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At least 1,045 records · Page 58Linked to original sources
PubMed2002

Prevention of mouse lung tumors by budesonide and its modulation of biomarkers.

Chemopreventive drugs have the potential to decrease the morbidity and mortality of lung cancer. The development of these drugs could be expedited by the application of surrogate end-point biomarkers that demonstrate chemopreventive efficacy. In this study, the ability of budesonide to prevent lung tumors in mice was characterized further and its effects on biomarkers were determined. Lung tumors were induced in female strain A mice by vinyl carbamate (16 mg/kg) administered once weekly for 2 consecutive weeks. Four weeks later the mice started to receive 0.6, 1.2 or 2.4 mg/kg budesonide continually in the diet until killed at week 20. Budesonide caused a dose-dependent decrease in the multiplicity of lung tumors of 25, 58 and 82%, respectively. Budesonide (2.4 mg/kg diet) administered starting at weeks 4, 10 or 16, decreased tumor multiplicity by 82, 66 and 30% at week 20. Administering 2.4 mg/kg budesonide at weeks 4-20 or 20-35 and killing the mice at week 35 did not significantly decrease the yield of tumors, although both treatment regimens did decrease the size of the tumors and the progression of adenomas to carcinomas. Thus, budesonide delayed the appearance of lung tumors and decreased their growth and progression to carcinomas. To determine the effect of limited exposure to budesonide on biomarkers, it was administered for only 7 days prior to death at week 35. Budesonide decreased the proliferating cell nuclear antigen labeling in lung adenomas, carcinomas, parenchyma and bronchial airways by 87.6, 59.0, 41.1 and 25.4%, respectively. Budesonide treatment also increased the protein level of the p21 and p27 genes and increased the mRNA level of p21. Thus, short-term treatment with budesonide modulated biological and molecular end-points in lung tumors that might be developed further as biomarkers for its clinical chemopreventive efficacy in the lung.

Adenocarcinoma↗
PubMed2000

Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin.

Distant metastases are the major cause of morbidity and mortality in women with breast cancer. The ability to predict the metastatic proclivity is essential in choosing the optimal treatment. Tumor size and grade, which are frequently used markers in node-negative breast cancer patients, are inadequate markers for prognosis and individualized treatment design. The steps in metastatic progression include angiogenesis, invasion, and changes in adhesion characteristics. We developed a strategy for choosing biomarkers representing these steps in malignant progression to identify patients with occult metastases who will need chemotherapy and spare those women whose tumors have not developed the capacity to spread. To evaluate the added significance of E-cadherin to that of nm23-H1 and angiogenesis in determining metastatic proclivity, we used archival material from 168 node-negative breast cancer patients who were treated with mastectomy without any adjuvant chemotherapy or hormone therapy. Immunohistochemistry was used to detect E-cadherin and nm23-H1 expression, whereas angiogenesis was determined by microvessel count (MVC) after immunohistochemical staining. The median follow-up is 14 years. We found that E-cadherin is better in identifying the poor prognosis patients. The 14-year disease-free survival (DFS) is 84%, 80%, and 56% in patients with high, intermediate, and low E-cadherin. The worst prognosis group using nm23-H1 and MVC as biomarkers has a 14-year DFS of 62%. In this group, if E-cadherin is low, the 14-year DFS is further decreased to 44%. Nm23-H1 and MVC are better in identifying the good prognosis patients. The long-term DFS is >90% if MVC is low or if nm23-H1 is high. Multivariate analysis shows that E-cadherin, nm23-H1, and MVC are more significant prognostic biomarkers than tumor size or grade. Loss of E-cadherin appears to be a latter step in the metastatic progression compared to angiogenesis and the loss of nm23-H1 expression.

Adult↗
PubMed2005

Identifying new PCR targets for pathogenic bacteria using top-down LC/MS protein discovery.

