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PubMed2004

Human in vivo radiation-induced biomarkers: gene expression changes in radiotherapy patients.

After initially identifying potential biomarkers of radiation exposure through microarray studies of ex vivo irradiated human peripheral white blood cells, we have now measured the in vivo responses of several of these biomarker genes in patients undergoing total body irradiation. Microarray analysis has identified additional in vivo radiation-responsive genes, although the general in vivo patterns of stress-gene induction appear similar to those obtained from ex vivo white blood cell experiments. Additional studies may reveal correlations between responses and either diagnosis or prognosis, and such in vivo validation marks an important step in the development of potentially informative radiation exposure biomarkers.

Adult↗
PubMed1999

Urinary follicle stimulating hormone can be used as a biomarker to assess male reproductive function.

AIM: To develop an algorithm for use in population-based studies to assess testicular function by measurements of total urinary follicle stimulating hormone (FSH). METHODS: Total concentrations of urinary FSH were measured in a group of 44 men at the University of California, Davis (UCD) and were compared to FSH measurements in serum. On the basis of these and other published data, a urinary FSH value of >2 ng/mg creatinine (Cr) was selected as the cutoff point to identify men with elevated serum FSH ( > 12 IU/L) or low sperm counts ( < 20 million/mL). RESULTS: The sensitivity and specificity of this algorithm for detecting elevated serum FSH in a group of 58 agricultural workers in the People' s Republic of China were 100% and 50%, respectively. The sensitivity and specificity of this algorithm for detecting low sperm counts in a population of 105 infertility patients at UCD were 58 % and 76 %, respectively. CONCLUSION: This test may have particular value in identifying populations with no evidence of testicular toxicity, and in which labor-intensive semen studies may not be feasible.

Biomarkers↗
PubMed2003

Tobacco carcinogens, their biomarkers and tobacco-induced cancer.

The devastating link between tobacco products and human cancers results from a powerful alliance of two factors - nicotine and carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?

Humans↗
PubMed1996

Overview of diisocyanate occupational asthma.

Surveillance programs established around the world have determined that diisocyanate chemicals are the most common cause of occupational asthma. In the United States approximately 100,000 workers are exposed to these chemical compounds in the workplace each year and 5-10% of these workers will develop occupational asthma. There are no known reliable risk factors or biomarkers which can be used to predict which exposed worker will develop diisocyanate-occupational asthma. Diisocyanate-occupational asthma workers manifest characteristic physiologic responses after specific bronchoprovocation which correlate with pathologic changes in their airways. However, the mechanism(s) for diisocyanate-occupational asthma remains unclear. Specific IgE antibody production to diisocyanates is found in only 10-30% of these workers. Bronchial biopsies and bronchoalveolar lavage have confirmed the presence of T-lymphocytes and eosinophils in the airways of these workers suggesting that T-cell mediated immune responses are more likely to play a central role in this disease. It is essential to diagnose diisocyanate-occupational asthma as early as possible in order to prevent or reduce the significant asthma morbidity associated with continuous long term exposure to these chemicals. Treatment of choice is removal of the worker from further exposure. Prospective studies evaluating larger populations of diisocyanate-exposed workers is essential for a better understanding of the pathogenesis and natural course of diisocyanate-occupational asthma.

Asthma↗
PubMed2006

Equation for calculating the concentration of solvent in air that discriminates between exposure and non-exposure based on biomarker concentrations in the urine of workers.

To develop a new method for evaluating the intensity of workers. exposures to toluene alone or toluene in mixed solvents, regression equations were calculated between the concentrations of toluene to which workers were exposed and the concentrations of hippuric acid or toluene in workers. urine samples taken at the end of their shifts. Thereafter, the discriminant exposure concentration of the solvents in air, which was the concentration considered to discriminate exposure from non-exposure within a fixed level of error using fiducial ranges of individual specimens (DEC-I) or using confidence ranges of regression equation (DEC-R), was measured by a scale. The devised equations were applied to calculate DEC-I or DEC-R accurately using the formulas expressing a regression line and its fiducial ranges or confidence ranges. The equations can calculate not only more precise values of DEC-I or DEC-R than can be measured by a scale, but can also calculate values corresponding to any level of error. Moreover, DEC-I and DEC-R can be defined by the equations. The concentration capable of discriminating TLV (threshold limit value) exposure from non-TLV exposure was estimated using fiducial ranges (DTL-I) and then using confidence ranges of the regression equation (DTL-R).

