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Results for “Biomarker variability”

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PubMed2005

Extraction and processing of high quality RNA from impalpable and macroscopically invisible prostate cancer for microarray gene expression analysis.

Molecular analyses of early-stage prostate cancers are necessary to assess their potential clinical significance based on established and/or novel biomarkers for tailored clinical management. A prerequisite for the application of RNA-based analyses of such, mostly macroscopically-undetectable, small prostate carcinomas is the recovery and preservation of sufficient RNA quantities and quality. Furthermore, in prostate cancer, heterogeneity is a common phenomenon that includes a juxtaposition of different tissue compositions and variable histological grades within the same tumor focus. To better understand the molecular mechanisms of prostate cancer, it is essential to correlate molecular data with a specific cell type. Here, we present a tissue collecting protocol which is aligned with the preoperative evaluation of tumor localization. In combination with the technique of laser microdissection and pressure catapulting, we are able to preserve RNA of high quality from homogeneous cell populations of macroscopically-undetectable small prostate carcinomas. To obtain the necessary RNA quantities for whole genome cDNA microarrays, the isolated total RNAs were amplified by T7-based RNA-polymerase in vitro transcription. The microarray analyses (Human Unigene Set RZPD3.1) resulted in 216 differentially expressed genes (191 down-regulated, 25 up-regulated). Among these were several known prostate cancer relevant genes, such as AMACR, TARP, LIM, GPR160 (all up-regulated), CAV1, NTN1, MT1X; CLU, TRIM29, SPARCL1 and HSPB8 (all down-regulated).

Down-Regulation↗

PubMed2006

Application of nonlinear analysis methods for identifying relationships between microbial community structure and groundwater geochemistry.

The relationship between groundwater geochemistry and microbial community structure can be complex and difficult to assess. We applied nonlinear and generalized linear data analysis methods to relate microbial biomarkers (phospholipids fatty acids, PLFA) to groundwater geochemical characteristics at the Shiprock uranium mill tailings disposal site that is primarily contaminated by uranium, sulfate, and nitrate. First, predictive models were constructed using feedforward artificial neural networks (NN) to predict PLFA classes from geochemistry. To reduce the danger of overfitting, parsimonious NN architectures were selected based on pruning of hidden nodes and elimination of redundant predictor (geochemical) variables. The resulting NN models greatly outperformed the generalized linear models. Sensitivity analysis indicated that tritium, which was indicative of riverine influences, and uranium were important in predicting the distributions of the PLFA classes. In contrast, nitrate concentration and inorganic carbon were least important, and total ionic strength was of intermediate importance. Second, nonlinear principal components (NPC) were extracted from the PLFA data using a variant of the feedforward NN. The NPC grouped the samples according to similar geochemistry. PLFA indicators of Gram-negative bacteria and eukaryotes were associated with the groups of wells with lower levels of contamination. The more contaminated samples contained microbial communities that were predominated by terminally branched saturates and branched monounsaturates that are indicative of metal reducers, actinomycetes, and Gram-positive bacteria. These results indicate that the microbial community at the site is coupled to the geochemistry and knowledge of the geochemistry allows prediction of the community composition.

Bacteria↗

PubMed1996

[Role pf genetic and other biomarkers in the prognostication of postoperative course in patients with lung cancer].

Relationships between genetic polymorphisms (ABO, RH, HP, TF, GC, Pi, ACP1, PGM1, GLO1, PTC) and some clinical, biochemical, and functional parameters were studied in patients with epidermoid carcinoma of the lung who were divided into 2 groups: those with uncomplicated and complicated postoperative courses of the disease. They were found to be different in the two groups. The values of ESR, albumin, lymphocytes, vital capacity, and RQ are the most distinctive signs that differentiate the patient groups. A high correlation was found between the signs in patients with an uncomplicated postoperative course. A less correlation between the signs, as a higher intergroup variability in the majority of the signs under study suggests that there is a significantly impaired physiological homeostasis in the group of patients with a complicated course. Comparing the mean values and dispersions shows their equal direction in the two groups of patients irrespective of their genetic polymorphism. The GC system is associated with profound changes of the studied signs in the group of patients with an uncomplicated course and GC*1F carriage should be regarded as a poor factor in the prognosis of the disease.

Adult↗

PubMed2005

Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death.