We have investigated the use of a top-down liquid chromatography/mass spectrometric (LC/MS) approach for the identification of specific protein biomarkers useful for differentiation of closely related strains of bacteria. The sequence information derived from the protein biomarker was then used to develop specific polymerase chain reaction primers useful for rapid identification of the strains. Shiga-toxigenic Escherichia coli (STEC) strains were used for this evaluation. The expressed protein profiles of two closely related serotype 0157:H7 strains, the predominant strain implicated in illness worldwide, and the nonpathogenic E. coli K-12 strain were compared with each other in an attempt to identify new protein markers that could be used to distinguish the 0157:H7 strains from each other and from the E. coli K-12 strain. Sequencing of a single protein unique to one of the 0157:H7 strains identified it as a cytolethal distending toxin, a potential virulence marker. The protein sequence information enabled the derivation of genetic sequence information for this toxin, thus allowing the development of specific polymerase chain reaction primers for its detection. In addition, the top-down LC/MS technique was able to identify other unique biomarkers and differentiate nearly identical 0157:H7 strains, which exhibited identical phenotypic, serologic, and genetic traits. The results of these studies demonstrate that this approach can be expanded to other serotypes of interest and provide a rational approach to identifying new molecular targets for detection.

Bacterial Proteins↗
PubMed2004

Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25 344 genes.

Little is known about the genetic mechanisms of anaplastic thyroid cancer (ATC). This is the most virulent of all human malignancies, and it is believed to result from transformation of differentiated thyroid cancers. To identify a set of genes involved in the development of ATC, we investigated expression profiles of 11 cell lines derived from ATC using a cDNA microarray representing 25 344 genes. Semi-quantitative RT-PCR experiments carried out for some genes that had shown altered expression on the microarray verified frequent over-expression of destrin, HSPA8, stathmin, LDH-A, ATP5A1, PSMB6, B23, HDP-1 and LDH-B, and frequent under-expression of thyroglobulin, PBP and c-FES/FPS genes among the cell lines and also among ten primary ATCs. In addition to mRNA expression studies, up-regulation of GDI2, destrin and stathmin were confirmed with immunohistochemical analysis. The extensive list of genes identified provides valuable information towards understanding the development of ATC, and provides a source of possible biomarkers for diagnosis and/or molecular targets for the development of novel drugs to treat ATC.

Biomarkers, Tumor↗
PubMed2005

Environmental agent susceptibility assessment using existing and novel biomarkers as rapid noninvasive testing methods.

This study is part of a project aimed at developing and validating novel noninvasive methods for the detection of biomarkers of endocrine disrupters (EDs) directly in the mucus of aquatic species, to identify novel functional biomarker(s) for EDs, and to verify their applicability for field studies. The multidisciplinary approach chosen aims at the development of an integrated testing strategy utilizing in vitro protocols to identify water and sediment fractions with potential endocrine-disrupting activity; the identification, characterization, and measurement of new biomarker(s) for EDs; the development and validation of a dipstick-based test method; and the development of (computer-assisted) predictive models. Some results of the first year of the project are presented here.

Animals↗
PubMed2025

In vitro protocol demonstrating five functional steps of trained immunity in mice: Implications on biomarker discovery and translational research.

We developed an in vitro methodology to study trained immunity using murine bone-marrow-derived macrophages stimulated with β-glucan and lipopolysaccharide (LPS). Longitudinal analysis of interleukin (IL)-6 and tumor necrosis factor (TNF) production demonstrates that trained macrophages secrete higher cytokine levels following primary stimulation with β-glucan compared to unstimulated macrophages (step 1). After a resting period, trained macrophages return to basal levels of cytokine production (step 2) but rapidly produce enhanced levels of IL-6 and TNF after secondary stimulation with LPS, compared to macrophages individually stimulated with either β-glucan (step 3) or LPS (step 4) alone. The combined cytokine production of macrophages after single stimulation with β-glucan (stimulus 1) and LPS (stimulus 2) is significantly lower than the cytokine levels produced by trained macrophages sequentially stimulated with both β-glucan and LPS (stimulus 1 + 2) (step 5). These results experimentally reproduce the distinctive functional stages that macrophages undergo during the training process.

Animals↗
PubMed2004

Potential pathologic markers for prostate chemoprevention studies.

The field of exploring potential biomarkers for prostate cancer prevention continues to expand rapidly. In addition to a limited scope of histologic alterations, mainly PIN, a growing array of promising technologies (eg, computer-assisted analysis), and molecules involved in cell-cycle regulations, angiogenesis, and structural and numerical chromosomal alterations are potential candidates for surrogate endpoint biomarkers for prevention trials. Before any these potential candidates are adopted, however, the technical, interpretational, and validation requirements must be satisfied. More important, it is crucial to demonstrate that modulation of the frequency of the biomarker decreases the rate of cancer development.

Adenocarcinoma↗
PubMed1997

Chronic toxicity of environmental contaminants: sentinels and biomarkers.

