression of high-risk lesions.

Application of surface‐enhanced laser desorption/ionization technology to the detection and identification of urinary parvalbumin‐α: A biomarker of compound‐induced skeletal muscle toxicity in the rat

Abstract: In toxicity studies, compound-induced changes are typically evaluated using a combination of endpoints and there are often a number of potential markers in biological fluids which can indicate toxic change in tissues and organs. However, some biomarkers are not specific to the organ of injury and therefore there is a continuing search for more sensitive and specific indicators of target organ toxicity. In experiments to assess the potential diagnostic usefulness of surface-enhanced laser desorption/ionization (SELDI) ProteinChip technology, skeletal muscle toxicity was induced in Wistar Han rats by administering 2,3,5,6-tetramethyl-p-phenylenediamine (TMPD). The skeletal muscle toxicity was monitored using established endpoints such as increase in serum aldolase (Aldol), aspartate aminotransferase (AST) and histopathology, and also using SELDI retentate chromatography mass spectrometry of urine samples. Clear differences in urinary protein patterns between control and TMPD-treated animals were observed on the ProteinChip surfaces. Additionally a specific urine marker protein of 11.8 kDa was identified in TMPD-dosed rats, and the detection of the marker was related to the degree of skeletal muscle toxicity assessed by recognized clinical pathology endpoints. The 11.8 kDa protein was identified as parvalbumin-alpha. These experiments demonstrated the potential of urinary parvalbumin-alpha as a specific, noninvasive, and easily detectable biomarker for skeletal muscle toxicity in the rat and the potential of SELDI technology for biomarker detection and identification in toxicology studies.

Validity of mercury exposure biomarkers

Abstract: I. Application of exposure biomarkers in the Arctic 236 II. Hair-mercury as exposure biomarker 237III. Sources of variation 237 IV. Temporal variation along hair strands 239 V. Association with other biomarkers 241

Carbon monoxide as a biomarker and therapeutic agent

Abstract: The present invention relates to the use of carbon monoxide (CO) as a biomarker and therapeutic agent of heart, lung, liver, spleen, brain, skin and kidney diseases and other conditions and disease states including, for example, asthma, emphysema, bronchitis, adult respiratory distress syndrome, sepsis, cystic fibrosis, pneumonia, interstitial lung diseases, idiopathic pulmonary diseases, other lung diseases including primary pulmonary hypertension, secondary pulmonary hypertension, cancers, including lung, larynx and throat cancer, arthritis, wound healing, Parkinson's disease, Alzheimer's disease, peripheral vascular disease and pulmonary vascular thrombotic diseases such as pulmonary embolism. CO may be used to provide anti-inflammatory relief in patients suffering from oxidative stress and other conditions especially including sepsis and septic shock. In addition, carbon monoxide may be used as a biomarker or therapeutic agent for reducing respiratory distress in lung transplant patients and to reduce or inhibit oxidative stress and inflammation in transplant patients.

The Role of Retinoid X Receptor Messenger RNA Expression in Curatively Resected Non-Small Cell Lung Cancer

Abstract: Background: Retinoid X receptors (RXRs) have inhibitory effects on non-small cell lung cancer (NSCLC) cell growth, and RXRβ expression is reduced in NSCLC specimens compared with normal lung tissue. We hypothesized that suppressed RXR expression might be a prognostic factor of worse clinical outcome in patients with NSCLC. Experimental Design: Using a quantitative real-time reverse transcription-PCR (TaqMan) method, we analyzed RXRα, RXRβ, and RXRγ mRNA expression in normal lung tissue and matching tumor samples from 88 patients with NSCLC. Results: The median mRNA expression levels of all three RXR subtypes were frequently decreased in tumor tissues compared with matching normal lung tissue (RXRα, 67%; RXRβ, 55%; RXRγ, 89%). The RXRα ( P = 0.001) and RXRγ ( P P = 0.0005), whereas a trend toward worse survival was observed for patients with low RXRα expression. Multivariate analysis indicated that low RXRβ expression is an independent predictor of worse survival in patients with NSCLC ( P = 0.017). Conclusion: Suppressed mRNA expression of all three RXR subtypes is a frequent event in NSCLC. Reduced RXRβ expression might be an important biomarker for more aggressive disease in patients with NSCLC.

Delivery of high-quality biomarker assays.

