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Results for “Biomarker variability”

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PubMed2026

Aerobic Fitness and Health-Related Phenotypes: A Two-Stage Phenome-Wide Mendelian Randomization Study.

PURPOSE: We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. METHODS: Genetically determined aerobic fitness, as operationalized by Cai et al., served as the exposure instrument. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association studies (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for validation. Associations were estimated using the MR-Robust Adjusted Profile Score method, controlled for multiple testing (5% false discovery rate) and unaffected by violations of MR assumptions (directional concordance between discovery and validation; no evidence of horizontal pleiotropy across inverse-variance weighted, MR-Egger, weighted-median, and weighted-mode methods; negative control analysis on hair color). RESULTS: We identified 108 discovery associations, of which 34 remained valid and statistically significant after validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure. CONCLUSIONS: Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Humans↗

PubMed2005

Potentiation of the vitellogenic response to 17alpha-ethinylestradiol by cortisol in the fathead minnow Pimephales promelas.

The effects of elevated plasma cortisol levels on vitellogenin (VTG) induction were examined in the fathead minnow (Pimephales promelas) in an attempt to evaluate the potential influence of stress on this commonly used biomarker of estrogenicity. Two separate experiments were conducted in which fish plasma cortisol was elevated to various levels for 14 d by noninvasive additions of cortisol to the aquaria water. Fathead minnows were exposed to either cortisol alone, 17alpha-ethinylestradiol (EE2) alone, or a combination of the two hormones, and plasma levels of VTG as well as liver expression of VTG mRNA were measured. Both experiments gave similar results, with an exposure to 4 ng/L of EE2 resulting in significantly greater levels of plasma VTG in the presence of, compared to that in absence of, cortisol, whereas exposure to cortisol alone at concentrations between 144 and 800 microg/L had no effect on plasma VTG levels. This potentiation of the EE2-induced vitellogenesis by cortisol was dose-dependent, with plasma VTG reaching 125, 167, and 295% of the values obtained with EE2 alone when 144, 360, and 800 microg/L of cortisol, respectively, were added to the water. Liver mRNA results were consistent with plasma VTG, although they generally were more variable. The present study demonstrates that cortisol does not independently induce vitellogenesis but can potentiate estrogen-induced VTG synthesis in fathead minnow. The implications of these findings for the use of VTG as a biomarker of estrogenicity are discussed.

Animals↗

PubMed2026

Tumor Mutational Landscape and Its Correlation With Histopathological Characteristics in Breast Cancer.

BACKGROUND/AIM: In breast cancer, knowledge of the associations between clinicopathologic characteristics, genetic changes, and subtype-specific patterns is expanding. This study investigated how pathological and clinical variables affect the actionability of Next Generation Sequencing (NGS)-based tumor molecular data. MATERIALS AND METHODS: 227 breast cancer patients referred to Genekor's laboratory for tumor molecular profile analysis were included in the study. Pathology records were used to assess critical clinicopathological features, including HER2, ER, PR, Ki67, grade, metastatic site, and age. A 1021-gene NGS-based multigene panel was utilized to assess tumor biology alongside tumor mutational burden (TMB) and microsatellite instability (MSI). RESULTS: Comprehensive genomic profiling revealed that 95.6% of the patients harbored at least one oncogenic or likely oncogenic alteration, highlighting the high diagnostic yield of NGS-based testing. Distinct subtype-specific patterns were observed: HR+/HER2- tumors were enriched for PIK3CA and ESR1 gene alterations, whereas triple-negative breast cancer (TNBC) was dominated by TP53 alterations. Clinically actionable alterations were most common in HR+/HER2- tumors (~60% on-label), whereas TNBC more often harbored off-label or trial-associated targets. The inclusion of tumor-agnostic biomarkers (TMB/MSI) increased on-label actionability up to 64.5% in HR+/HER2- tumors, primarily driven by TMB-high cases. Median TMB values were low, and age was the only independent predictor. Furthermore, the presence of actionable alterations was significantly higher in metastatic tumors, and TP53 alterations were associated with aggressive tumor characteristics. CONCLUSION: Comprehensive NGS-based genomic profiling identifies clinically actionable alterations in over half of breast cancer patients, with substantial variability across molecular subtypes. The HR+/HER2- subtype demonstrates the highest prevalence of on-label actionable biomarkers. These findings support the routine implementation of comprehensive genomic profiling, especially in metastatic HER2-negative breast cancer, to guide precision oncology strategies and enable enrollment in biomarker-driven clinical trials.