Alpha-methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation >0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cut-points were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cut-point on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cut-point developed using prostate cancer-specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.

Biomarkers, Tumor↗

PubMed2003

Sources of polycyclic aromatic hydrocarbon exposure in non-occupationally exposed Koreans.

Urinary 1-hydroxypyrene (1-OHP), an exposure biomarker for polycyclic aromatic hydrocarbons (PAHs), was used to identify potential sources of PAH exposure for 660 Koreans who were not occupationally exposed to PAHs (65% male; 35% female; mean age, 36.5 +/- 11.1 years). In this study, 74% of subjects had detectable levels of urinary 1-OHP, with a concentration range of 0.001-3.796 microg/L (median, 0.079 microg/L). A backward elimination was conducted: five variables were selected with a significance level for removal of P < or = 0.1. The results of this study showed that residence in areas with relatively poor environmental conditions (Seoul and Suwon) was strongly associated with high concentrations of urinary 1-OHP (P = 0.007), while consumption of fried chicken and length of time spent outdoors had marginal positive associations with urinary 1-OHP levels (P = 0.06 and P = 0.09, respectively). Compared with the above three factors, tobacco smoking and urinary cotinine levels were poorly associated with urinary 1-OHP (P = 0.16 and 0.23, respectively). Pear consumption had an inverse association with urinary 1-OHP levels (P < 0.01). Individual variations in urinary 1-OHP concentrations were evaluated by considering the subjects' age, sex, and genetic polymorphisms in enzymes involved in the metabolism of PAHs. Among the individual variations, GSTT1-present subjects showed higher 1-OHP levels than GSTT1-absent subjects in cities having 10-microm particulate matter (PM(10)) levels and population density lower than those of Seoul and Suwon (P < 0.05). These epidemiological results suggest that the above factors that should be considered in preventing PAH exposure.

Adult↗

PubMedDate not supplied

Two-stage evaluation of exposure to mercury and biomarkers of neurotoxicity at a hazardous waste site.

Communities surrounding the Rocky Mountain Arsenal (RMA), a Superfund site in Colorado, were studied in order to determine whether exposures to mercury were greater among persons who resided there than among residents of a comparison area 12-15 miles distant. From a census-based stratified random sample, 469 persons were interviewed and urine samples were obtained for biomonitoring. Mercury was detected in urine from 32 (6.8%) of the 469 persons sample at a detection limit of 5 ppb. Trace levels of mercury (detectable, but nonquantifiable) were found in 80 (17.1%) of the persons sampled. Neither the frequency of detection, the arithmetic mean, nor the geometric mean value for urine mercury was found to be statistically different when persons living near the site were compared to persons from the more distant comparison area. The risk of mercury exposure associated with demographic variables, residence, occupation, hobbies, dietary habits, water supply, housing, and activity patterns was evaluated. In the second stage of the evaluation, the Neurobehavioral Core Test Battery (NCTB) is being used to assess individual functional deficits and nervous system disorders associated with exposure to mercury and other neurotoxic chemicals.

Adolescent↗

PubMed1999

Behavioral biomarkers of aging: illustration of a multivariate approach for detecting age-related behavioral changes.

The goal of the current project is to develop a multivariate statistical strategy for the formation of behavioral indices of performance and, further, to apply this strategy to establish the relationship between age and important characteristics of performance. The strategy was to begin with a large set of measures that span a broad range of behaviors. The behavioral effects of the following variables were examined: Age (4, 12, 24, and 30 months), genotype [Fischer 344 and a hybrid (F1) of Fischer 344 and Brown Norway (F344xBN)], gender (Fischer 344 males and Fischer 344 females), long-term diet (ad lib diet or dietary restriction beginning at 4 months of age), and short-term diet (ad lib diet or dietary restriction during testing). The behavioral measures were grouped into conceptually related indicators. The indicators within a set were submitted to a principal component analysis to help identify the summary indices of performance, which were formed with the assumption that these component scores would offer more reliable and valid measures of relevant aspects of behavioral performance than would individual measures taken alone. In summary, this approach has made a number of important contributions. It has provided sensitive and selective measures of performance that indicated contributions of all variables: psychological process, age, genotype, gender, long-term and short-term diet and has increased the sensitivity of behavioral measures to age-related behavioral impairment. It has also improved task-manageability by decreasing the number of meaningful variables without losing important information, consequently providing a simplification of the pattern of changes.

