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Results for “Biomarker variability”

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PubMed2002

Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans.

The nematode Caenorhabditis elegans is an important model for studying the genetics of ageing, with over 50 life-extension mutations known so far. However, little is known about the pathobiology of ageing in this species, limiting attempts to connect genotype with senescent phenotype. Using ultrastructural analysis and visualization of specific cell types with green fluorescent protein, we examined cell integrity in different tissues as the animal ages. We report remarkable preservation of the nervous system, even in advanced old age, in contrast to a gradual, progressive deterioration of muscle, resembling human sarcopenia. The age-1(hx546) mutation, which extends lifespan by 60-100%, delayed some, but not all, cellular biomarkers of ageing. Strikingly, we found strong evidence that stochastic as well as genetic factors are significant in C. elegans ageing, with extensive variability both among same-age animals and between cells of the same type within individuals.

Aging↗

PubMed1991

Predictive factors for effective salvage therapy of nonseminomatous germ cell tumors of testis.

Twenty-four patients with metastatic and chemotherapy-refractory nonseminomatous germ cell tumors of the testis were treated with various chemotherapy regimens upon failure. Eight of the 24 patients (33%) are alive and disease-free after salvage therapy with a median follow-up of sixteen months. Prognostic factors tested included those known to be predictive for initial response to therapy (clinical stage and degree of elevation of the biomarkers). In addition, time to initiation of salvage therapy and response to initial chemotherapy were assessed as variables. Our data suggest that patients with solitary organ metastases following relapse, and response to initial chemotherapy are favorable predictors for response to salvage treatment. All the patients with solitary organ metastases (5/5 [100%]) but only 3/19 (16%) of the patients with multiple metastatic sites were salvaged. Patients with delayed initiation of salvage therapy had a reduced likelihood of achieving a complete remission but this was not statistically significant. The variables identified need to be incorporated into future trials testing the efficacy of salvage therapy for patients with nonseminomatous tumors of the testis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2026

Comprehensive quality profiling and comparative metabolic characterization of seven dominant fresh-eating Chinese olive (Canarium album Lour.) cultivars in Southern China.

Fresh-eating Chinese olive (Canarium album Lour.) is a subtropical fruit endemic to southern China with considerable commercial value, yet systematic quality characterization of dominant cultivars remains scarce. This study established a multi-dimensional quality dataset for seven dominant cultivars from Fujian and Guangdong provinces, integrating nutritional components, soluble sugars, organic acids, mineral elements, volatile profiles, and non-targeted metabolomics. Significant cultivar-specific differences were observed across all evaluated dimensions: "Lingfeng" exhibited a sugar-dominant low-acid profile, whereas "Sanleng" showed elevated phenolic constituents accumulation. Volatile profiling identified terpenoid-based candidate discriminatory biomarkers, and metabolomic analysis revealed phenylpropanoid biosynthesis, tryptophan metabolism, and starch and sucrose metabolism as the most variable pathways. Correlations between untargeted profiling and targeted absolute quantification validated untargeted result reliability and revealed their complementarity in nutritional evaluation. These findings provide baseline data for FECO germplasm evaluation and targeted industrial utilization.

China↗

PubMed2007

Hyperoxia in the intensive care unit: why more is not always better.

PURPOSE OF REVIEW: Hyperoxic inspired gas is essential for patients with hypoxic respiratory failure; it is also suspected, however, as a contributor to the pathogenesis of acute lung injury. Several recent studies in humans, animals, and cell culture have identified mechanisms by which hyperoxia may exert deleterious effects on critically ill patients. This review identifies relevant new findings regarding hyperoxic lung injury in the context of providing guidance for future clinical studies. RECENT FINDINGS: Recent studies have clarified the roles of both receptor-mediated and mitochondrial cell death pathways in experimental hyperoxic lung injury. Studies in animals demonstrate that hyperoxia interacts with mechanical stretch to augment ventilator-induced lung injury. Finally, studies in humans implicate hyperoxia in impairment of host defense responses to infections. SUMMARY: Although hyperoxia has not been conclusively identified as a clinically important cause of lung injury in humans, animal data strongly implicate it. Reports of interaction effects between hyperoxia and both mechanical ventilation and host defense suggest that clinical studies of hyperoxia must take these variables into account. Accumulating data about how hyperoxia initiates cell death provide guidance for development of both biomarkers to identify hyperoxia-induced injury and pharmacological interventions to limit hyperoxia's adverse effects.