Humans↗

PubMed2001

Biomarkers of exposure and effect in flounder (Platichthys flesus) exposed to sediments of the Adriatic sea.

The modifications of several biomarkers were investigated in flounder (Platichthys flesus) when exposed in the laboratory to sediment samples collected from the Northern Adriatic Sea. Besides clean sand used as a control substrate, fish were exposed to sediments sampled offshore the delta of the Po River, the harbour of Trieste, and from the industrial harbour of Venice (Porto Marghera). After six days of exposure, the enzyme activities ethoxyresorufin-O-deethylase (EROD), UDP glucuronyltransferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GPx), were assayed in fish liver. In addition, the contents of reduced glutathione (GSH), nonprotein thiols (SH), total sugars and extractable lipids were also determined in hepatic tissue, as well as the number of micronucleated hepatocytes and biliary concentrations of fluorescent aromatic compounds (FAC). Despite some variability within treatment groups, differences among exposed organisms were evident and consistent with known contaminant levels of sampled areas. Microsomal activities (EROD, UD-PGT) and FAC levels were the most sensitive exposure indicators. Variations in the other biomarkers showed only tendencies which although not statistically significant were generally consistent with the contamination pattern.

Animals↗

PubMed2005

Classification and selection of biomarkers in genomic data using LASSO.

High-throughput gene expression technologies such as microarrays have been utilized in a variety of scientific applications. Most of the work has been done on assessing univariate associations between gene expression profiles with clinical outcome (variable selection) or on developing classification procedures with gene expression data (supervised learning). We consider a hybrid variable selection/classification approach that is based on linear combinations of the gene expression profiles that maximize an accuracy measure summarized using the receiver operating characteristic curve. Under a specific probability model, this leads to the consideration of linear discriminant functions. We incorporate an automated variable selection approach using LASSO. An equivalence between LASSO estimation with support vector machines allows for model fitting using standard software. We apply the proposed method to simulated data as well as data from a recently published prostate cancer study.

Journal Article↗

PubMed2001

Absence of somatic hypermutation of immunoglobulin heavy chain variable region genes in precursor B-lymphoblastic lymphoma: a study of four cases in childhood and adolescence.

Somatic mutation (SM) analysis provides a useful tool for understanding the suitable stage of differentiation of normal and neoplastic B cells. B-cell precursor neoplasms are considered to be somatically premutational. However, no reports have been made on the sequence analysis of SM in rearranged immunoglobulin heavy chain variable region (VH) genes in precursor B-lymphoblastic lymphoma (PB-LBL); as for B-cell acute lymphoblastic leukemia (B-ALL), the variable frequency of SM of the VH genes has been described. To better distinguish PB-LBL from B-ALL based on the stage at which differentiation occurs, we analyzed the SM of the VH genes in 4 children and adolescents with PB-LBL. In all 4 cases, there was no SM in complementarity-determining regions 1, 2, and 3 and in framework regions 2 and 3 of the VH genes, except for 1 mutation in 1 of 2 polymerase chain reaction products from 1 patient. Our data showed the absence of SM of lymphoma cells in PB-LBL, in addition to the developmentally regulated rearrangement of VH genes at the stage of B-cell precursor cells. The lack of mutation in VH gene sequences suggests that SM may differ between PB-LBL and B-ALL.

Adolescent↗

PubMed1998

Evaluation of biomarkers of survival response in hormone-refractory prostate cancer patients treated with suramin.