Age Factors↗

PubMed2006

Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia.

PURPOSE: Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. PATIENTS AND METHODS: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. RESULTS: ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. CONCLUSION: There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Biomarkers, Tumor↗

PubMed2004

Population pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies.

PURPOSE: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a novel anticancer agent in clinical development. The objectives of this study were to develop a population pharmacokinetic model for 17AAG and its major metabolite, 17AG, and to investigate influences of patient characteristics and biochemical markers on pharmacokinetic parameters estimated for 17AAG and 17AG. EXPERIMENTAL DESIGN: In a phase I clinical study, 17AAG was administered by intravenous infusion to 43 patients with refractory, advanced malignancies. Plasma concentrations of 17AAG and 17AG were determined by high-performance liquid chromatography. Plasma concentration vs time data were modeled using NONMEM. Nine covariates (age, sex, performance status, weight, height, body surface area, AST, bilirubin and serum creatinine) were investigated for their influences on individual pharmacokinetic parameters. RESULTS: Plasma concentration vs time data were best described by a two-compartment model for 17AAG and a one-compartment model for 17AG. Volumes of distribution were 24.2 and 89.6 l for 17AAG. Total elimination clearances were 26.7 and 21.3 l/h for 17AAG and 17AG, respectively. Both fixed and random effects pharmacokinetic parameters were well estimated. None of the covariates explained the interindividual variability in 17AAG and 17AG pharmacokinetic parameters or improved the fit of the model based on objective function changes. CONCLUSIONS: A population pharmacokinetic model was developed to describe 17AAG and 17AG population pharmacokinetic parameters and interindividual variabilities. There were substantial interindividual variabilities in 17AAG and 17AG pharmacokinetic parameters despite BSA-normalized dosing.

Adult↗

PubMed2005

Chronic fatigue syndrome: the need for subtypes.

Chronic fatigue syndrome (CFS) is an important condition confronting patients, clinicians, and researchers. This article provides information concerning the need for appropriate diagnosis of CFS subtypes. We first review findings suggesting that CFS is best conceptualized as a separate diagnostic entity rather than as part of a unitary model of functional somatic distress. Next, research involving the case definitions of CFS is reviewed. Findings suggest that whether a broad or more conservative case definition is employed, and whether clinic or community samples are recruited, these decisions will have a major influence in the types of patients selected. Review of further findings suggests that subtyping individuals with CFS on sociodemographic, functional disability, viral, immune, neuroendocrine, neurology, autonomic, and genetic biomarkers can provide clarification for researchers and clinicians who encounter CFS' characteristically confusing heterogeneous symptom profiles. Treatment studies that incorporate subtypes might be particularly helpful in better understanding the pathophysiology of CFS. This review suggests that there is a need for greater diagnostic clarity, and this might be accomplished by subgroups that integrate multiple variables including those in cognitive, emotional, and biological domains.

Diagnosis, Differential↗

PubMed1990

Effect of external beam radiation therapy on serum prostate-specific antigen.

The effect of external beam radiation on serum prostate-specific antigen (PSA) was determined in 20 patients with nonmetastatic carcinoma of the prostate. An abnormal PSA was measured in 91 percent and 93 percent, respectively, of the samples collected prior to or during radiation therapy. By seven months, 8/15 men still had an abnormal PSA level. Four of 5 men with an elevated PSA at least twenty-three months after radiation therapy had a positive prostatic biopsy, and 3/3 patients with a normal PSA had a negative ultrasonically guided biopsy. The rate of decline of serum PSA after radiation therapy is variable. These preliminary data suggest that serum PSA may be useful for assessing the local response of prostate cancer to radiation therapy.

Adenocarcinoma↗

PubMed1994

Prognostic significance of pS2 protein expression in pulmonary adenocarcinoma.

In the present study, pS2 protein expression in pulmonary adenocarcinoma was investigated on paraffin-embedded sections obtained from 170 patients. 28 (16%) patients showed varying degrees of pS2 protein expression in the cytoplasm of tumour cells, as detected by immunohistochemical staining with anti-pS2 protein antibody. There was a significant association between pS2 protein expression and larger tumour size, and the acinar or bronchiolo-alveolar subtype. However, no significant correlations between pS2 protein status and the other clinicopathological factors, i.e. T-factor, N-factor, stage and histological differentiation, were shown. In contrast to breast cancer, patients with pS2-positive pulmonary adenocarcinomas had a significantly worse prognosis than those with pS2-negative pulmonary adenocarcinomas; this was true for stage I patients, as well as for all patients. Multivariate analysis showed that pS2 protein expression was a discriminating variable in overall survival. These findings suggest that pS2 protein status is a possible prognostic indicator in pulmonary adenocarcinoma.