Due to the use of a limited number of species and subchronic exposures, current ecological hazard assessment processes can underestimate the chronic toxicity of environmental contaminants resulting in adverse responses of sentinel species. Several incidences where sentinel species have responded to the effects of chronic exposure to ambient levels of environmental contaminants are discussed, including the development of neoplasia in fish, immunosuppression in marine mammals, pseudohermaphrodism in invertebrates, teratogenicity in amphibians, and aberrations in the sexual development of fish and reptiles. Biomarkers of chronic toxicity, including DNA mutations, alterations in specific protein and mRNA levels, and perturbations in metabolism, are presented. The incorporation of appropriate surrogate species and biomarkers of chronic toxicity into standard toxicity characterizations is proposed as a means of significantly refining the ecological hazard assessment process.

Amphibians↗
PubMed1996

Early detection research program at the NCI.

The Early Detection Branch, Division of Cancer Prevention and Control, National Cancer Institute, has created a program called The Early Detection Research Network (EDRN). EDRN's mission is to support translational research leading to early detection of cancer. The objectives are to (i) establish a network of institutions with the facilities, resources, personnel and interest to undertake biomarker research in early cancer detection; (ii) advance the understanding of the molecular basis of tumorigenesis in relation to screening, early detection and risk assessment; (iii) identify potential biomarkers that can be used as outcome measures or as intermediate end-points for cancer screening studies and (iv) respond to late-breaking developments in the field of biomarkers in a timely fashion. This program has the singular purpose of studying biologic, molecular and genetic markers relevant to the early detection of prostate, colorectal, lung, head and neck, bladder and breast cancers.

Colorectal Neoplasms↗
PubMed2005

Evaluating technologies for classification and prediction in medicine.

Modern technologies promise to provide new ways of diagnosing disease, detecting subclinical disease, predicting prognosis, selecting patient specific treatment, identifying subjects at risk for disease, and so forth. Advances in genomics, proteomics and imaging modalities in particular hold great potential for assisting with classification/prediction in medicine. Before a classifier can be adopted for routine use in health care, its classification accuracy must be determined. Standards for evaluating new clinical classifiers however, lag far behind the well established standards that exist for evaluating new clinical treatments. In this paper, we discuss a phased approach to developing a new classifier (or biomarker). It mirrors the internationally established phase 1-2-3 paradigm for therapeutic drugs. The defined phases lead to a logical sequence of studies for classifier development. We emphasize that evaluating classification accuracy is fundamentally different from simply establishing association with outcome. Therefore, study objectives and designs differ from the familiar methods of clinical trials. We discuss these briefly for each phase.Finally, we argue that classifier development requires some rethinking of traditional data analysis techniques. As an example we show that maximizing the likelihood function to fit a logistic regression model to multiple predictors, can yield a poor classifier. Instead we demonstrate that an approach that maximizes an alternative objective function characterizing classification accuracy performs better.

Diagnostic Techniques and Procedures↗
PubMed2006

Real-time quantitative PCR to detect changes in synovial gene expression in rheumatoid arthritis after corticosteroid treatment.

Synovial biomarkers are increasingly important in the development of novel therapeutic agents for the treatment of rheumatoid arthritis (RA). To identify biomarkers correlating with changes in clinical disease activity, real-time quantitative PCR (Q-PCR) was used to evaluate changes in synovial gene expression after treatment with corticosteroids. Patients with active RA received either oral prednisolone (n=10, 60 mg daily for the first week and 40 mg daily for the second week) or placebo (n=11) for 14 days. Real-time Q-PCR was used to quantify gene expression of tumour necrosis factor (TNF)alpha, IL1beta, IL8 and matrix metalloproteinase (MMP) 1 in synovial tissue samples obtained through an arthroscopic procedure before and after treatment. mRNA levels were reported as relative expression units compared with a cell-based standard. Statistical analysis was performed using an analysis of covariance model. Prednisolone markedly decreased IL8 and MMP1 expression compared with placebo, and the CIs excluded the likelihood of no effect. A trend towards reduction was seen in IL1beta and TNFalpha mRNA expression in the prednisolone group, although CIs included the value for no effect. These data suggest that Q-PCR can be used to measure synovial mRNA expression of mediators implicated in the pathogenesis of RA in small proof-of-concept trials.

Adult↗
PubMed2006

Genomics of hepatitis B and C infections: diagnostic and therapeutic applications of microarray profiling.

