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PubMed1995

Comodulation of cellular polyamines and proliferation: biomarker application to colorectal mucosa.

Polyamines are low molecular weight aliphatic amines required for normal cellular growth which are ubiquitously found in all living tissues. Polyamine biosynthesis is known to increase with mitogenesis, and elevated polyamine concentrations are found in hyperproliferative tissues. Quantitation of tissue polyamine content may thus provide a biochemical measure of proliferation, with potential biomarker application to the colonic mucosa where dysregulated epithelial proliferation is associated with cancer risk. This study was performed to validate polyamine analyses as a measure of cellular proliferation, and to preliminarily assess polyamine characteristics when applied to clinical samples. Using FHC, a human colonic epithelial cell line, for in vitro experimentation, deoxycholic acid or retinol was added to freshly passaged cultures to either stimulate or inhibit proliferation, respectively. Parallel cultures were then assayed for (1) proliferation by sulforhodamine B staining; and (2) polyamine content by a high-performance liquid chromatographic method. Deoxycholic acid stimulated, and retinol inhibited proliferation in dose-dependent fashion. Polyamine content, specifically the spermidine content and the spermidine/spermine ratio, also increased or decreased in response to culture with deoxycholic acid or retinol, respectively. Significant linear correlations between proliferation and spermidine (r = 0.858, P < 0.001), and with the spermidine/spermine ratio (r = 0.574, P < 0.05) were observed. When quantitative polyamine analyses were applied to human colonic specimens, replicate mucosal sampling revealed a high degree of intra-individual variability, indicating a heterogeneous distribution of polyamines within anatomically confined colonic segments. The results support a role for quantitative polyamine analyses as a correlative measure of colonic epithelial proliferation; however, intraindividual variability may limit the utility of colorectal biomarker measurements.

Biomarkers↗
PubMed2007

Expression of biomarkers of interferon type I in patients suffering from chronic diseases.

Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (beta2mg) and 2-5 oligoadenylate synthetase (2-5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing-remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, beta2mg and 2-5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed2003

Further evaluation of the basic nature of the human biological aging process based on a factor analysis of age-related physiological variables.

This study aimed to reexamine whether there exists a primary aging process that controls the rate of aging in a number of different functions. Eighty-six adult males who successively received a 2-day routine health checkup test for 7 years from 1992 to 1998 at the Kyoto Red Cross Hospital were selected as subjects. Nine candidate biomarkers of aging were selected from the 25 physiological variables based on the investigation of age-related changes. A principal factor analysis was applied to the partial correlation matrix for 9 selected biomarkers calculated by controlling for age. Furthermore, a confirmatory factor analysis in testing first- and second-order factor models was applied to the covariance matrix for 9 biomarkers. The results of these factor analyses revealed that there existed one general factor and three system-specific factors. Therefore, biological age changes can be viewed as a time-dependent complex integration of the primary and secondary aging processes.

Adult↗
PubMed2001

Variability in aflatoxin-albumin adduct levels and effects of hepatitis B and C virus infection and glutathione S-transferase M1 and T1 genotype.

Exposure to aflatoxin B1 (AFB1), an important cofactor in the etiology of hepatocellular carcinoma in Taiwan, is influenced by dietary and other factors. The present study examined the intraindividual variability in AFB1-albumin adducts, the most reliable long-term biomarker of AFB1 exposure, and whether the baseline or follow-up adduct levels and the intraindividual variability in adduct levels are modified by endogenous and environmental factors. The study measured AFB1-albumin adduct levels among 264 healthy male residents of three townships (Hu-Hsi, Ma-Kung, and Pai-Hsa) of Penghu Islets, Taiwan, at two different time points with a median interval of 1.68 years (range 1.00-3.17 years). There was a generalized reduction in the adduct levels, with the median values being 22.1 pmol/mg (range 5.0-355.8 pmol/mg) at time 1 and 14.3 pmol/mg (range 5.0-205.2 pmol/mg) at time 2. This intraindividual variability in adduct levels was inversely associated with the age of subjects and the time interval between the two blood draws. The variability in adduct levels was lower among subjects in Hu-Hsi and Pai-Hsa townships as compared to those in Ma-Kung. No significant association was observed for the intraindividual variability in AFB1-albumin adducts with regard to the season when blood was drawn. There was also no significant association between intraindividual variability and hepatitis B surface antigen, anti-hepatitis C virus (anti-HCV), glutathione S-transferase (GST) M1, or GSTT1 status. In conclusion, we found substantial intraindividual variability in the AFB1 exposure (as determined by AFB1-albumin adducts) in Taiwan, which was probably more likely related to dietary or other environmental influences rather than to endogenous factors (e.g., hepatitis B/C viral infection or GST M1/T1 genetic status).

