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Results for “Biomarker variability”

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PubMed2005

Proteomic cancer classification with mass spectrometry data.

The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The biological variability among patient samples as well as the huge dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we focus here on cancer classification using mass spectrometry (MS) for proteomic profiling and biomarker identification. Recent advances in MS technology are starting to enable high-throughput profiling of the protein content of complex samples. For cancer classification, the protein samples from cancer patients and noncancer patients or from different cancer stages are analyzed through MS instruments and the MS patterns are used to build a diagnostic classifier. To illustrate the importance of feature selection in cancer classification, we present a method based on support vector machine-recursive feature elimination (SVM-RFE), demonstrated on two cancer datasets from ovarian and lung cancer.

Biomarkers, Tumor↗

PubMed2026

Development and Validation of a Multimodal Clinical, Pathologic, and Genomic Model for Breast Cancer Recurrence.

PURPOSE: To develop and validate a multimodal recurrence-risk model integrating histology, genomic testing, and clinical variables. METHODS: We developed AI-Path, a whole-slide image biomarker for recurrence prediction trained in CALGB 9344, and validated it in three independent cohorts: TAILORx, a multi-site Chicago cohort, and the MDX-BRCA cohort. We then integrated AI-Path with Oncotype DX Recurrence Score (RS), tumor size, and nodal status into a Cox model, PathClinRS, fit using 60% of cases from TAILORx, with the remaining 40% held out for validation. The primary end point was distant recurrence-free interval. Performance was assessed using Harrell's concordance index (C-index) and Kaplan-Meier analyses. RESULTS: A total of 12,418 patients were included. In TAILORx, AI-Path outperformed RS for distant recurrence (C-index, 0.682 vs 0.647; P = .038), driven by superior prediction of late recurrence (0.656 vs 0.567; P < .001). In node-negative disease, PathClinRS outperformed RSClin in the TAILORx fitting (0.72 vs 0.70; P = .016) and validation sets (0.74 vs 0.70; P = .004). In node-positive disease, PathClinRS outperformed RSClinN+ in Chicago (0.94 vs 0.74; P < .001) and MDX-BRCA (0.71 vs 0.66; P = .004) cohorts. Compared with NATALEE eligibility, PathClinRS identified nearly twice as many high-risk node-negative patients while maintaining a comparable 10-year distant recurrence risk (16.7% vs 16.6% per NATALEE eligibility in TAILORx fitting; 21.0% vs 19.4% in TAILORx validation). PathClinRS identified 68% of intermediate risk premenopausal patients as low-risk with no evidence of chemotherapy benefit, compared to only 36% identified as low risk by standard clinicopathologic criteria. CONCLUSION: Digital histopathology provides prognostic information complementary to genomic assays and has the potential to personalize therapy beyond existing clinicogenomic tools.

Journal Article↗

PubMed2006

Chemokine receptors as biomarkers in multiple sclerosis.

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Adult↗

PubMed1992

Characterization and nucleotide sequences of the variable regions of a monoclonal antibody against alpha-fetoprotein.

alpha-Fetoprotein (AFP) is a well-known tumor marker of hepatocellular carcinoma (HCC). Monoclonal antibodies against AFP possessing specific binding ability to HCC are potential candidates for immunoscintigraphy and immunotherapy. A new monoclonal antibody against AFP (0325-6-9) was isolated. Its specificity and targeting tumor ability were characterized by enzyme-linked immunosorbent assay (ELISA), cell immunostain and complement killing. These results suggest that 0325-6-9 is specific to hepatoma cells. The nucleotide sequences of variable regions of 0325-6-9 were determined by M13 dideoxynucleotide sequencing method. With the information of nucleotide sequence, this antibody then could be modified by recombinant technology for its usage in in vivo diagnosis and immunotherapy.

Amino Acid Sequence↗

PubMed2005

Effects of estradiol and progesterone on the variability of the micronucleus assay.