Animals↗

PubMed2005

Advanced glycation end products and bone loss during aging.

It is well known that bone mass density decreases with age. Age-related bone mass loss is ascribed to several factors. Nonenzymatic glycation has been proposed as a new potential factor in the loss of bone during aging. In this study we evaluated the concentration of pentosidine, an advanced glycation end product, in cortical and trabecular bone and in the plasma of subjects undergoing orthopedic surgery. The relationship between these parameters and a clinical index of osteoporosis was also studied. Samples of bone and plasma of 104 nondiabetic subjects (74 women and 30 men), 72 +/- 1 years old, were studied. Pentosidine was determined by HPLC after decalcification and hydrolysis. The radiologic Singh index was evaluated blindly by orthopedic surgeons to provide the degree of osteoporosis. Pentosidine concentration of cortical bone shows a significant exponential increase with age (r = 0.610, P < 0.001). This increase, however, is not seen in the trabecular bone, which is characterized by a large spread in the data. Interestingly the concentration of cortical pentosidine is also related to the Singh score (r(s) = -0.274, P < 0.01). Plasma pentosidine has a significant exponential correlation with age (r = +0.339, P < 0.001) and a linear correlation with the cortical bone pentosidine (r = +0.248, P < 0.05). This study demonstrates that pentosidine increases exponentially in cortical bone during aging, and is thus a good biomarker for the degree of bone mass density loss. The trabecular bone concentration of pentosidine is more variable, probably because of the turnover rate and the local environment; plasma pentosidine might provide information on the bone turnover rate.

Aged↗

PubMed1996

The challenge of mechanism-based modeling in risk assessment for neurobehavioral end points.

The mathematical form for a dose-time-response model is ideally not just a convenience for summarizing or fitting a particular data set--it represents a hypothesis. The more this hypothesis reflects a mechanistically sophisticated view of the likely reality, the more it can lead to potentially informative validating or invalidating types of predictions about the results of real experiments and (in the long run) reasonably credible predictions outside the range of direct observations. This paper first reviews some distinctive features of the nervous system and neurotoxic responses and theoretically explores some basic quantitative implications of these features. Relationships are derived for how dose-response relationships for the inhibition of function should depend on the numbers of neurons in series or redundant parallel arrangements that are required or capable of performing the function. Previous work is reviewed in which some less nervous-system-specific features were the foci of quantitative risk-assessment modeling for specific neurotoxic end points. These include a) rates of repair of putatively reversible damage in the case of acrylamide; b) human interindividual variability in susceptibility to fetal/developmental effects in the case of methylmercury; and c) opportunities to use intermediate biomarkers to assist in integrated animal toxicological and epidemiologic investigations of the chronic cumulative risks posed by agents that contribute to neuronal loss with increasing age and pathology.

Behavior↗

PubMed2026

Comprehensive Somatic Profiling of Gastroenteropancreatic Neuroendocrine Neoplasms.