Microarray profiling offers many potential advances in diagnostic and therapeutic intervention in human disease because of its unparalleled ability to conduct high-throughput analysis of gene expression. However, limitations of this technique relate in part to issues regarding the various methodologies and experimental designs as well as difficulties in the interpretation of results. Despite this, microarray profiling has led to a better understanding of the molecular pathogenesis of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Key events in clearance and the development of chronicity of HCV have been identified that may prove to have a role in the development of future treatments. In addition, pharmacogenomic studies of interferon-based treatment for chronic HCV and HBV have provided mechanistic insights into the therapeutic action of interferons. These advances have implications with respect to the development of improved therapeutic agents. New biomarkers for cancer screening and gene profiles with prognostic value for survival have also been developed for hepatocellular carcinoma, which frequently complicates chronic viral hepatitis. Thus, microarray profiling offers enormous potential for improvements in antiviral therapy and our understanding of blood-borne viral hepatitis.

Animals↗
PubMed2004

A dietary pattern derived to explain biomarker variation is strongly associated with the risk of coronary artery disease.

BACKGROUND: In previous studies, dietary patterns were derived in different populations without regard to a specific outcome. OBJECTIVE: The objective was to apply a new statistical method to construct a specific dietary pattern that is strongly associated with the risk of coronary artery disease (CAD). DESIGN: We applied reduced rank regression to a sample of 200 cases and 255 controls from the Coronary Risk Factors for Atherosclerosis in Women (CORA) Study. The CAD-specific dietary pattern was constructed by choosing intake data for 49 food groups as predictors and 5 established biomarkers for CAD as responses. RESULTS: A high score for the constructed dietary pattern was characterized by high intakes of meat, margarine, poultry, and sauce and low intakes of vegetarian dishes, wine, vegetables, and whole-grain cereals. After adjustment for known CAD risk factors, the relative risks from the lowest to the highest quintiles of the pattern score were 1.0, 1.1, 3.6, 6.2, and 12.3 (95% CI: 4.9, 30.9; P for trend < 0.0001). There was an approximate 4.5-fold difference in C-reactive protein and a 2-fold difference in C-peptide between the highest and lowest score quintiles of the study population. HDL-cholesterol concentrations ranged from 70 mg/dL in the lowest quintile to 49 mg/dL in the highest quintile of dietary pattern score. CONCLUSION: The new statistical method, reduced rank regression, may be a useful tool for identifying dietary patterns that simultaneously affect the concentrations of known CAD biomarkers and the risk of developing CAD.

Adult↗
PubMed2006

Earthworm biomarkers in ecological risk assessment.

Earthworms have had a notable contribution in terrestrial ecotoxicology. They have been broadly used to assess environmental impact from metal pollution, and they are typical test organisms (e.g., Eisenia) in standardized toxicity tests. Several reviews and international workshops have stressed the need for increasing the understanding and applicability of earthworm biomarkers in the ecological risk assessment (ERA) process. This review summarizes recent available information concerning the most investigated earthworm biomarkers. In earthworms, the use of biomarkers has been focused on assessing metal pollution, and available data on biomarker responses to organic contaminants are rather limited. The potential for applying earthworm biomarkers in the standardized toxicity tests is suggested in view of their significant contribution to the risk assessment of contaminated soils (e.g., estimation of bioavailable and bioactive fraction or sublethal effects). Field studies involving earthworm biomarkers are still scarce and are summarized according to their main practical approaches in retrospective ERA: biological surveys, laboratory tests of the soil, simulated field studies, and in situ exposure bioassays. Despite the great volume of laboratory studies on earthworm biomarkers, future lines of research are suggested besides the recommendations made by others: (1) the potential and limitations of the inclusion of biomarkers in the standardized toxicity tests should be examined under a well-defined weight-of-evidence framework; (2) it is necessary to develop operating guidelines to standardize earthworm biomarker assays, an important step to apply biomarkers in a regulatory context; (3) molecular and physiological biomarkers should be directly linked to behavioral changes with significant ecological implications, an important step in considering them as ecotoxicological biomarkers; and (4) biomarkers to organic pollutants of current concern (e.g., polycyclic aromatic hydrocarbons, anti-ChE and pyrethroid insecticides, polybrominated flame retardants, etc.) need to be developed and validated in the field. Also, an increase in the knowledge of earthworm biomarkers is undoubtedly useful in assessing the effectiveness of procedures for recovering/protecting the environment (e.g., phytoremediation or agrienvironment schemes) besides its potential use in the ERA framework.

