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PubMed2004

Biological relevance of adduct detection to the chemoprevention of cancer.

Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B(1) adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention. "We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1995

Significance of individual sensitivity to chemicals: elucidation of host susceptibility by use of biomarkers in environmental health research.

Biomarker research has become the predominant theme for study of human dose-host-response relations to environmental chemicals. Increasing interest has been focused on identifying markers for host susceptibility, with mixed results. Efforts to identify markers for host variability in carcinogenic risk, on the basis of theoretical knowledge of carcinogen metabolism, have been disappointing. New work in the area of acquired risk modifiers, such as nutritional status, is theoretically attractive, but results have been limited. Impressive achievements have been made in the area of immunological variability, which may elucidate the molecular basis of as well as provide practical biomarkers for several diseases. The problem of multiple chemical sensitivities, on the other hand, has proved refractory to biomarker research, reflecting inadequate knowledge of the mechanism and inappropriate application of biomarker methods.

Biomarkers↗
PubMed2005

High-throughput biomarker discovery and identification by mass spectrometry.

Native peptides and proteins are of increasing interest in biomedical research because they hold promise to represent a large number of useful diagnostic and therapeutic biomarkers. Discovery attempts from patient samples have to deal with the complexity of biology from a disease perspective as well as with a high individual variability. High throughput screening of samples is therefore the strategy of choice to detect relevant peptidic biomarkers, and requires a high order of automation particularly in the detection process. In this contribution, a novel technical approach employing a fully automated MALDI-TOF/TOF mass spectrometer is described. This approach combines high throughput biomarker discovery with the identification of corresponding endogenous peptides in one instrument and from the same set of samples. The degree of automation allows the analysis of thousands of chromatographic fractions corresponding to up to one hundred patient samples per day. The applied relative quantification via Differential Peptide Display((R)) is performed in a label-free way and shows a dynamic range of up to four orders of magnitude in the accessible peptide concentrations. The typical limit of detection is in the mid- to low-picomolar range for body fluids such as blood plasma, urine and cerebrospinal fluid. Sequence assignment via MALDI-TOF/TOF mass spectrometry is carried out either in an overview approach, characterizing rapidly the peptide composition e.g. of a novel sample, or in a directed approach, analyzing a list of biomarker candidates deduced from statistically significant abundance differences from the biomarker discovery process.

Biomarkers↗
PubMed2006

Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency.

BACKGROUND & AIMS: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease. METHODS: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production. RESULTS: CVID patients with gastrointestinal symptoms differed from asymptomatic CVID patients by having significantly longer duration of disease and lower body mass index, D-xylose absorption, serum albumin, CD4/CD45RA cells, CD3/CD25 cells, and natural killer cells. Symptomatic CVID patients showed diffuse histologic inflammatory changes in the duodenal and colonic mucosa including villus blunting, increased lamina propria and intraepithelial lymphocytes, and epithelial apoptosis, less frequently seen in asymptomatic patients. LPMCs from symptomatic CVID patients produced significantly higher T-helper (Th) 1 cytokines, interleukin-12, and interferon-gamma. Compared with the Th1 cytokines produced by LPMCs from Crohn's disease, CVID patients did not produce excess amounts of interleukin-23, interleukin-17, or tumor necrosis factor-alpha. CONCLUSIONS: The idiopathic inflammatory bowel disease associated with gastrointestinal symptoms in CVID is a unique combination of diverse histologic findings accompanied by excessive Th1 cytokine production, distinct from that in Crohn's disease. These data show that human gut mucosal inflammatory disease can occur with excess interleukin-12 and interferon-gamma production alone and provide a rationale for developing targeted therapies for this complication of CVID.

Adult↗
PubMed2026

Development of a Computational Histology Artificial Intelligence-Powered Prognostic Biomarker in Colorectal Cancer in The Cancer Genome Atlas.