Hormone-refractory prostate cancer (HRPC) patients often have nonmeasurable disease. In such patients, predictive biomarkers other than tumor response may be required to compare therapeutic effects. We examined the predictive value for survival of various clinical and laboratory parameters, including prostate-specific antigen (PSA), in HRPC patients treated with suramin. Data from 103 HRPC patients were analyzed using various survival analyses, the likelihood ratio approach, and logistic regression analyses. When pretreatment factors, percentage decrease in PSA at 4 weeks from start of treatment (deltaPSA), and updated survival data were fit by a multivariate Cox proportional hazards model, acid phosphatase, lactate dehydrogenase, and deltaPSA were significant, with risk ratios close to 1. There was a decrease in likelihood ratio with increasing APSA. A logistic regression model was developed to predict the probability of <1 year of survival from the start of treatment. Hemoglobin and deltaPSA were found to be significant variables. However, in view of the complexities involving the relationship between PSA expression and prostate cancer growth and possible selective effect of treatment on PSA, further prospective testing is necessary. Therefore, deltaPSA cannot necessarily be used as a biomarker for survival response in individual patients during the evaluation of the therapeutic response of HRPC to new antineoplastic drugs.

Acid Phosphatase↗

PubMed2004

Biological variation of the natriuretic peptides and their role in monitoring patients with heart failure.

BACKGROUND: B-type natriuretic peptide (BNP) and the inactive metabolite NT-proBNP are proven tests for diagnosis and staging of severity for patients with heart failure. However, the utility of these biomarkers for monitoring the success of drug therapy remains to be determined. Results of longitudinal studies on serial blood testing must be linked to overall patient morbidity and mortality outcomes. We previously determined the 8-week biological variability (BV) of BNP and NT-proBNP assays in healthy subjects and the 1-day BV for BNP alone in patients with compensated and stable heart failure. From these studies, the percent statistical change in serial samples of approximately 100% difference was estimated (95% confidence). METHODS: We applied the biological variability concepts to the serial results of BNP and NT-proBNP collected from patients with heart failure and compared the performance of these two markers. RESULTS: While there are minor differences in the results between the assays from one time period to another, the overall interpretation of results are essentially identical. Moreover, the majority of individual serial time points are not significantly different from the previous value. CONCLUSION: Frequent testing (e.g. daily) for BNP and NT-proBNP to monitor therapy for patients with CHF is not indicated, as overall changes require several days to become evident.

Biomarkers↗

PubMed2004

Free circulating soluble CD52 as a tumor marker in chronic lymphocytic leukemia and its implication in therapy with anti-CD52 antibodies.

BACKGROUND: The CD52 antigen is a glycoprotein anchored on the cell membrane of mature B and T lymphocytes, monocytes, and eosinophils. Alemtuzumab (CAMPATH-1H; anti-CD52) is currently approved for the treatment of patients with refractory chronic lymphocytic leukemia (CLL). The authors investigated the possibility that CD52 may be shed from cells and, once soluble, may bind to injected alemtuzumab, forming immune complexes. METHODS: The authors used Western blot analysis, immunoprecipitation, and enzyme-linked immunoadsorbent assay to investigate the presence of soluble CD52 (sCD52) in the plasma specimens of 117 patients with CLL. They also used in vitro mixing experiments to examine the ability of sCD52 to compete with cells and sequester therapeutic alemtuzumab. RESULTS: The authors detected high levels of sCD52 in the plasma specimens of patients with CLL. sCD52 can compete with cells in vitro for binding to alemtuzumab, and can form complexes in patients receiving alemtuzumab. Plasma levels of sCD52 were found to be correlated (r)with Rai stage (P = 0.0001), beta-2-microglobulin (beta-2M) levels (P = 0.00002), soluble CD23 levels (r = 0.42, P < 0.001), and immunoglobulin mutation status (P = 0.003). In the multivariate analysis adjusted for beta-2M level, patients with sCD52 levels > 2336 nM/L had a nearly 4-fold increase in risk of death. Higher levels of plasma alemtuzumab were achieved when levels of sCD52 were lower. CONCLUSIONS: These data not only demonstrated that sCD52 was detectable and useful in the staging and monitoring of patients with CLL, but also showed that sCD52 formed immune complexes with alemtuzumab and may influence the efficacy and toxicity of alemtuzumab therapy.