Adult↗
PubMed2000

Potential roles of genetic biomarkers in colorectal cancer chemoprevention.

Colorectal cancer is a significant cause of morbidity and mortality in industrialized societies and the second most frequent cause of cancer death in the United States. Surrogate endpoint biomarkers are gaining wide acceptance in early diagnosis and short-term cancer chemoprevention trials in place of cancer endpoints. Molecular genetic biomarkers can be useful tools in identifying subjects at risk of developing cancer and screening for early cancers amenable to complete cure. They may be useful both in predicting and assessing response to a given therapy and in determining prognosis after an initial diagnosis has been made. Ideally, biomarkers should fulfill some, if not all, of the following criteria: variability of expression between phases of carcinogenesis, association with cancer risk, ability to undergo modification in response to a chemopreventive agent, and finally, permit ease of measurement. In consideration of colorectal cancer chemoprevention, several genetic biomarkers seem to meet many of these criteria, as they do exhibit distinct variability of expression at different phases of carcinogenesis, are often strongly associated with increased cancer risk (especially the hereditary/familial syndromes), are generally able to be measured relatively easily through peripheral blood sampling (germline mutations) or by colonic mucosal sampling by endoscopic techniques (somatic mutations). In some cases, genetic biomarkers have also been demonstrated to undergo modification in response to a chemopreventive agent. With further understanding of the genetic and molecular changes involved in sporadic and familial colorectal carcinogenesis, genetic biomarkers appear to hold great potential for the identification of subjects at high risk of developing colorectal cancer, as well as the development of novel chemopreventive approaches and form a promising area for further research.

Anticarcinogenic Agents↗
PubMed2003

Laboratory issues: use of nutritional biomarkers.

Biomarkers of nutritional status provide alternative measures of dietary intake. Like the error and variation associated with dietary intake measures, the magnitude and impact of both biological (preanalytical) and laboratory (analytical) variability need to be considered when one is using biomarkers. When choosing a biomarker, it is important to understand how it relates to nutritional intake and the specific time frame of exposure it reflects as well as how it is affected by sampling and laboratory procedures. Biological sources of variation that arise from genetic and disease states of an individual affect biomarkers, but they are also affected by nonbiological sources of variation arising from specimen collection and storage, seasonality, time of day, contamination, stability and laboratory quality assurance. When choosing a laboratory for biomarker assessment, researchers should try to make sure random and systematic error is minimized by inclusion of certain techniques such as blinding of laboratory staff to disease status and including external pooled standards to which laboratory staff are blinded. In addition analytic quality control should be ensured by use of internal standards or certified materials over the entire range of possible values to control method accuracy. One must consider the effect of random laboratory error on measurement precision and also understand the method's limit of detection and the laboratory cutpoints. Choosing appropriate cutpoints and reducing error is extremely important in nutritional epidemiology where weak associations are frequent. As part of this review, serum lipids are included as an example of a biomarker whereby collaborative efforts have been put forth to both understand biological sources of variation and standardize laboratory results.

Behavior↗
PubMed2004

Individualizing therapy in acute coronary syndromes: using a multiple biomarker approach for diagnosis, risk stratification, and guidance of therapy.

Patients with non-ST-elevation acute coronary syndromes (ACS) are typically grouped together and treated with similar approaches to therapy despite tremendous variability in clinical presentation and prognosis. The cardiac troponins are biomarkers of myocardial necrosis that have recently been evaluated in conjunction with markers of neurohormonal activation such as brain natriuretic peptide, and markers of systemic inflammation such as C-reactive protein, to further characterize risk in the individual patient presenting with ACS. Measurement of biomarkers that reflect different components of the underlying pathophysiology appears to provide independent and complementary risk stratification information in patients with non-ST-elevation ACS. This review summarizes the rationale for a multimarker approach to risk stratification in ACS and also discusses other cardiac biomarkers under active investigation. One of these of particular interest is soluble CD40 ligand, a biomarker that may not only indicate active inflammation and platelet activation associated with ACS, but may also exhibit direct prothrombotic properties that mediate early atherogenesis, plaque rupture, and thrombosis.