Animals↗
PubMed1997

[A study on the relation between nitric oxide and abnormal development of embryos].

The authors investigated the effects of arsenic on mouse embryo and yolk-sac placenta (YSP) during a critical period of early morphogenesis by means of histochemical staining technique, scanning electron microscope (SEM) and so on. There were no obvious poinsoning signs of pregnant female mice. Experimental results showed there was a dose-response relationship between arsenic level and iNOS expression (P < 0.05). Histopathological changes under SEM and light microscope were noticed, including retardation of yolk-sac growth and vessels differentiation, atrophic microvilli and disintegrative or cavernous damages of both endodermal epithelium and mesodermal mesothelium in particular. With the increase of arsenic concentration, teratogenic rate and mortality increased. The maximum incidences were 56.8% and 24.7% respectively. Dysmorphogenetic embryos were characterized by open neural tube, hydropericardium and abnormal flexions. We firstly discovered excessive NO was involved in embryonic development and teratogenesis. iNOS can serve as an effective biomarker in teratological research.

Animals↗
PubMed2005

Can a marker be a surrogate for development of cancer, and would we know it if it exists?

Carcinogenesis proceeds through a very long preclinical period. Our collective hope is that multiple opportunities exist for chemoprevention to arrest or reverse progression towards malignancy. In the hope of faster progress with fewer subjects and lower total cost, much effort is being expended on the search for reliable biomarkers to predict the likelihood of developing cancer and/or to signal the effectiveness of chemopreventive therapy. Considerable attention is paid to identifying those markers that can act as surrogate markers for cancer development, since favorable modulation of the surrogate end-point biomarker (SEBM) may demonstrate effectiveness of a putative preventive treatment. However, the complexity of the biology challenges our ability to measure the effectiveness of attempts to arrest or reverse carcinogenesis, other than through costly and time-consuming prospective trials with disease state as the endpoint. Despite much work, to date no prehistologic biological or molecular intermediate marker has been validated for sporadic cancers. Several factors accounting for the difficulties encountered in SEBM development are reviewed. Discussion is focused on the common thread of the complexity of the underlying biological changes in carcinogenesis limiting the effectiveness of any single biomarker. Additionally, the incidence of sporadic cancers is also low, further limiting the positive predictive value of any putative prognostic marker. Recent successes in development of chemopreventive agents show the concept is valid and worth pursuing, but the current strategies to develop biochemical and genetic markers to identify surrogate biomarkers is flawed, and need to be reassessed in light of the difficulties faced over the last 20 years.

Anticarcinogenic Agents↗
PubMed2006

Development and validation of a multiplex add-on assay for sepsis biomarkers using xMAP technology.

BACKGROUND: Sepsis is a common and often fatal disease. Because sepsis can be caused by many different organisms, biomarkers that can aid in diagnosing sepsis and monitoring treatment efficacy are highly warranted. New sepsis markers may provide additional information to complement the currently used markers. METHODS: We used a combination of in-house and commercially available multiplex immunoassays based on Luminex xMAP technology to assay biomarkers of potential interest in EDTA-plasma samples. RESULTS: A 3-plex assay for soluble urokinase plasminogen activator receptor (suPAR), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), and macrophage migration inhibiting factor (MIF) was developed and validated in-house. This 3-plex assay was added to a commercially available interleukin-1beta (IL-1beta), IL-6, IL-8, granulocyte/macrophage colony-stimulating factor, and tumor necrosis factor-alpha human cytokine panel. No cross-reactivity was observed when the assays were combined. Correlation between values obtained with the 8-plex, the 5-cytokine panel, the 3 in-house 1-plex assays, and a suPAR ELISA ranged from 0.86 to 0.99. Mean within- and between-run CVs were 8.0% and 11%, respectively. Recoveries of suPAR, sTREM-1, and MIF calibrators were 108%, 88%, and 51%, respectively. In plasma collected from 10 patients with bacterial sepsis confirmed by blood culture, the assay detected significantly increased concentrations of all 8 analytes compared with healthy controls. CONCLUSIONS: A commercially available xMAP panel can be expanded with markers of interest. The combined multiplex assay can measure the 8 analytes with high reproducibility. The xMAP technology is an appealing tool for assaying conventional cytokines in combination with new markers.

Biomarkers↗