Adenocarcinoma↗

PubMed2006

Urinary levels of matrix metalloproteinase 9 and 2 and tissue inhibitor of matrix metalloproteinase in patients with coronary artery disease.

OBJECTIVES: To evaluate the feasibility of an assay for urinary levels of matrix metalloproteinases (MMPs) and the potential usefulness of urinary MMPs as a marker of coronary atherosclerosis or acute coronary syndromes (ACS). METHODS AND RESULTS: We measured urine and plasma MMP-9, MMP-2 and urine tissue inhibitor of metalloproteinase (TIMP-1) in patients with ACS (n=27), patients with coronary artery disease (CAD), but no clinical instability (n=47) and a group of healthy volunteers (n=15) who were <35 years of age, had no risk factors for CAD and did not undergo angiography. Compared with volunteers, patients with ACS and CAD had higher urine MMP-9, urine TIMP-1, plasma MMP-9 and plasma MMP-2 levels, but these did not differ between those with CAD and ACS. Using the volunteers to roughly establish an upper limit of normal, 84% of the urine TIMP-1 values and 95% of the urine MMP-9 values were abnormally elevated among those with CAD and ACS. CONCLUSIONS: Urine MMP-9 and TIMP-1 levels are elevated in patients with CAD and ACS compared with healthy volunteers. A high percent of patients with CAD or ACS had elevated urine values of MMP-9 and TIMP-1 suggesting these variables might be a useful marker of atherosclerotic disease.

Acute Disease↗

PubMed2004

Measuring plasma B-type natriuretic peptide in heart failure: good to go in 2004?

Elevated plasma brain natriuretic (BNP) concentrations correlate with increased cardiac filling pressures. Therefore, increased BNP has been proposed as a marker for asymptomatic ventricular dysfunction, as an aid in the diagnosis of cardiac dyspnea, as an end point to assess the efficacy of heart failure therapy, and as a prognostic marker in heart failure. An understanding of the utility of BNP requires an appreciation of the sensitivity, specificity, and diagnostic accuracy of BNP in each of these clinical situations. At this time, there is strong evidence for the value of BNP in the evaluation of dyspnea of uncertain cause. Further population studies will need to be performed to refine the application of BNP to community cohorts and to determine its clinical value and cost-effectiveness as a screening tool in the early diagnosis of ventricular dysfunction. To make optimal use of BNP for the assessment of heart failure therapy and prognosis in individual patients, physicians will require additional information on the biological variability of BNP. Studies comparing the sensitivity, specificity, and predictive value of the available BNP and N-terminal pro-BNP assays need to be conducted in each of these clinical settings.

Biomarkers↗

PubMed2006

Affinity maturation of phage display antibody populations using ribosome display.

A comparison has been performed, using phage display or ribosome display, of stringent selections on antibody populations derived from three rounds of phage display selection. Stringent selections were performed by reducing concentrations of the antigen, bovine insulin, down to 1 nM. Higher affinity antibodies were isolated using ribosome display in a process that introduces random mutations across the clone population. Whereas the highest affinity antibody produced by phage display, D3, has a K(d) of 5.8 nM as a scFv fragment, ribosome display generated higher affinity variants of this antibody with K(d) values of 189 pM and 152 pM, without or with the use of error prone mutagenesis, respectively. The affinities were further increased for each antibody on conversion of the scFv fragments to whole IgG format, to a K(d) of less than 21 pM for the highest affinity variant of D3. Mutation of VH D101 of antibody D3 to glycine or valine, removing the salt bridge between K94 and D101 at the base of VHCDR3, was responsible for the enhanced affinity observed. In addition to the variants of D3, other unrelated antibodies of comparable or higher affinity for insulin, were isolated by ribosome display, but not phage display, indicating that ribosome display can enrich for different populations of antibodies. Affinity maturation of phage antibody populations using ribosome display is a valuable method of rapidly generating diverse, high affinity antibodies to antigen and should be readily applicable to the isolation of antibodies for the detection and assay of biomarkers.