To investigate chromosomal radiosensitivity of lymphocytes the micronucleus (MN) assay has been used for many years. The results of these studies suggest the use of the MN assay as a biomarker for cancer predisposition. However, the MN assay has still some limitations associated with the reproducibility and sensitivity. Especially a high intra-individual variability has been observed. An explanation for this high intra-individual variability is not yet available. In literature it is suggested that the high variability among females is attributable to hormonal status. In this study we investigated if the high intra-individual variability in micronucleus formation in lymphocytes of females after in vitro exposure to ionising radiation is caused by variations in hormone levels of estradiol (E2) and progesterone (PROG). For this, the MN assay was performed on blood samples of 18 healthy women during 7 consecutive weeks while the estradiol and progesterone levels were determined at the same time. The MN assay was also examined in cultures of isolated blood lymphocytes with estradiol or progesterone levels added in vitro. The results demonstrated that estradiol and progesterone levels have no influence on the variations in radiation-induced MN yields observed in blood samples of healthy women. These conclusions were confirmed by the "in vitro" experiments as no correlation between the MN yields and the concentrations of hormones (estradiol or progesterone) added in vitro to isolated lymphocytes cultures was observed.

Adult↗

PubMed2005

Biomarkers of space radiation risk.

Radiation risk estimates are based on epidemiological data obtained on Earth for cohorts exposed predominantly to acute doses of gamma rays, and the extrapolation to the space environment is highly problematic and error-prone. The uncertainty can be reduced if risk estimates are compared directly to space radiation-induced biological alterations, i.e. by detecting biomarkers in astronauts. Chromosomal aberrations in peripheral blood lymphocytes are the only biomarker that can provide simultaneous information on dose, dose equivalent and risk, and they have been measured extensively in astronauts during the past 10 years. Individual relative risks calculated from chromosomal aberration measurements in crew members after single space missions in low-Earth orbit fall in the same range as the estimates derived from physical dosimetry, suggesting that the current system for radiogenic risk evaluation is essentially sound. However, the output of the biomarker test is dependent upon the sampling time. Recent results show a fast time-dependent decay of chromosomal aberrations in blood lymphocytes after space flight and a lack of correlation between translocations and cumulative dose in astronauts involved in two to five space missions. This "time factor" may reflect individual variability and time dependence in the risk produced by exposure to cosmic radiation during the flight. Biomarkers may be superior to dose in predicting space radiation risk, pending technical improvements in sensitivity, and validation by epidemiological studies.

Biomarkers↗

PubMed2003

Biologic and methodologic issues for nutritional biomarkers.

Nutritional biomarkers are used for a variety of purposes in large-scale population surveys and epidemiologic studies as well as smaller clinical studies. The main reasons for using nutritional biomarkers are to provide measures of nutritional status that have less error than dietary data, nutrient status for nutrients with inadequate dietary data, to obtain a more proximal and integrated assessment of nutrient status that incorporates metabolism, to assess dietary change and compliance in intervention studies, and dietary intake for the validation of dietary questionnaires. However, often there is oversight by the investigators regarding biologic and laboratory issues, which have implications for the utility of nutritional biomarkers. This article reviews some of the physiologic issues that contribute to between-person variability in nutrient status and the utility and meaning of specimens from various body compartments. Issues related to the collection and storage of biologic specimens are addressed, although it is recommended that investigators contact laboratory colleagues at the beginning of any study for updated information. The necessity for blind quality surveillance of laboratory analyses beyond the normal procedures employed by collaborating laboratories also is addressed. The advantages and disadvantages of nutritional biomarkers are reviewed, especially in comparison with using dietary methodology.

Absorption↗

PubMed2002

Biomarkers of genetic damage for cancer epidemiology.