Abstract: Biomarker measurements now support key decisions throughout the drug development process, from lead optimization to regulatory approvals. They are essential for documenting exposure-response relationships, specificity and potency toward the molecular target, untoward effects, and therapeutic applications. In a broader sense, biomarkers constitute the basis of clinical pathology and laboratory medicine. The utility of biomarkers is limited by their specificity and sensitivity toward the drug or disease process and by their overall variability. Understanding and controlling sources of variability is not only imperative for delivering high-quality assay results, but ultimately for controlling the size and expense of research studies. Variability in biomarker measurements is affected by: biological and environmental factors (e.g., gender, age, posture, diet and biorhythms), sample collection factors (e.g., preservatives, transport and storage conditions, and collection technique), and analytical factors (e.g., purity of reference material, pipetting precision, and antibody specificity). The quality standards for biomarker assays used in support of nonclinical safety studies fall under GLP (FDA) regulations, whereas, those assays used to support human diagnostics and healthcare are established by CLIA (CMS) regulations and accrediting organizations such as the College of American Pathologists. While most research applications of biomarkers are not regulated, biomarker laboratories in all settings are adopting similar laboratory practices in order to deliver high-quality data. Because of the escalation in demand for biomarker measurements, the highly-parallel (multi-plexed) assay platforms that have fueled the rise of genomics will likely evolve into the analytical engines that drive the biomarker laboratories of tomorrow.

The AD7C-NTP neuronal thread protein biomarker for detecting Alzheimer's disease

Abstract: Dementia in Alzheimer's disease (AD) is ultimately due to cell loss mediated by several mechanisms including, apoptosis, impaired mitochondrial function, and possibly necrosis. A second major neuroanatomic correlate of dementia is aberrant cortical neuritic sprouting with abundant proliferation of dystrophic neurites. Early in vivo detection of AD will require non-invasive assays of highly sensitive and relatively specific biomarkers that reflect these fundamental abnormalities in cellular function. The AD-associated neuronal thread protein (AD7c-NTP) gene encodes an approximately 41 kD membrane-spanning phosphoprotein that causes apoptosis and neuritic sprouting in transfected neuronal cells. The AD7c-NTP gene is over-expressed in AD beginning early in the course of disease. In the brain, increased AD7c-NTP immunoreactivity is associated with phospho-tau-immunoreactive cytoskeletal lesions, but not with amyloid-? accumulations. The levels of AD7c-NTP in postmortem brain tissue correlate with the levels measured in paired ventricular fluid samples, suggesting that the protein is secreted or released by dying cells into cerebrospinal fluid (CSF). In this regard, elevated levels of AD7c-NTP can be detected in both CSF and urine of patients with early or moderately severe AD, and the CSF and urinary levels of AD7c-NTP correlate with the severity of dementia. The newest configuration of the AD7c-NTP assay, termed "7c Gold", has greater than 90% sensitivity and specificity for detecting early AD. The aggregate results from a number of studies suggest that AD7c-NTP is an excellent biomarker that could be helpful in the routine clinical evaluation of elderly patients at risk for AD.

Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion.

Abstract: Purpose: The study was conducted to determine whether immunohistochemical analysis of Ki-67, p53, and bcl-2 in patients with non-small-cell lung cancer is associated with a higher rate of brain metastases and whether the intrapatient expression of these biomarkers (in the primary tumors vs. brain lesions) is similar. Methods and Materials: At the M. D. Anderson Cancer Center, tumors from 29 case patients with primary lung tumor and brain metastasis and 29 control patients with primary lung tumor but no brain metastasis were resected and examined for immunohistochemical expression. Ki-67, p53, and bcl-2 were analyzed in resected primary lung, lymph node, and metastatic brain tumors. Each control patient was matched by age, gender, and histology to a patient with brain metastasis. Results: No significant differences in patient survival characteristics were detected between the case group and control group. Also, difference in patient outcome between the two groups was not generally predicted by biomarker analysis. However, when the groups were combined, the biomarker analysis was predictive for certain patient outcome end points. Using median values as cutoff points between low and high expression of biomarkers, it was observed that high expression of Ki-67 (>40%) in lung primaries was associated with poorer disease-free survival ( p = 0.04), whereas low expression of p53 in lung primaries was associated with poorer overall survival ( p = 0.04), and these patients had a higher rate of nonbrain distant metastases ( p = 0.02). The patients with brain metastases were particularly prone to developing nonbrain distant metastases if the percentage of p53-positive cells in brain metastases was low ( p = 0.01). There was a positive correlation in the expression of Ki-67 ( p = 0.02)( r 2 = 0.1608), as well as p53 ( p r 2 = 0.7380), between lung primaries and brain metastases. Compared to Ki-67 and p53, bcl-2 was the least predictive. Conclusion: Differences in biomarker expression between the case and control groups did not serve as significant predictors of brain metastasis or patient survival. There was a strong correlation between lung primary biomarker expression and brain metastasis expression for Ki-67 and p53. Univariate analysis showed that low p53 and high Ki-67 expression predicted poor prognosis. This study shows that there may be a strong correlation between biomarker expression in non-small-cell lung cancer primary tumors and their brain metastases.