BACKGROUND: The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is rising, yet their biological heterogeneity and variable response to treatments remain poorly understood. Comprehensive genomic characterization may uncover somatic drivers and inform biomarker-driven therapeutic strategies. METHODS: We retrospectively analyzed clinically ordered next-generation sequencing (NGS) results from tumor samples of 111 patients with confirmed GEP-NENs treated at Johns Hopkins Hospital between 2020 and 2022. Pathogenic and likely pathogenic mutations were identified using OncoKB, CHASMplus, and COSMIC databases. Mutational patterns were correlated with clinical characteristics and overall survival using univariate and multivariate analyses. RESULTS: In this retrospective study of 111 patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), somatic pathogenic or likely pathogenic mutations were identified in 79% of cases. The most frequent alterations involved TP53 (19%), MEN1 (17%), and chromatin remodeling genes such as DAXX (9%) and ATRX (6%). Notably, we also identified a subset of patients (9%) patients with mutations typically associated with hematologic malignancies. Distinct co-mutation and mutual exclusivity patterns were observed between pancreatic and non-pancreatic NENs. Poorly differentiated or high-grade tumors correlated with mutations in TP53, KRAS, and CDKN2A. Mutations in KRAS, DAXX/ATRX, and hematologic malignancy-associated genes were independently associated with worse overall survival. CONCLUSIONS: This study reveals distinct somatic mutation patterns in GEP-NENs associated with tumor differentiation, grade, primary site, and survival. The identification of hematologic malignancy-associated mutations in a subset of GEP-NENs suggests possible shared molecular phenotypes with poor prognostic implications. The presence of KRAS mutations supports exploring pan-RAS inhibitors as potential therapies in select patients. These findings highlight the clinical utility of genomic profiling in GEP-NENs.

Neuroendocrine neoplasms↗

PubMedDate not supplied

Soil microbial communities associated with Bt and non-Bt corn in three soils.

The effects of expression of Cry endotoxin by Bt corn (transgenic corn engineered to express Bacillus thuringiensis toxin) on soil microbial community structure were assessed in a growth chamber experiment. Two lines of transgenic corn expressing different Cry endotoxins were compared with their respective non-transgenic isolines in three soil types with differing textures. Phospholipid fatty acid (PLFA) profiles from bulk soil and community-level physiological profiles (CLPP) from the rhizosphere community were used to assess community structure. Differences in PLFA profiles due to soil type were significant, accounting for 73% of the total variability in the dataset. Differences in bacterial and fungal CLPP profiles due to soil type were statistically significant, but probably not biologically important, accounting for 6.3 and 3.8% of the total variability, respectively. Neither expression of Cry endotoxin nor corn line had a significant effect on microbial profiles, except in the high-clay soil where both factors significantly affected bacterial CLPP profiles (accounting for 6.6 and 6.1% of the variability in that soil, respectively). Expression of Cry endotoxin also significantly reduced the presence of eukaryotic PLFA biomarker in bulk soils, although it is unclear which groups of eukaryotes were affected. We conclude that the effects of transgenic Bt corn in this short-term experiment are small, and longer-term investigations are necessary.

Aluminum Silicates↗

PubMed2001

[Genetic polymorphism and cancer].

The clinical pathological significance of genetic polymorphism in cancer is reviewed from the following standpoint. 1) Genetic diagnosis of cancer, especially for loss of heterozygosity 2) Interference with laboratory data: For example, the polymorphisms in secretor and Lewis genes make effect on the serum levels of CA19-9. 3) Cancer susceptibility: Molecular epidemiological studies revealed some genetic polymorphisms were related with cancer susceptibility and were useful for biomarkers of cancer risk. 4) Drug sensitivity: The differences in drug toxicity are sometimes attributed to genetic variability in some enzymes responsible for drug metabolism. When the polymorphisms related with drug degradation were examined, the exact drug would have been selected for each individual. Genetic polymorphisms are strongly related with clinical practice of cancer. After the information about genetic polymorphisms is accumulated, tailor-made medicine(therapy/prevention/diagnosis) will be applicable to medical care of individuals.

Genetic Predisposition to Disease↗

PubMed2002

Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors.