Cancer is a disease of altered gene expression involving a complex array of epigenetic events, gene mutation, chromosome rearrangements and altered chromosome number. The coincidence of genotoxic events with the induction of cancer has fueled great interest in molecular/cytogenetic epidemiological studies aimed at linking polymorphisms in genes for DNA repair and carcinogen metabolism and biomarkers of DNA/chromosome damage with cancer risk. These studies are now being expanded to include the role of dietary factors that are known to be important in DNA metabolism and repair such as folic acid, vitamin B12 and zinc. The use of DNA damage biomarkers as a surrogate for cancer would greatly facilitate our capacity to identify the most important risk factors for cancer however these biomarkers need validation. The Nordic and Italian prospective cohort studies have confirmed that elevated rates of chromosome aberrations in lymphocytes are predictive of cancer risk and similar studies are now underway to validate other biomarkers such as the micronucleus assay which are more practical to apply in the larger population setting. Validation of these biomarkers requires a thorough understanding of the importance of methodological, demographic, environmental and dietary variables and the ongoing HUMN project is a good example how this can be achieved for the micronucleus assay. The capacity to study human populations has opened up new opportunities to define acceptable DNA damage rates and to establish recommended dietary allowances for genomic stability. Controlling DNA damage rate to its possible minimum is likely to have an important impact in preventing cancer and other DNA damage-related degenerative diseases including ageing.

Animals↗

PubMed2006

CYP1A2 and NAT2 phenotyping and 3-aminobiphenyl and 4-aminobiphenyl hemoglobin adduct levels in smokers and non-smokers.

Some aromatic amines are considered to be putative bladder carcinogens. Hemoglobin (Hb) adducts of 3-aminobiphenyl (3-ABP) and 4-aminobiphenyl (4-ABP) have been used as biomarkers of exposure to aromatic amines from cigarette smoke. One of the goals of this study was to determine intra- and inter-individual variability in 3-ABP and 4-ABP Hb adducts and to explore the predictability of ABP Hb adduct levels based on caffeine phenotyping. The study was conducted in adult smokers (S, n = 65) and non-smokers (NS, n = 65). The subjects were phenotyped for CYP1A2 and NAT2 using urinary caffeine metabolites. Blood samples were collected twice within 6 weeks and adducts measured by GC/MS. The levels of 4-ABP Hb adducts were significantly (p < 0.0001) greater in S (34.5 +/- 21.06 pg/g Hb) compared to NS (6.3 +/- 3.02 pg/g Hb). The levels of 3-ABP Hb adducts were below the limit of quantification (BLOQ) in most (82%) of the NS and about 10-fold lower in S (3.6 +/- 3.29 pg/g Hb) compared to 4-ABP Hb adducts. No differences were observed in the adduct levels between weeks 1 and 6 in the smokers, suggesting that a single sample would be adequate to monitor cigarette smoke exposure. The regression model developed with CYP1A2, NAT2 phenotype and number of cigarettes smoked (NCIG) accounted for 47% of the variability in 3-ABP adducts, whereas 32% variability in 4-ABP adducts was accounted by CYP1A2 and NCIG. The ratio of 4-ABP Hb adducts in adult S:NS was approximately 5:1, whereas 3-ABP Hb adducts levels were BLOQ in some S, exhibited large interindividual variability ( approximately 91% compared to 57% for 4-ABP Hb) and poor dose response relationship. Therefore, 4-ABP Hb adduct levels may be a more useful biomarker of aminobiphenyl exposure from cigarette smoke.

Adult↗

PubMed1991

Variable gastrointestinal and urologic cancers in a Lynch syndrome II kindred.

There are no premonitory physical signs or biomarkers which can identify the genotypic status in Lynch syndrome II. Diagnosis is therefore dependent on the pedigree, with attention to cancer of all anatomic sites, inclusive of those cardinal features of its natural history. The tumor spectrum in Lynch syndrome II has continued to expand commensurately with increasing interest in this disorder. We report a family showing the constant cancer features of this syndrome but, in addition, occurrences of carcinoma of the bile duct, urologic system, and extremely early-onset carcinoma of the pancreas, in patients in the direct genetic lineage who were considered to be candidates for having inherited the deleterious genotype. Diagnosis of Lynch syndrome II is crucial in targeting its surveillance and management.

Colonic Neoplasms↗

PubMed2006

Quantitative MRI biomarkers of cognitive morbidity in temporal lobe epilepsy.