Adult↗

PubMed2006

Search for correlations between serotonin 5-HT1A receptor expression and cognitive functions--a strategy in translational psychopharmacology.

RATIONALE: Animal studies and studies of human aging have suggested that the serotonin 5-HT1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits. OBJECTIVES: The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT1A receptor binding potential (BP) and cognitive functioning. MATERIALS AND METHODS: Twenty-four male control subjects, age 20-55 years, were examined with [11C]WAY100635 PET and a battery of cognitive tests. 5-HT1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region. RESULTS: There was a severalfold of variability in 5-HT1A BP between individuals. We found no significant correlation between regional [11C]WAY100635 binding and cognitive performance. CONCLUSIONS: The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.

Adult↗

PubMed1999

Urinary 3H-tetracycline and pyridinium crosslinks differ in their response to calcium restriction in mature and aged rats.

The aim of this study was to evaluate bone resorption (BR) in rats by two methods: chronic 3H-tetracycline labeling (3HTC) and pyridinium crosslink excretion (PYDX), and compare the sensitivity of these markers in two age groups. Female Sprague-Dawley rats at 12-29 weeks of age ("mature", n = 12) and at 40-57 weeks of age ("aged", n = 22) were examined. Skeletal incorporation of 3HTC in aged rats was 43 +/- 8% of that in mature animals (P < 0.01), indicating an age-related decrease in bone turnover. BR was modulated over 9 weeks by calcium restriction (CR), measured by urinary excretion of both 3HTC and PYDX, and compared with age-matched, calcium-adequate controls. At baseline, urinary excretion of 3HTC was not significantly different between age groups, whereas urinary PYDX was 14-20% higher in mature compared with aged rats (P < 0.01). CR produced a 32-39% peak increase in BR (P < 0.01) compared with controls that did not differ significantly between marker or age group. Urinary 3HTC was elevated at weeks 1-3 (P < 0. 01) and reached maximal values at week 2 (32 +/- 17%). Urinary PYDX, however, was not elevated until week 2, reached maximal levels at week 3 (39 +/- 15%), and remained elevated until week 6 (P < 0.01). These data indicate that although both markers are elevated by CR, marker response differs with age, and variability exists for acute and chronic responses.

Age Factors↗

PubMed1994

P53 mutation in a series of epithelial ovarian cancers from the U.K., and its prognostic significance.

In an initial study of 20 fresh ovarian tumour samples, we compared the immunohistochemical positivity of staining of the p53 protein with the presence of missense mutations of the p53 gene. This revealed a prevalence of 50% with a perfect correlation between mutation and immunohistochemical staining. Detection of the p53 protein by immunohistochemistry was, therefore, used as a reliable indicator for the presence of P53 mutation, and was applied to a study of an archival series of 93 ovarian tumours. Positive immunostaining of the p53 protein was observed in 47% of this series. Cox regression was used to assess whether various clinical variables and P53 mutation were related to survival. As a result, it was found that positive staining of the p53 protein was independent of age, tumour differentiation, tumour type, though possibly not stage. There was some evidence that p53 positivity was associated with reduced survival after adjusting for other variables, but the result was not statistically significant.

Biomarkers, Tumor↗

PubMed2005

A "floral" variant of nodal marginal zone lymphoma.