BACKGROUND: Risk stratification in colorectal cancer (CRC) plays an important role in treatment decision-making. As such, prognostic biomarkers that can augment risk stratification have clinical value. Quantitative histologic features from routine hematoxylin and eosin (H&E)-stained whole slide images (WSIs) provide a novel avenue for biomarker discovery. In this study, we explored the potential for a computational histology artificial intelligence (CHAI) platform to develop and validate a prognostic biomarker in CRC. METHODS: The Cancer Genome Atlas Colorectal Adenocarcinoma project was utilized for this study, with inclusion of all subjects (stage I-IV) with available digitized H&E specimens. The cohort was split into development and validation cohorts by a stratified random split. The previously developed CHAI platform was applied in the development cohort to construct a continuous risk score from histologic features associated with progression-free interval (PFI) that was dichotomized based on an optimized cutpoint for distinguishing PFI into a high risk CHAI (+) and lower risk CHAI (-). PFI was compared between CHAI (+) and CHAI (-) patients in the validation cohort in multivariable Cox proportional hazards models. Time-dependent area under the curve (tdAUC) and C-indices were also calculated for PFI. RESULTS: A total of 583 participants were included in the study, with 409 assigned to the validation cohort. The CHAI biomarker classified 229 participants (56%) as CHAI (+) and 180 (44%) as CHAI (-) in the validation set. CHAI (+) participants had worse PFI in a multivariable analysis adjusting for available clinicopathologic variables (hazard ratio (HR) = 2.65; 95% confidence interval (CI), 1.63-4.30). TdAUC for the CHAI biomarker was 0.60 (95% CI, 0.53-0.67) at 12 months, 0.62 (0.55-0.69) at 36 months, and 0.67 (0.55-0.79) at 60 months; the C-index was 0.62 (95% CI, 0.58-0.67). CONCLUSIONS: The CHAI platform was used to develop a prognostic digital pathology biomarker in CRC. This demonstrates the feasibility and potential to apply this artificial intelligence-based digital pathology biomarker platform for risk stratification in CRC and supports its further study.

Artificial intelligence↗
PubMedDate not supplied

Toenail trace element levels as biomarkers: reproducibility over a 6-year period.

We assessed the reproducibility over a 6-year period of 16 trace elements measured in toenails by comparing levels in paired specimens collected in 1982-1983 and 1988 from 127 women in the United States. The Spearman correlation coefficients for the reproducibility of toenail levels of selenium and arsenic (both known to reflect intake of these elements) were 0.48 and 0.54. Correlations for other elements ranged from 0.26 (copper) to 0.58 (zinc). In utilizing biomarkers to assess exposure in epidemiological studies of cancer and other chronic disease, random within-person variability in exposure leads to attenuation of measures of association between exposure and disease. We demonstrate the effect of such variability on odds ratios from a hypothetical case-control study. For a true odds ratio of 3.0 (for a comparison of the highest quintile versus the remaining 4 quintiles of exposure) the odds ratios which would be observed in the presence of the degree of within-person variability demonstrated in this study were 2.15 for toenail arsenic and 1.67 for toenail copper levels. Toenail concentrations of certain trace elements are useful biomarkers of exposure in which a single sample is assumed to represent long-term exposure. However, substantial attenuation in measures of association may occur.

Adult↗
PubMed2005

Seasonal variations of selected biomarkers in sand gobies Pomatoschistus minutus from the Guadalquivir Estuary, Southwest Spain.

Sand gobies, Pomatoschistus minutus, were collected monthly from September 2002 to August 2003 at a station situated 8 km upstream from the mouth of the Guadalquivir estuary (southwest Spain). Physical parameters of the water and selected biomarkers of organic pollution were recorded in the fish to discuss its potential as a sentinel species in estuaries. The biomarkers selected were the activities of catalase (CAT), 7-ethoxyresorufin-O-deethylase (EROD), and glutathione S-transferase (GST) in the liver and acetylcholinesterase (AChE) and lipid peroxidation (LP) in the head. The results showed an increase in total protein synthesis in late spring and early summer coinciding with the reproductive period as well as the release of fresh water from a dam situated 110 km upstream. During the same period, a significant depletion of hepatic GST and head AChE but higher LP levels in this tissue suggest exposure to pesticides such as those applied to crops established along the course of the river and reaching the estuary mostly when the freshwater discharges occur. Changes in CAT and EROD activities fluctuated randomly and were not noted as seasonally dependent. Biomarker fluctuations in sand goby are discussed as normal seasonal variations, but other variables-such as potential local pollution inputs-cannot be disregarded.

Acetylcholinesterase↗
PubMed2004

Free and total urinary 2-butoxyacetic acid following dermal and inhalation exposure to 2-butoxyethanol in human volunteers.