Angina, Unstable↗
PubMed2004

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

BACKGROUND: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. METHODS: We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing. RESULTS: When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01). CONCLUSIONS: The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Age Factors↗
PubMed1997

Pilot study of free and conjugated urinary mutagenicity during consumption of pan-fried meats: possible modulation by cruciferous vegetables, glutathione S-transferase-M1, and N-acetyltransferase-2.

Epidemiological and experimental evidence indicates that consumption of fried meats in conjunction with certain genotypes of phase I and II metabolism genes poses an elevated risk for colorectal cancer. Parallel to this, the consumption of cruciferous vegetables is associated with a reduced risk of colon cancer. Therefore, we designed a 6-week pilot feeding study to evaluate the effect of these variables on urinary mutagenicity, which is a biomarker associated with fried-meat consumption. Eight subjects were fed fried meats daily for six weeks; four ate cruciferous vegetables, and four ate non-cruciferous vegetables. Urinary mutagenicity was evaluated in the presence of S9 in strain YG1024 of Salmonella, which is a frameshift strain that overproduces acetyltransferase. C18/methanol extracts of 24-h urines collected once each week were tested unhydrolyzed (free mutagenicity) and hydrolyzed (total mutagenicity); the difference between the two was the conjugated mutagenicity. Although not significant, the levels of conjugated urinary mutagenicity doubled among crucifera consumers and decreased to 30% of the initial levels among non-crucifera consumers, suggesting the possibility that crucifera may enhance the level of conjugated urinary mutagenicity resulting from consumption of fried meats. Such an effect would be consistent with the documented ability of cruciferous vegetables to induce phase II enzymes. The NAT2 rapid phenotype was significantly associated with approximately 2-fold increases in conjugated (p = 0.05) and total (p = 0.004) urinary mutagenicity relative to NAT2 slow subjects, consistent with the elevated risk confirmed by the NAT2 rapid phenotype for colorectal cancer among meat consumers. An approximately 2-fold increase in urinary mutagenicity among the GSTM1- subjects relative to the GSTM1+ subjects approached significance for free (p = 0.18) and total (p = 0.13) urinary mutagenicity. This is the first report on (a) the mutagenicity of hydrolyzed urine, which was consistently more mutagenic than unhydrolyzed urine; (b) the potential enhancement of conjugated urinary mutagenicity by crucifera; and (c) the association of the rapid NAT2 and possibly the GSTM1- phenotype with elevated levels of fried meat-associated urinary mutagenicity.

Aged↗
PubMed2006

The clinical course of acute disseminated encephalomyelitis.

The objective of this review is to describe recent advances in understanding the clinical course of pediatric and adult acute disseminated encephalomyelitis (ADEM), especially the risk of relapse and conversion to multiple sclerosis (MS). The diagnosis of ADEM is reached on clinical grounds, typically in the setting of a post-infectious meningoencephalitic syndrome associated with multifocal neurological symptoms and signs, magnetic resonance imaging (MRI) evidence of white matter lesions and exclusion of other causes. Although typically monophasic, several case series demonstrate 'multiphasic' or 'recurrent' forms of ADEM with clinical relapses occurring within a short interval of disease onset. Furthermore, the estimated risk of developing MS is substantial for both children (0-33%) and adults (approximately 35%). Advances in neuroimaging have identified some MRI features that have predictive value for a relapsing course but they are not accurate enough for therapeutic decision-making; a diagnosis of monophasic ADEM should be made with caution in all cases, especially those presenting in adulthood. Research in ADEM and related disorders remains hampered by lack of prospective studies, specific and reproducible clinical case definitions and variable follow-up methods. Standardization of these variables would facilitate identification of more accurate diagnostic and prognostic variables, discovery and testing of potential objective biomarkers that would, in turn, allow early prediction of a relapsing course and appropriate therapeutic interventions.

Encephalomyelitis, Acute Disseminated↗
PubMed2026

Proteomic and machine learning analysis predicts treatment response signatures in Myasthenia Gravis.