We describe 6 cases of a specific variant of nodal marginal zone lymphoma with "floral" lymph follicles in patients ranging in age from 18 to 66 years. All 6 patients had lymphadenopathy, either local (n = 5) or systemic (n = 1), and good performance status (0), and none had fever, weight loss, or night sweating. They all underwent excisional biopsy. Histologically, all lesions had a distinctive morphology, with proliferation of medium-sized atypical lymphoid cells in the marginal zone, hyperplastic lymph follicles with enlarged germinal centers, and a thickened mantle zone. In places, folliculolysis was observed. On immunohistochemical staining, the atypical lymphoid cells showed a B-cell phenotype (CD20 +), IgM positivity in 2 of 5 cases, and negativity for CD5, CD10, CD23, CD43, bcl-6, and IgD. Polymerase chain reaction examination for immunoglobulin heavy chain in 5 cases showed monoclonality in all. Five patients did not receive adjuvant chemotherapy and had no recurrences. The patient with systemic lymphadenopathy received chemotherapy and had a complete response without relapse. This variant should be differentiated from the usual nodal marginal zone lymphoma because of its specific clinical and pathological features.

Adolescent↗

PubMed1998

The effect of dust-protective respirator mask and the relevance of work category on urinary 1-hydroxypyrene concentration in PAH exposed electrode paste plant workers.

Large amounts of polycyclic-aromatic hydrocarbons (PAH) are found in the work environment of electrode paste workers. Inhalation and skin uptake are both important routes for PAH exposure. We have studied the effect of dust-protective respirator masks by measuring urinary 1-hydroxypyrene as a biomarker for PAH exposure. Eighteen workers divided into work categories at the factory were monitored by personal air sampling and urinary 1-hydroxypyrene every work shift for two consecutive weeks. In the second week of the study, the workers were encouraged to wear respirator masks persistently, which resulted in a significant reduction in urinary 1-hydroxypyrene in end-of-shift samples (paired t-test, P = 0.009). When correcting urinary 1-hydroxypyrene for ambient air pyrene we found on average 41% reduction in urinary 1-hydroxypyrene concentration in the second week of the intervention study. There was a work-category dependent variation in the correlation between end-of-shift urinary 1-hydroxypyrene samples and pyrene measured in the breathing zone of the workers, most likely due to variable skin uptake of pyrene; the overall correlation coefficient was 0.26 (P = 0.015). The 1-hydroxypyrene concentration in pre- and post-shift urine samples varied between 0.7 and 69.6 mumol/mol creatinine in the normal work week, and depended on the work category. The particulate PAH exposure ranged from 0.6 to 21.4 micrograms/m3. The ratio of particulate pyrene to benzo[a]pyrene varied from 1.6 to 8.0 amongst the various work categories within the same plant. Multiple regression analysis showed that smoking and work day are explanatory variables for the concentration of 1-hydroxypyrene in urine. Thirty-nine percent of the variation in the urinary 1-hydroxypyrene level at the end of shift could be explained by the independent variables pyrene concentration in air, smoking habits, work day, use of respiratory mask, work category and age.

Biomarkers↗

PubMed2002

Immunohistochemical expression of metallothionein in human bladder cancer: correlation with histopathological parameters and patient survival.

PURPOSE: We assessed metallothionein expression and its patterns of distribution as possible prognostic variables in bladder cancer with regard to histopathological parameters. MATERIALS AND METHODS: We stained 91 formalin fixed, paraffin embedded tissue specimens of bladder cancer from 91 patients with no history of treatment using an immunohistochemical technique for metallothionein. Relationships between immunoreactivity for metallothionein and histopathological parameters were examined. In addition, these parameters, including metallothionein, were evaluated as potential prognostic markers. RESULTS: Metallothionein was detected in 33 of 91 bladder cancers (36.3%). There were significant relationships of metallothionein expression with high grade, high stage and nonpapillary growth pattern tumors. There was no specific correlation of metallothionein expression with the interval to intravesical recurrence. In the 31 patients who underwent radical cystectomy a significant relationship between metallothionein immunoreactivity and cancer specific survival was found. CONCLUSIONS: Our findings suggest that a close correlation exists of metallothionein expression with histopathological parameters and metallothionein expression can be a useful prognostic variable for bladder cancer.

Adult↗

PubMed2000

Immunophenotypic discrepancies between granulocytic and erythroid lineages in peripheral blood of patients with paroxysmal nocturnal haemoglobinuria.