Amino Acid Sequence↗

PubMed2003

Molecular markers to identify patients at risk for recurrence after primary treatment for prostate cancer.

Accurate prognostication is a prerequisite for accurate therapeutics and management of prostate cancer because indolent tumors may require no intervention, whereas aggressive tumors lead to patient mortality. There is a critical need to define these subgroups of patients with prostate cancer differing in clinical outcome. Prognostic nomograms based on clinical data provide useful predictions of clinical states and outcomes, but they need further refinements to improve accuracy and universality. Genomic and proteomic analyses have provided many novel markers that may help define prognostic parameters based on the underlying biology of prostate cancer progression at the molecular level. These molecular markers are likely to augment traditional prognostic modalities by providing a set of molecularly defined and quantifiable variables. Encompassing the genome, transcriptome, and proteome of prostate cancer will likely provide "molecular signatures" that will bridge prognostication, prediction, and treatment in a single continuum.

Adenocarcinoma↗

PubMed2003

CAP variables and arousals as sleep electroencephalogram markers for primary insomnia.

OBJECTIVE: Polysomnographic (PSG) measures consistently reflect poor sleep quality and effective treatment in insomniac patients. METHODS: The PSG findings of 47 patients (18 M and 29 F, 42.5+/-10 years) meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for a diagnosis of primary insomnia were compared with those of 25 age- and gender-balanced healthy subjects (controls) without sleep complaints. After one adaptation night to the sleep lab, each patient underwent two randomized double-blind PSG recordings. Twenty-four patients followed a placebo-drug sequence and 23 a drug-placebo succession. Active treatment consisted of widely used hypnotic drugs, i.e. zolpidem, triazolam, zopiclone, brotizolam. Conventional PSG measures, electroencephalogram (EEG) arousals and CAP variables (including phase A subtypes) were quantified and statistically analyzed. RESULTS: Compared to controls, insomniac patients under placebo showed a significant increase of CAP rate, subtypes A1 and A2, EEG arousals, nocturnal wakefulness and stage 1, associated with reduced values of total sleep time and slow wave sleep (stages 3 and 4). In insomniac patients, sleep quality was significantly improved by hypnotic treatment. Compared to placebo, active medication significantly reduced CAP rate, subtypes A1 and A2, but had only marginal effects on subtypes A3 and on EEG arousals. Under hypnotic treatment total sleep time, nocturnal awakenings, stage 1 and slow wave sleep recuperated normal values. The most significant correlation between sleep quality and PSG variables was found for CAP rate (P<0.0001). CONCLUSIONS: PSG investigation extended to CAP variables and EEG arousals can be an important procedure for the diagnosis of primary insomnia and evaluation of treatment efficacy.

Adult↗

PubMed2002

Serum tetranectin is an independent prognostic marker in colorectal cancer and weakly correlated with plasma suPAR, plasma PAI-1 and serum CEA.

Soluble tetranectin (TN) was measured preoperatively in serum from 567 patients with primary colorectal cancer and levels were tested for association with prognosis. The prognostic significance of TN was also compared to that of plasminogen-activator inhibitor-1 (PAI-1), urokinase plasminogen activator (uPAR) and carcinoembryonic antigen (CEA). Significantly shorter survival was found for patients with TN levels below a cut-off point of 7.5 mg/l compared to patients with levels above, as illustrated by Kaplan-Meier curves. By Cox analyses, log TN, log soluble uPAR as well as log CEA were found to have an independent prognostic value for survival (log TN: HR = 0.47, 95% CI: 0.29-0.76); log soluble uPAR: HR = 1.65, 95% CI: 1.18-2.31; log CEA: HR = 1.I1, 95% CI: 1.03-1.20). Based on the multivariate model, a patient with a combination of low levels of TN and PAI-1 and elevated levels of soluble uPAR and CEA had a 2.43 increased risk as compared to a patient with median levels of these biochemical markers. Significant correlations were found with Dukes' stages for all the biochemical markers and between the respective biochemical markers. The findings confirm that TN is a strong prognostic factor in patients with colorectal cancer. TN may be valuable as a prognostic variable in future studies evaluating new treatment strategies for colorectal cancer.

Adenocarcinoma↗