PURPOSE: The goal of this study was to identify potential protein markers in lung adenocarcinomas. EXPERIMENTAL DESIGN: A series of 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung samples were examined for quantitative differences in protein expression using two-dimensional PAGE. Candidate proteins were identified using matrix-assisted laser desorption/ionization mass spectrometry or peptide sequencing. The levels of the individual isoforms of nine proteins found to be overexpressed in the lung tumors were examined. Potential mechanisms for overexpression were examined by comparing mRNA expression levels, assessed using oligonucleotide arrays, to the protein values in the same samples. RESULTS: Antioxidant enzyme AOE372, ATP synthase subunit d (ATP5D), beta1,4-galactosyltransferase, cytosolic inorganic pyrophosphatase, glucose-regulated M(r) 58,000 protein, glutathione-S-transferase M4, prolyl 4-hydroxylase beta subunit, triosephosphate isomerase, and ubiquitin thiolesterase (UCHL1) were identified as being significantly overexpressed in lung adenocarcinomas. The expression of these proteins was increased from 1.4- to 10.6-fold as compared with uninvolved lung tissue. The expression of the individual protein isoforms was correlated with 10 clinicopathological variables as well as with each gene's mRNA level in the same sample. Both isoforms of glucose-regulated M(r) 58,000 protein were found to be significantly correlated with their mRNA expression profiles (P < 0.05), indicating that increased transcription likely underlies the increased expression of these proteins. CONCLUSIONS: Two-dimensional PAGE and mass spectrometry can identify proteins showing increased expression in lung adenocarcinoma. The association of specific isoforms of these proteins with clinical variables and understanding the regulation of their expression will aid in determination of their potential use as biomarkers in this cancer.

Adenocarcinoma↗

PubMedDate not supplied

Biological age and 12-year cognitive change in older adults: findings from the Victoria Longitudinal Study.

BACKGROUND: Although recent cross-sectional findings indicate that markers of biological age (BA) mediate chronological age (CA) differences in cognitive performance, little is known about their influence on actual cognitive changes. OBJECTIVE: The purpose of this investigation is to examine CA and BA as predictors of 12-year cognitive change in a longitudinal sample of older adults. METHODS: Data from the Victoria Longitudinal Study (VLS) were examined for 125 adults between 67 and 95 years of age. Biomarkers, including visual and auditory acuity, grip strength, peak expiratory flow, blood pressure, and body mass index, were submitted to a factor analysis and a composite BA variable was computed based on factor loadings. Intraindividual change across 5 waves of measurement (3-year intervals) was examined as a function of CA and BA for 5 cognitive domains: verbal processing speed, working memory, reasoning, episodic memory, and semantic memory. RESULTS: The latent structure of biomarkers was consistent with previous investigations of functional age and a common factor view of biological aging. Results of hierarchical linear modeling showed that BA predicted actual cognitive change (decline) independent of CA. CONCLUSIONS: As a predictor of cognitive performance in late life, CA is a proxy for biological and environmental influences. We have shown that biological influences are independent predictors of actual cognitive change in older adults. This supports the view that cognitive decline is not due to aging per se, but rather is likely due to causal factors that operate along the age continuum.

Aged↗

PubMed2025

CoxKAN: Kolmogorov-Arnold networks for interpretable, high-performance survival analysis.

MOTIVATION: Survival analysis is a branch of statistics that is crucial in medicine for modeling the time to critical events such as death or relapse, in order to improve treatment strategies and patient outcomes. Selecting survival models often involves a trade-off between performance and interpretability; deep learning models offer high performance but lack the transparency of more traditional approaches. This poses a significant issue in medicine, where practitioners are reluctant to use black-box models for critical patient decisions. RESULTS: We introduce CoxKAN, a Cox proportional hazards Kolmogorov-Arnold Network for interpretable, high-performance survival analysis. Kolmogorov-Arnold Networks (KANs) were recently proposed as an interpretable and accurate alternative to multi-layer perceptrons. We evaluated CoxKAN on four synthetic and nine real datasets, including five cohorts with clinical data and four with genomics biomarkers. In synthetic experiments, CoxKAN accurately recovered interpretable hazard function formulae and excelled in automatic feature selection. Evaluations on real datasets showed that CoxKAN consistently outperformed the traditional Cox proportional hazards model (by up to 4% in C-index) and matched or surpassed the performance of deep learning-based models. Importantly, CoxKAN revealed complex interactions between predictor variables and uncovered symbolic formulae, which are key capabilities that other survival analysis methods lack, to provide clear insights into the impact of key biomarkers on patient risk. AVAILABILITY AND IMPLEMENTATION: CoxKAN is available at GitHub and Zenodo.