BACKGROUND: Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease with variable treatment responses with a need for biomarkers to guide therapeutic decision making. Proteomic profiling, coupled with machine learning, offers a hypothesis-free approach to identify multi-protein signatures associated with treatment response. METHODS: We analyzed sera collected at entry (baseline) from participants in a phase 3 trial randomized trial comparing thymectomy plus prednisone versus prednisone alone, along with matched controls using liquid chromatography-mass spectrometry. We derived disease-specific proteomic signatures and evaluated associations between baseline proteins and 6-month clinical outcomes using multiple machine-learning approaches with internal validation. RESULTS: Baseline serum proteomes distinguished MG from controls, with pathway enrichment implicating complement activation, immunoglobulin production, and T-cell receptor signaling. Distinct protein panels predicted 6-month clinical improvement within each treatment arm. In the thymectomy-plus-prednisone group, models captured non-linear relationships of predictive proteins in contrast with the predominant additive patterns observed in the prednisone-alone group. Predictive proteins were enriched for T-cell signaling and leukocyte trafficking functions, providing insight into treatment-specific biology. CONCLUSIONS: Baseline serum proteomics captures core disease characteristics of MG and predicts short-term clinical response in a treatment-specific manner. While our results require validation in independent cohorts, these findings could enable biomarker-guided selection of thymectomy, refine risk stratification, and furnish mechanistic readouts for future MG trials and clinical care. We aim to conduct future studies using -omic approaches to validate these baseline predictive biomarkers and pathways of treatment response in patients with MG.

Adult↗
PubMed2026

Multi-level Transcriptomic and Machine-learning Analyses Identify MZT1 as a Proliferation-associated Prognostic Marker in Lung Adenocarcinoma.

BACKGROUND/AIM: Lung adenocarcinoma (LUAD) exhibits substantial molecular heterogeneity and variable clinical outcomes, highlighting the need for biomarkers that reflect core tumor biological processes. Centrosome-associated proteins regulate mitotic fidelity and genome stability, yet their roles in LUAD remain incompletely defined. In this study, we systematically characterized mitotic spindle organizing protein 1 (MOZART1; MZT1) and related family members in LUAD. MATERIALS AND METHODS: We performed integrated analyses combining bulk transcriptomic datasets, survival modeling, gene set enrichment, immune deconvolution, machine-learning based prognostic modeling, and single-cell RNA sequencing. Expression patterns and clinical associations of MZT family genes were evaluated across pan-cancer and LUAD cohorts. RESULTS: MZT family genes were consistently upregulated in tumor tissues, with MZT1 showing the most robust expression pattern. Elevated MZT1 expression was significantly associated with reduced overall survival. Functional analyses revealed coordinated activation of proliferative and genome maintenance pathways, including G2/M checkpoint regulation, E2F and MYC signaling, and DNA repair. A multivariable analysis indicated that the prognostic association of MZT1 was reduced after adjusting for canonical proliferation markers, suggesting partial overlap with established proliferation signals. The LASSO-based Cox model demonstrated stable time-dependent predictive performance at 1-, 3-, and 5-year survival. Immune analyses indicated associations between MZT1 expression and tumor microenvironmental features. Single-cell analysis showed that MZT1 expression was predominantly enriched in malignant epithelial cells and associated with proliferative cellular states. Protein-level validation supported concordance with transcriptomic findings. CONCLUSION: MZT1 is a proliferation-associated marker that integrates clinical risk, transcriptional programs, cellular heterogeneity, and predictive modeling in LUAD, providing a potential framework for biomarker development and risk stratification.

Humans↗
PubMed2003

Selected nutritional biomarkers predict diet quality.

OBJECTIVE: To examine associations of biomarkers of nutrient intake with overall diet quality. SUBJECTS: A convenience sample of 102 healthy postmenopausal women in Seattle, Washington (USA). DESIGN AND METHOD: Participants attended a study centre where they provided fasting blood specimens and completed a 122-item validated food-frequency questionnaire (FFQ). Data from the FFQ were used to calculate Diet Quality Index (DQI) scores and categorise women as having diets of excellent, good, fair or poor quality. The blood specimens were analysed for nine phospholipid fatty acids (as percentage of total) and serum concentrations of vitamin C, alpha-tocopherol, gamma-tocopherol, vitamin B12, folate and six carotenoids. Multivariate linear regression was used to model associations of the nutrient biomarkers with DQI scores. RESULTS: Compared with women with poor-quality diets, women with excellent diets, as measured by the DQI, had higher plasma concentrations of vitamin C (P for trend=0.01), alpha-tocopherol (P for trend=0.02) and beta-cryptoxanthin (P for trend=0.03). Women with excellent diets also had lower proportions of plasma phospholipid fatty acids of two potentially atherogenic fatty acids: stearic acid (P for trend=0.01) and behenic acid (P for trend=0.03). A group of six biomarkers explained a moderate proportion of the total variability in DQI scores (36%). CONCLUSIONS: These objective measures of dietary intake support the use of the DQI as a useful tool to measure dietary patterns.