PURPOSE: To determine the relation between neuropsychological morbidity, quantitative magnetic resonance imaging (MRI) measures of whole brain structure, and clinical seizure factors reflecting epilepsy cause, course, and treatment. METHODS: Quantitative MRI measurements of total (whole brain) cerebrospinal fluid (CSF) and gray- and white-matter volumes and clinical seizure features were examined in relation to summary indices of cognitive morbidity in 96 patients with temporal lobe epilepsy. MRI volumes were adjusted for intracranial volume (ICV), and cognitive scores were adjusted for age, education, and gender, based on a sample of 82 healthy controls. RESULTS: Whole-brain volumes (gray, white, and CSF) were abnormal in chronic temporal lobe epilepsy patients compared with controls and were related significantly to neuropsychological morbidity, especially total CSF. Statistical modeling demonstrated that markers of total atrophy (CSF) was the primary mediator of the relation between clinical seizure variables and neuropsychological morbidity. CONCLUSIONS: Quantitative measurements of overall brain abnormality (atrophy) in temporal lobe epilepsy are clinically meaningful markers that are associated with increased cognitive morbidity. These biomarkers appear to mediate the adverse effects of some clinical seizure variables on cognition.

Adolescent↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed1998

Assessment of the biologic markers p53, Ki-67, and apoptotic index as predictive indicators of prostate carcinoma recurrence after surgery.

BACKGROUND: This study was designed to evaluate the potential of the molecular and cellular markers p53, Ki-67, and apoptotic index (AI) as adjuncts to the commonly available variables of tumor grade, clinical stage, and serum prostate specific antigen to predict prostate carcinoma recurrence after radical prostatectomy. METHODS: Representative punch biopsy specimens of prostate carcinoma from whole mount paraffin blocks were evaluated from 47 men who underwent radical prostatectomy. Two groups were defined: those without evidence of prostate carcinoma recurrence after 5 years of follow-up (N = 30) and those with carcinoma recurrence (N = 17). Gleason grade, clustered p53 immunostaining, Ki-67 immunostaining, and AI were determined by standard techniques. RESULTS: All variables tested were associated with disease recurrence by univariate analysis: AI (P = 0.005), clustered p53 immunostaining (P = 0.0070), and Ki-67 immunostaining (P = 0.0390). Using multivariate analyses that included each biomarker with routinely available features, only AI (P = 0.0234) and clustered p53 immunostaining (P = 0.0389) added independent prognostic information (Ki-67 immunostaining, P = 0.1285). In the final logistic regression model that included standard variables with AI and p53, only AI reached statistical significance (P = 0.0332). CONCLUSIONS: The continued assessment of additional biomarkers for prostate carcinoma recurrence is important to identify better those patients who may be candidates for early adjuvant therapy and also to further our understanding of the neoplastic potential of a particular malignancy.

Aged↗

PubMed2005

Organochlorine contaminant and retinoid levels in blubber of common dolphins (Delphinus delphis) off northwestern Spain.

The effect of age, sex, nutritive condition and organochlorine concentration on blubber retinoid concentrations was examined in 74 common dolphins incidentally caught off northwestern Spain. Age and blubber lipid content were strong determinants of the retinoid concentrations in males, while these variables did not account for the variation found in females. Retinoids were positively correlated with organochlorines in males and negatively in females. However, pollution levels were moderate and likely to be below threshold levels above that a toxicological response is to be expected. Thus, a cause-effect relationship between organochlorine and retinoid concentrations could not be properly established, and the observed correlation may be the result of an independent association of the two variables with age. Further research on the influence of the best predictor variables on retinoid dynamics is required to implement the use of retinoids as biomarkers of pollutant exposure in cetaceans.

Age Factors↗

PubMed2007

Mild cognitive impairment: current research and clinical implications.

Mild cognitive impairment refers to the transitional state between the cognitive changes of normal aging and the fully developed clinical features of dementia. This topic has received a great deal of attention in the literature in recent years and is being proposed for clinical applications as well. Clinical guidelines, including the original memory-focused criteria and the more recent broadly defined set of criteria, will be presented. The clinical outcome of individuals with mild cognitive impairment will be discussed and several explanations for variability in the literature will be considered. Predictors of progression, including genetic, neuroimaging, biomarker, and clinical characteristics, will be presented, as will the controversies regarding the underlying neuropathology of mild cognitive impairment. The recently completed mild cognitive impairment clinical trials will be discussed and the lessons learned from them translated into recommendations for future investigations. Finally, the clinical utility of mild cognitive impairment, its incorporation into clinical practice, and directions for future research will be proposed.