Humans↗

PubMedDate not supplied

Urinary hexane diamine to assess respiratory exposure to hexamethylene diisocyanate aerosol: a human inhalation study.

The use of urinary hexane diamine (HDA) as a biomarker to assess human respiratory exposure to hexamethylene diisocyanate (HDI) aerosol was evaluated. Twenty-three auto body shop workers were exposed to HDI biuret aerosol for two hours using a closed exposure apparatus. HDI exposures were quantified using both a direct-reading instrument and a treated-filter method. Urine samples collected at baseline, immediately post exposure, and every four to five hours for up to 20 hours were analyzed for HDA using gas chromatography and mass spectrometry. Mean urinary HDA (microg/g creatinine) sharply increased from the baseline value of 0.7 to 18.1 immediately post exposure and decreased rapidly to 4.7, 1.9 and 1.1, respectively, at 4, 9, and 18 hours post exposure. Considerable individual variability was found. Urinary HDA can assess acute respiratory exposure to HDI aerosol, but may have limited use as a biomarker of exposure in the workplace.

Adolescent↗

PubMed2004

Gases and organic solvents in urine as biomarkers of occupational exposure: a review.

A brief review of urine analysis in studies of occupational exposure to volatile organic compounds and gases is provided. Analysis of exhaled breath for volatile compounds does not have a long history in occupational medicine. A number of studies has been undertaken since the 1980s, and the methods are well enough accepted to be put forward as biological equivalents of threshold limit values (TLVs) for some volatile organic compounds (VOCs) such as acetone; methanol; methyl ethyl ketone (MEK); methyl isobutyl ketone (MIBK); tetrahydrofurane; dichloromethane. In the last 20 years many scientific articles have shown that the urinary concentrations of unchanged solvents are correlated with environmental exposure and could be used for biological monitoring. The use of urine analysis of unchanged solvents in occupational applications is not yet widespread. Nonetheless, in the short time since its application, a number of important discoveries has been made, and the future appears bright for this branch of analysis. In this paper, the basic concepts and methodology of urine analysis are briefly presented with a critical revision of the literature on this matter. The excretion mechanisms of organic solvents in urine are discussed, with regard to biological variability, and the future directions of research are described.

Biomarkers↗

PubMed2001

Increased levels of biochemical markers of bone turnover in relation to persistent immune activation in common variable immunodeficiency.

BACKGROUND: Based on the involvement of cytokines and growth factors in bone homeostasis, we hypothesised that patients with common variable immunodeficiency (CVI), characterised by persistent immune activation in vivo, may have disturbed bone metabolism as evaluated by biochemical markers of bone turnover. MATERIALS AND METHODS: Serum levels of tumour necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), bone-specific alkaline phosphatase (B-ALP), osteocalcin, carboxyterminal crosslinking telopeptide of type I collagen (CTX-I), insulin-like growth factor (IGF)-I and IGF binding protein-3 (IGFBP-3) were measured in 25 patients with CVI and compared to 25 age- and sex-matched healthy controls. RESULTS: Patients with CVI had significantly higher serum levels of CTX-I and B-ALP, and significantly lower serum levels of IGF-I and IGFBP-3 compared to controls as shown in cross-sectional, and as for B-ALP and CTX-I, also during longitudinal testing. No differences were observed for osteocalcin between the two groups. The elevated B-ALP and decreased IGF-I and IGFBP-3 levels were most pronounced in a subgroup of CVI patients characterised by persistent activation of proinflammatory cytokines in vivo. Raised B-ALP and decreased IGF-I and IGFBP-3 were also significantly correlated with enhanced IL-6 and TNF-alpha levels in these patients. CONCLUSIONS: The present study suggests that persistent immune activation in vivo, with raised levels of proinflammatory cytokines, may be related to disturbed bone homeostasis in CVI patients, further supporting an interaction between immune related mediators and bone metabolism in humans.

Adult↗

PubMed1998

Identification of functional human splenic memory B cells by expression of CD148 and CD27.