OBJECTIVES: To assess excretion kinetics of free and total (free + conjugated) 2-butoxyacetic acid (BAA) following dermal and inhalation exposure to butoxyethanol (BE). METHODS: Six male volunteers were dermally exposed for 4 h to a 50% aqueous solution of BE on an area of 40 cm(2) of the volar forearm. Six other male volunteers were exposed by inhalation (mouth only) to 93 mg m(-3) BE for 30 min. As biological indices of exposure, BE in blood and total and free BAA in urine were measured. RESULTS: Following inhalation exposure, the 24-h cumulative excretion of free and total BAA in urine amounted to 5.5 +/- 2.7 and 12.8 +/- 4.0 mg, respectively. After dermal exposure, 147.1 +/- 61.0 and 346 +/- 52 mg, respectively, of free and total BAA were excreted in urine up to 48 h after the onset of exposure. The proportion of conjugated BAA in single urine samples increased after dermal exposure in time from 45+/-30% in the first collection period to 92+/-2% after 48 h. The elimination half-life of total BAA following dermal exposure was longer than that of free BAA (5.1 +/- 0.6 and 3.8 +/- 0.4 h, respectively). The interindividual variation in the cumulative excreted amount after inhalatory exposure was higher (49%) for free BAA than for total BAA (31%). The average dermal flux amounted to 3.5 mg cm(-2) h(-1) independently of whether free or total BAA was used for the calculation, and, again, the interindividual variation in the estimated fluxes was higher for free BAA than for total BAA (41% and 15%, respectively). CONCLUSION: The interindividual variation in the extent of conjugation is large, and the degree of conjugation increases with time. Due to lower interindividual variability, total BAA is superior to free BAA as a biomarker of exposure.

Administration, Cutaneous↗
PubMed2005

Correlations between estimated and true dietary intakes: using two instrumental variables.

PURPOSE: We describe a new application of the method of triads that allows an estimate of the correlation between a dietary questionnaire measure (Q) and true intake (T). METHODS: Three surrogate variables Q, M, and P are observed where M and P are both instrumental (often biological) variables. A reference dietary method (R) is not required. The variables M and P may be concentration rather than recovery biomarkers. Estimating equations produce Corr(Q,T), Corr(M,T), Corr(P,T), conditional on assumptions about error correlations. Correlations between errors in both Q and a reference dietary measure can also be estimated if R is available. A small validation study of California Seventh-day Adventists provided food frequency, repeated 24-hour dietary recalls (R), and biological data (blood, overnight urines, and subcutaneous fat). RESULTS: Values of Corr(Q,T) ranged between 0.40 and 0.66. Values of Corr(R,T) were higher, between 0.48 and 0.83. Estimated correlations between errors in R and Q were all positive. CONCLUSIONS: When carefully chosen, M and P, rather than M and R, should better satisfy assumptions about error correlations. Food frequency data and repeated 24-hour recalls both provide estimates of T, but the latter has greater validity. Standard errors suggest that for good precision Corr(Q,T) requires large validation studies (2000-3000 subjects).

Adult↗
PubMed2005

Quantitative analysis of the low molecular weight serum proteome using 18O stable isotope labeling in a lung tumor xenograft mouse model.

With advancements in the analytical technologies and methodologies in proteomics, there is great interest in biomarker discovery in biofluids such as serum and plasma. Current hypotheses suggest that the low molecular weight (LMW) serum proteome possesses an archive of clipped and cleaved protein fragments that may provide insight into disease development. Though these biofluids represent attractive samples from which new and more accurate disease biomarkers may be found, the intrinsic person-to-person variability in these samples complicates their discovery. Mice are one of the most extensively used animal models for studying human disease because they represent a highly controllable experimental model system. In this study, the LMW serum proteome was compared between xenografted tumor-bearing mice and control mice by differential labeling utilizing trypsin-mediated incorporation of the stable isotope of oxygen, 18O. The digestates were combined, fractionated by strong cation exchange chromatography, and analyzed by nanoflow reversed-phase liquid chromatography coupled online with tandem mass spectrometry, resulting in the identification of 6003 proteins identified by at least a single, fully tryptic peptide. Almost 1650 proteins were identified and quantitated by two or more fully tryptic peptides. The methodology adopted in this work provides the means for future quantitative measurements in comparative animal models of disease and in human disease cohorts.