Aged↗
PubMed2005

The use of Mytilus galloprovincialis acetylcholinesterase and glutathione S-transferases activities as biomarkers of environmental contamination along the northwest Portuguese coast.

With the aim of using Mytilus galloprovincialis acetylcholinesterase (AChE) and glutathione S-transferases (GST) activities as biomarkers of environmental contamination in risk assessment studies along the northwest Portuguese coast, the objective of this study was to provide background information related to: (1) baseline values of these enzymatic activities both in reference and contaminated areas and their responsiveness as indicators of exposure to environmental contaminants; (2) the importance of seasonal variations of such biomarkers in M. galloprovincialis along this area. For this, the activity of these enzymes was seasonally determined in mussels collected from four sites, including a reference and three stations with different contamination sources along the referred area. Statistically significant differences on both enzymatic activities were found among the four sampling stations, at the four sampling periods. In comparison to the reference station, lower AChE and higher GST activity values were found in mussels collected in stations potentially contaminated by pesticides and domestic/industrial effluents and in mussels collected in the vicinity of an oil refinery and an industrial/mercantile harbour, respectively. The results obtained in this work highlighted the potential suitability of these biomarkers to be used as components of environmental monitoring programs in risk assessment studies along the northwest Portuguese coast. Since a seasonal variation in both enzymatic activities was found, the possible implications of such variability in the use of these enzymes as environmental biomarkers are also discussed.

Acetylcholinesterase↗
PubMed1992

Effects of hepatotoxicants on the induction of microsomal monooxygenase activity in sunfish liver by beta-naphthoflavone and benzo[a]pyrene.

Effects of chemically induced hepatic injury on biotransformation enzymes in fish were studied. Sunfish hybrids (Lepomis macrochirus x L. cyanellus) were dosed per os with allyl formate (ALF) and carbon tetrachloride (CCl4), and the induction of liver EROD (7-ethoxyresorufin O-deethylase) activity was subsequently challenged by injections of beta-naphthoflavone (BNF) and benzo[a]pyrene (B[a]P). Hepatotoxicity of chemical treatments was assessed using blood enzymes (ASAT, ALAT, and LDH) along with other biochemical variables. Both hepatotoxicants partially abolished the induction of EROD (maximally by 76-89%), and the decrease in induction was dose related. The cytosolic activity of glutathione S-transferase (GST) in the liver decreased in parallel with the decrease in EROD induction. Fish receiving high doses of ALF exhibited significantly less microsomal and blood plasma proteins and, occasionally, were jaundiced. These symptoms, however, were less sensitive indicators of hepatotoxicity than alterations in liver EROD and GST. Both ALF and CCl4 increased the activities of hepatic enzymes in the blood plasma, indicating cytotoxicity. In addition B[a]P, unlike BNF, also increased plasma activities of LDH and ALAT at a dose inducing liver EROD, implying simultaneous hepatotoxicity at high sublethal levels of this xenobiotic. These data suggest that hepatotoxic chemicals absorbed by fish may act antagonistically by decreasing the degree of induction of the cytochrome P450 system relative to the inherent capacity of inducing xenobiotic chemicals present in the environment. Therefore, when assessing the toxicological status of water using fish health biomarkers, it is advisable to measure a concert of metabolic and biochemical variables instead of any single biomarker.

Alanine Transaminase↗
PubMed2001

Variability in acetylcholinesterase and glutathione S-transferase activities in Chironomus riparius Meigen deployed in situ at uncontaminated field sites.

An in situ system was used to expose fourth instar Chironomus riparius Meigen larvae for 48-h at 13 uncontaminated river sites across southeast England. Acetylcholinesterase (AChE) and glutathione S-transferase (GST) activities were measured in individual larvae recovered from these sites. Activities of both biomarkers varied almost twofold across the sites, with statistically significant differences detectable between sites. There were no clear relationships between biomarker activities and physical or chemical characteristics measured at each site. This study shows that biomarker measurements can be used successfully in conjunction with an in situ system. However, the results of statistically significant biomarker results must be treated with caution because natural variability in responses can occur even in the absence of toxicant exposure.

Acetylcholinesterase↗