Aging↗

PubMed2001

Tissue sphinganine as a biomarker of fumonisin-induced apoptosis.

NCTR measured sphinganine concentrations in the livers of mice and in the livers and kidneys of rats in conjunction with a tumour bioassay. In our model of the tumour incidence, target-tissue levels of sphinganine serve as a biomarker for a dose response of fumonisin B1 on cell death. Initially we questioned the utility of sphinganine levels in this role because they were highly variable when compared across time points. In spite of this concern, a conceptual framework and data are presented that support the use of sphinganine as a biomarker for a dose response of fumonisin B1 on cell death. This framework is reasonably consistent with observed sphinganine concentrations in the examined tissues, the literature on fumonisin's effects on sphingolipid synthesis, and our hypothesized mechanism through which fumonisin B1 increases age-specific tumour incidence.

Animals↗

PubMed2005

Functional foods for coronary heart disease risk reduction: a meta-analysis using a multivariate approach.

BACKGROUND: It has been difficult to identify the appropriate bioactive substance for the development of new functional foods associated with coronary heart disease, because the results of many clinical studies are contradictory. OBJECTIVE: The objective of this study was to use the multivariate statistical approach known as principal component analysis (PCA) followed by a mixed model to process data obtained from a meta-analysis aimed at evaluating simultaneously the effect of ingestion of 1 of 3 types of bioactive substances (n-3 fatty acids, soluble fibers, and phytosterols) on 1 or more of 4 biomarkers (plasma total cholesterol, triacylglycerol, LDL cholesterol, and HDL cholesterol). DESIGN: Five independent variables (number of patients per study, dose, age, body mass index, and treatment length) and 4 dependent variables (percentage change in blood total cholesterol, LDL, HDL, and triacylglycerol) from 159 studies and substudies were organized into a matrix. The original values were converted to linear correlation units, which resulted in a new matrix. RESULTS: Two principal components were enough to explain 63.73% and 84.27% of the variance in the independent and dependent variables, respectively. Phytosterols and soluble fibers had a hypocholesterolemic effect, whereas n-3 fatty acids lowered triacylglycerol and increased total, LDL, and HDL cholesterol. The PCA and mixed model showed that this behavior was independent of dose, number of patients per study, age, and body mass index but was associated with treatment length. CONCLUSIONS: PCA is useful for summarizing available scientific information in examinations of health claims for foods and supplements.

Cholesterol↗

PubMed2004

Comparison of two dust collection methods for reservoir indoor allergens and endotoxin on carpets and mattresses.

Variable methods of dust collection may lead to uncertainty in the measurement of biomarkers. The purpose of this study was to examine the effect of two different dust collection devices on dust weight, Der p 1, Fel d 1, and endotoxin levels. We compared: (1) a nylon mesh sock inserted between the furniture attachment and the vacuum hose (the reference method) and (2) the ALK device. Duplicate dust samples were collected for 2 min from 2 m(2) of 37 living room floors and from each longitudinal half of 37 mattresses. Measurement of Der p 1 and Fel d 1 were by double monoclonal antibody enzyme-linked immunosorbent assay (ELISA) and endotoxin by a Limulus Amobocyte Lysate assay. Geometric mean ratios (95% confidence intervals) were calculated to show the differences between sampling devices for each measurement. Compared with the ALK device, the reference method collected significantly more dust from floors (sevenfold) and mattresses (threefold) and more total Der p 1, Fel d 1, and endotoxin in both sites. Floor, but not mattress, Der p 1 concentrations were also significantly higher (threefold) using our reference method. We recommend that, in order to minimize sampling device bias, allergen and endotoxin are expressed as a concentration, and that the bed is considered the major source of allergen exposure. Practical Implications Dust sampling equipment can influence the dust yield. In order to have confidence in comparisons of allergen and endotoxin reservoir levels between centers, standardization in the use of sampling equipment is important.

Air Pollution, Indoor↗