Animals↗
PubMed2026

Peripheral inflammation and executive function among community samples across the lifespan: A systematic review and meta-analysis.

Higher levels of peripheral inflammatory markers are proposed to disrupt cognitive processes; however, the extent to which this relationship applies to executive functions, specifically, has yet to be systematically evaluated. The current meta-analysis synthesizes all available literature measuring the association between peripheral inflammation and executive functions among community individuals across the lifespan. This systematic review searched Web of Science, PubMed, and PsycINFO for published and unpublished studies, in the English language, that assessed the association between markers of peripheral inflammation and self-report and behavioral measures of executive function. In addition to methodological and demographic information, correlation/beta coefficients were extracted from included studies to quantify the association between inflammation and executive functions. This review included 58 studies, 41 of which were included in the random-effects meta-analysis (N = 255,539). Among community individuals, higher levels of CRP and IL-6 were associated with poorer executive functioning. These results did not differ when models accounted for potential confounding variables. Meta-regressions revealed that the relationship between inflammatory biomarkers and executive function did not differ as a function of age, adiposity, or percentage of the sample who identified as female. Results of the present review indicate that higher levels of specific inflammatory markers are associated with lower performance on executive function measures; however, we observed significant heterogeneity in the study design and measurement of both inflammation and executive functioning, suggesting important considerations for future research.

Humans↗
PubMedDate not supplied

Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials.

BACKGROUND: Findings from the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials showed that tamoxifen benefited women with oestrogen-receptor-positive tumours and negative axillary nodes, and that chemotherapy plus tamoxifen was more effective than tamoxifen alone. We present long-term findings from those trials and relate them to age, menopausal status, and tumour oestrogen-receptor concentrations. We also discuss the extent of progress made in the treatment of such patients. METHODS: B-14 patients were randomly assigned to placebo (n=1453) or tamoxifen (n=1439); B-20 patients to tamoxifen (n=788) or cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT, n=789). Primary endpoints were recurrence-free survival and overall survival estimated according to patients' age, menopausal status, and tumour oestrogen-receptor concentration. Smoothed recurrence rates were used to measure patterns of recurrence as a continuous function of age. FINDINGS: Compared with placebo, tamoxifen benefited women in B-14 through 15 years, irrespective of age, menopausal status, or tumour oestrogen-receptor concentration (hazard ratio [HR] for recurrence-free survival 0.58, 95% CI 0.50-0.67, p<0.0001; HR for overall survival 0.80, 0.71-0.91, p=0.0008). In B-20, the benefit from CMFT over 12 years was greater than that from tamoxifen alone (HR for recurrence-free survival 0.52, 0.39-0.68, p<0.0001; HR for overall survival 0.78, 0.60-1.01, p=0.063). When CMFT was compared with placebo, there were reductions in treatment failure of about 65% in all age-groups. INTERPRETATION: Much benefit has been achieved in treatment of women with oestrogen-receptor-positive tumours and negative nodes. When planning systemic therapy for such patients of all ages, it should be understood that some have tumours with variable concentrations of oestrogen-receptors, a surrogate for other biomarkers associated with tumour growth and response to treatment. Older women tend to have higher tumour oestrogen-receptor concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true. Consequently, the notion that use of tamoxifen or chemotherapy should be based only on age is too restrictive.

Aged↗
PubMedDate not supplied

Investigation of the mouse serum proteome.

With the rapid assimilation of genomic information and the equally impressive developments in the field of proteomics, there is an unprecedented interest in biomarker discovery. Although human biofluids represent increasingly attractive samples from which new and more accurate disease biomarkers may be found, the intrinsic person-to-person variability in these samples complicates their discovery. One of the most extensively used animal models for studying human disease is mouse because, unlike humans, they represent a highly controllable experimental model system. Unfortunately, very little is known about the proteomic composition of mouse serum. In this study, a multidimensional fractionation approach on both the protein and the peptide level that does not require depletion of highly abundant serum proteins was combined with tandem mass spectrometry to characterize proteins within mouse serum. Over 12 300 unique peptides that originate from 4567 unique proteins-approximately 16% of all known mouse proteins-were identified. The results presented here represent the broadest proteome coverage in mouse serum and provide a foundation from which quantitative comparisons can be made in this important animal model.