p97 as a biomarker for Alzheimer disease

Abstract: The search is ongoing for a reliable serum biomarker for AD. The level of iron is elevated in the brain of Alzheimer's disease (AD) patients. Our studies have demonstrated that the level of the iron transport protein, p97, is increased in the serum of AD patients but not in various control groups. These results have recently been confirmed by another laboratory who extended our findings by demonstrating that p97 is not elevated in other neurodegenerative diseases. This qualifies p97 as a potentially powerful biomarker specific for AD. Although the relationship between increased level of iron and p97 in the AD brain is not well understood, our research supports the hypothesis that p97 over-expressed by senile plaque associated reactive microglia is exocytosed and appears in blood. The relationship between elevated levels of serum p97 and AD, together with the possible future clinical application of p97 are considered in this report.

Method of monitoring neuroprotective treatment

Abstract: Methods for monitoring and evaluating the efficacy of neuroprotective treatment of a patient suffering from neurological damage by measuring the amount of at least one biomarker in a biological sample taken from the patient during or after treatment

Alveolar Macrophages as Biomarkers of Pulmonary Irritation in Kitchen Workers

Abstract: Objectives: Alveolar macrophages (AM) are used as a biomarker of pulmonary irritation due to occupational exposure in the AM test. The aim of this study was to investigate whether there is a co-variation between the number of AM and exposure to cooking fumes. Materials and methods: The study group consisted of 62 volunteers. People who worked in a kitchen preparing hot meals were considered as occupationally exposed (35 persons). The exposed group was further divided into highly and slightly exposed persons according to the levels of fat aerosols and aldehydes in the working atmosphere. People who were not preparing hot meals were considered as unexposed (27 persons). The number of AM was counted in smears prepared from expectorate samples from each participant. Samples were taken on three different days. Results: Highly occupationally exposed persons had a higher number of AM in their samples than both slightly occupationally exposed persons and unexposed persons. Highly exposed smokers had a statistically significantly higher number of AM compared with both slightly and unexposed smokers (P ≤ 0.05). Conclusion: The results suggest an increase in the number of AM due to exposure to cooking fumes and a synergistic effect between occupational exposure and smoking.

Covariates and confounding in epidemiologic studies using metabolic gene polymorphisms

Abstract: The relationship between exposure and disease when biomarkers are introduced in an epidemiologic study is explored and summarized. In molecular epidemiologic studies, biologic measurements play a major role as markers of exposure, disease or susceptibility to disease and/or exposure. In this scenario, the definition and management of confounding factors may change. Sometimes the presence or activation of the biomarker is partially caused by the relevant environmental exposure, and therefore the 2 variables (exposure and biomarker) should not be always treated as confounders of each other. Models of exposure-disease association in the presence of biologic markers are presented. The concept of confounders is reviewed in light of the role of biomarkers in the pathway between exposure and disease. © 2002 Wiley-Liss, Inc.

A simple biomarker to exclude the presence of low grade inflammation in apparently healthy individuals.

Abstract: BACKGROUND Atherosclerosis is accompanied by a low grade inflammatory response. HYPOTHESIS To use erythrocyte aggregability as a biomarker to exclude the presence of low grade inflammatory response in apparently healthy individuals. METHODS The adhesiveness/aggregation of red blood cells was quantitated by using a simple slide test and image analysis. RESULTS We included 121 apparently healthy individuals and found a significant correlation between the degree of erythrocyte adhesiveness/aggregation and either the concentration of high sensitive CRP (r = 0.6, P < 0.001), erythrocyte sedimentation rate (r = 0.5, P < 0.0001) or fibrinogen (r = 0.5, P < 0.0001). By using certain cutoff points for the erythrocyte adhesiveness/aggregation test we could define individuals with a very low grade inflammatory response. CONCLUSIONS By using this inexpensive and rapid assessment, we could clearly discriminate between individuals with a very low inflammatory response and those with a more intense one. This biomarker should be further evaluated as a possible screening test for use in large populations of apparently healthy individuals in whom the detection of low grade inflammation might contribute to guiding appropriate lifestyle modifications and therapeutic interventions.