Memory B cells isolated from human tonsils are characterized by an activated cell surface phenotype, localization to mucosal epithelium, expression of somatically mutated immunoglobulin (Ig) variable (V) region genes, and a preferential differentiation into plasma cells in vitro. In spleens of both humans and rodents, a subset of memory B cells is believed to reside in the marginal zone of the white pulp. Similar to tonsil-derived memory B cells, splenic marginal zone B cells can be distinguished from naive follicular B cells by a distinct cell surface phenotype and by the presence of somatic mutations in their Ig V region genes. Although differences exist between human naive and memory B cells, no cell surface molecules have been identified that positively identify all memory B cells. In this study, we have examined the expression of the receptor-type protein tyrosine phosphatase CD148 on human B cells. CD148(+) B cells present in human spleen exhibited characteristics typical of memory B cells. These included an activated phenotype, localization to the marginal zone, the expression of somatically mutated Ig V region genes, and the preferential differentiation into plasma cells. In contrast, CD148(-) B cells appeared to be naive B cells due to localization to the mantle zone, the expression of surface antigens typical of unstimulated B cells, and the expression of unmutated Ig V region genes. Interestingly, CD148(+) B cells also coexpressed CD27, whereas CD148(-) B cells were CD27(-). These results identify CD148 and CD27 as markers which positively identify memory B cells present in human spleen. Thus, assessing expression of these molecules may be a convenient way to monitor the development of memory B cell responses in immunocompromised individuals or in vaccine trials.

B-Lymphocyte Subsets↗

PubMed1999

Diffuse large B cell lymphoma expressing the natural killer cell marker CD56.

The expression of the natural killer (NK) cell antigen, CD56, in hematological malignancies is rare. However, there are several reports that some hematological malignancies, such as T/NK cell lymphoma, multiple myeloma (MM) and acute myeloid leukemia (AML), express this molecule. In B cell non-Hodgkin's lymphomas (NHL), however, very limited number of cases have been reported to express CD56 molecule. Although one study has recently described that half of microvillous B cell lymphoma (MVL), an uncommon subset of large cell lymphoma, expressed CD56, there have been no reports about most common type of B-NHL, diffuse large B cell lymphoma (DLBL) other than a mention of weak CD56 expression in one of 83 DLBL. We herein presented the first case of diffuse large B cell lymphoma expressing CD56 clearly. The immunophenotype determined by immunostaining and flow cytometric analysis was CD10+, CD19+, CD20+, CD45RO-, CD3- and CD56+. On immunohistochemical study, neither bcl-2 nor TIA-1 was positive for tumor cell. Monoclonal immunoglobulin heavy chain (IgH) gene rearrangement was detected, and the sequence analysis of the variable region of IgH (VH) suggested that this tumor was derived from antigen selected post germinal center B cell. Conventional combination chemotherapy (CHOP) was administered, and the patient has still been in complete remission for 10 months.

Adolescent↗

PubMed1998

Biomarker assessment of the effects of coal strip-mine contamination on channel catfish.

A suite of biomarkers was used to evaluate acute (1-day) to semichronic (3-month) heavy metal-induced toxicity in channel catfish, lctalurus punctatus, caged at an abandoned strip mine and a noncontaminated reference site. Assays performed include indicators of metabolic, hematological, osmoregulatory, and genotoxic stress. Two cage designs were used to evaluate the importance of exposure routes: one excluding contact with the sediments and the other allowing contact with water and sediments. Significant DNA strand breakage was observed in catfish exposed to both exposure regimens, but evidence of DNA repair was observed only in water-exposed catfish. Transient increases in hemoglobin, delta-aminolevulinic acid dehydratase, and hematocrit levels were observed at 1 month's exposure for both exposure regimens, followed by a return to control levels for the duration of the study. Environmental conditions (i.e., weather-related changes in water quality) may have contributed to the variable plasma chloride and glucose levels observed in all catfish exposed to strip-mine wastes. The transient changes in biomarkers followed by a return to reference values represent an initial stress and an acclimation to normal levels.

Animals↗