In paroxysmal nocturnal haemoglobinuria (PNH), somatic mutation of the PIG-A gene is thought to result in altered expression of glycosylphosphatidylinositol (GPI)-anchored proteins. This study was performed to determine if there were any heterogeneities of cellular phenotypes between two major peripheral blood cells, erythrocytes and granulocytes. Using CD59-based immunocytometry, the patterns of CD59 expression were shown to be conserved in the circulating erythroid cells (reticulocytes and mature erythrocytes) in all 29 patients with PNH. Twenty-one patients had distinct combinations of PNH type I, II, and III cells in different lineages. Only eight patients exhibited similar patterns of CD59 expression between the two lineages. Approximately one third of the patients had PNH type II cells in either or both of the two lineages indicating variable lineage involvement. The proportion of abnormal granulocytes was higher than those of abnormal reticulocytes and erythrocytes. In patients with appropriate erythropoietic responses to haemolysis (RPI > 2.0), shift reticulocytes display predominantly PNH phenotypes. These immature erythroid cells with altered expression of GPI-anchored proteins may dominate the peripheral blood during periods of increased marrow activity resulting in greater phenotypic mosaicism in such patients. Discrepancies in expression of GPI-anchored proteins in PNH which are highly variable between the two lineages may be the result of their different life spans and the influence of complement-mediated cytolysis. The phenomena also indicated the possible occurrence of more than one PNH clones with variable clonal dominance.

Adolescent↗

PubMed2003

Recombinant antibodies against subcellular fractions used to track endogenous Golgi protein dynamics in vivo.

Generation of specific antibodies against enriched subcellular fractions is a powerful strategy to identify and characterize cellular components. We show that recombinant antibodies can be selected in vitro by phage display against complex subcellular fractions, namely microtubule-binding proteins and Golgi stacks. This technique has allowed us to overcome many limitations of the classical animal-based approach and generate cell biology-compliant antibodies. In addition, we show that intracellular expression of GFP-tagged recombinant antibodies can reveal the dynamics of endogenous proteins in vivo. Endogenous Giantin is very static and outlines the Golgi in living cells. It accumulates neither onto Golgi-derived tubules upon Brefeldin A treatment before Golgi disappearance, nor onto de novo formed Golgi mini-stacks upon microtubule depolymerization, and remains instead on the 'old' pericentriolar Golgi. This suggests that, in contrast to other Golgi matrix proteins, endogenous Giantin is very stably associated with the Golgi and does not efficiently recycle to the ER. Altogether, we show that the antibody phage display technique represents an efficient alternative to rapidly generate versatile antibodies that represent new tools to study protein function.

Animals↗

PubMed1998

Transforming growth factor beta1 (TGF-beta1) is a preoperative prognostic indicator in advanced gastric carcinoma.

It has been generally accepted that transforming growth factor beta1 (TGF-beta1) has both negative and positive effects on tumour growth and progression. This study analysed the prognostic value of TGF-beta1 mRNA in advanced gastric carcinoma. A reverse transcriptase-polymerase chain reaction analysis (RT-PCR) was used for TGF-beta1 in endoscopic biopsy specimens from 42 advanced gastric carcinomas. Thirty specimens expressed TGF-beta1 mRNA while 12 specimens did not. The follow-up duration ranged from 4 to 37 months (mean 22.8 months). TGF-beta1-positive group demonstrated a shorter overall survival compared with the TGF-beta1 -negative group (P=0.0014). A significant correlation was also found in the 32 patients who underwent curative resection (P=0.0048). Significant correlations were found between TGF-beta1 mRNA expression and both stage (P=0.0015) and nodal involvement (P=0.0060). Multivariate analysis demonstrated that only TGF-beta1 mRNA expression (P=0.0306) was an independent prognostic factor. All of ten patients who underwent non-curative resection expressed TGF-beta1 mRNA. Expression of TGF-beta1 mRNA in gastric biopsy specimens may be an important preoperative prognostic variable for advanced gastric carcinoma.

Aged↗