Amino Acid Sequence↗
PubMed2005

Serum levels of inflammatory cytokines at diagnosis correlate to the bcl-6 and CD10 defined germinal centre (GC) phenotype and bcl-2 expression in patients with diffuse large B-cell lymphoma.

Circulating inflammatory cytokines have a prognostic impact independent of the information provided by the International Prognostic Index (IPI) in diffuse large B-cell lymphoma (DLBCL). The present study characterized prognostic cytokines in relation to stage-specific B-cell differentiation antigens and bcl-2 protein expression, assessed by immunohistochemistry in de novo DLBCL. Serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha) were found to be significantly lower in patients with a germinal centre (GC) phenotype (co-expression of bcl-6 and CD10) compared with the non-GC phenotype. IL-6 and TNF-alpha levels were significantly elevated in patients expressing bcl-2 protein. Serum levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were not associated with the GC phenotype. On the contrary, both VEGF and bFGF were strongly correlated to bcl-2 expression. In survival analysis, IPI score remained the most important independent prognostic factor. However, IL-6 and VEGF, combined with non-GC phenotype and bcl-2 positivity, respectively, had a similar independent prognostic power as the IPI. In conclusion, our data suggest that inflammatory cytokines are differently distributed in the GC and non-GC phenotypes and correlate to bcl-2 expression. Combining these biomarkers may add to the prognostic information given by clinical variables in the IPI alone.

Adult↗
PubMed2005

Baseline micronuclei frequency in children: estimates from meta- and pooled analyses.

The number of studies evaluating the effect of environmental exposure to genotoxic agents in children has rapidly increased in the last few years. The frequency of micronuclei (MN) in peripheral blood lymphocytes determined with the cytokinesis block assay is among the most popular biomarkers used for this purpose, although large inter- and intralaboratory variability of this end point has been observed in population studies. The availability of reference measures is therefore necessary for laboratories to validate protocols and analytical procedures, and for molecular epidemiologists, as well, to estimate the statistical power of studies and to assess the quality of data. In this article, we provide estimates of the baseline frequency of MN in children, conducting a meta-analysis of MN frequency reported by field studies in children and a pooled analysis of individual data [available from published studies and from the Human Micronucleus International Collaborative Study (HUMN) database]. Thirteen articles were selected for meta-analysis, and individual data included in the pooled analysis were retrieved from the databases of 12 laboratories. Overall means of 4.48 [95% confidence interval (CI), 3.35-5.98] and 5.70 (95% CI, 4.29-7.56) MN per 1,000 binucleated cells were estimated by the meta- and pooled analysis, respectively. A clear effect of age was detected, even within the restricted range of pediatric age considered, with significantly lower frequency values in newborns. No influence of sex was found. The study showed the advantage of using data from large collaborative studies and suggested a synergistic use of meta- and pooled analysis.

Adolescent↗
PubMed2006

Cerebrospinal fluid diagnostic markers correlate with lower plasma copper and ceruloplasmin in patients with Alzheimer's disease.

Increasing evidence links Alzheimer's disease (AD) with misbalanced Cu homeostasis. Recently, we have shown that dietary Cu supplementation in a transgenic mouse model for AD increases bioavailable brain Cu levels, restores Cu, Zn-super oxide-1 activity, prevents premature death, and lowers A beta levels. In the present report we investigated AD patients with normal levels of A beta 42, Tau and Phospho-Tau in the cerebrospinal fluid (CSF) in comparison with AD patients exhibiting aberrant levels in these CSF biomarkers. The influence of these cerebrospinal fluid (CSF) diagnostic markers with primary dependent variables blood Cu, Zn and ceruloplasmin (CB) and secondary with CSF profiles of Cu, Zn and neurotransmitters was determined. Multivariate tests revealed a significant effect of factor diagnostic group (no AD diagnosis in CSF or AD diagnosis in CSF) for variables plasma Cu and CB (F=4.80; df=2, 23; p=0.018). Subsequent univariate tests revealed significantly reduced plasma Cu (-12.7%; F=7.05; df=1, 25; p=0.014) and CB (-14.1%; F=9.44; df=1, 24; p=0.005) levels in patients with aberrant CSF biomarker concentrations. Although only AD patients were included, the reduced plasma Cu and CB levels in patients with a CSF diagnosis of advanced AD supports previous observations that a mild Cu deficiency might contribute to AD progression.

Aged↗