Air↗
PubMed2001

Biomarkers in Barrett esophagus.

Barrett esophagus is a premalignant condition that may progress to adenocarcinoma. The risk of developing cancer has been estimated to be approximately 1 in 250 patient-years of observation; however, there appear to be subsets of patients at much higher risk. Risk stratification has previously been determined by histological identification of dysplasia. Several new biomarkers are being tested to help clinicians better determine the risk of cancer development. Although none of these biomarkers has been proven in a prospective study to predict the onset of cancer, they have been correlated with cancer development. Most of these are factors that have been associated with cancer development in other organs. These include assessment of cell proliferation, expression of cyclooxygenase 2, growth factors and oncogenes, secretory factors, cell cycle proteins, adhesion molecules, and aneuploidy and other genetic abnormalities. In addition to their role as potential cancer biomarkers, these factors have increasingly been reported as surrogate markers to monitor the effectiveness of conservative treatments for Barrett esophagus. In this article, biological markers are reviewed for their relevance in Barrett esophagus. Although most biological markers need to be evaluated further and, for most, prospective follow-up studies are lacking, at present abnormal ploidy status, P16 and P53 gene abnormalities, or allelic losses are the most extensively documented.

Barrett Esophagus↗
PubMedDate not supplied

Proteomic strategies and their application in cancer research.

The understanding of carcinogenesis and tumor progression on a molecular basis needs a detailed study of proteins as effector molecules and as critical components of the multiple interconnected signaling pathways that drive the neoplastic phenotype. Thus, the proteomic approach represents a powerful tool for the challenge of the post-genomic era. The term "cancer proteome" refers to the collection of proteins expressed by a given cancer cell and should be considered as a highly dynamic entity within the cell, which affects a variety of cellular activities. The emerging proteomic analysis platforms including 2D-PAGE, mass spectrometry technologies, and protein microarrays represent powerful tools to study and understand cancer. These systems aim to not only identify, catalogue, and characterize cancer proteins, but also to unveil how they interact to affect overall tumor progression. Moreover, recent studies on various cancers have reported promising results concerning the detection of novel molecular biomarkers useful in the early diagnosis of cancer and in drug discovery. Thus, a new subdiscipline named clinical proteomics, concomitant with new molecular technologies that are developed, demonstrates promise to discover new cancer biomarkers. The early diagnosis of cancer, even in a premalignant state, is crucial for the successful treatment of this disease. For these reasons, it is clear that the identification of biomarkers for the early diagnosis of cancer should represent one of the main goals of this emerging field of study.

Animals↗
PubMed2001

Conjugation of biomolecules with luminophore-doped silica nanoparticles for photostable biomarkers.

A new molecular conjugation method has been developed to label biomolecules with optically stable metalorganic luminophores, such as tris(2,2'-bipyridyl)dichlororuthenium(II) hexahydrate (Rubpy), which are otherwise not possible for direct linking with the biomolecules. Unique biochemical properties of the biomolecule can, thus, be associated with photostable luminophores. This opens a general way to conjugate desired biomolecules using a sensitive signal transduction method. It also promotes the application of excellent luminescent materials, especially those based on photostable metalorganic luminophores, in biochemical analysis and biomolecular interaction studies. The conjugation method is based on uniform luminophore-doped silica (LDS) nanoparticles (63 +/- 4 nm). These nanoparticles have been prepared using a water-in-oil (W/O) microemulsion method. The controlled hydrolysis of tetraethyl orthosilicate (TEOS) in W/O microemulsion leads to the formation of monodisperse LDS nanoparticles. The luminophores are doped inside the nanoparticles, and the particle's silica surfaces can be used to covalently bind with biomolecules. The luminophores are well-protected from the environmental oxygen when they are doped inside the silica network. As an example, we used an antibody for leukemia cell recognition. The antibody was first immobilized onto the luminophore-doped nanoparticle through silica chemistry and then was used for leukemia cell identification by an optical microscopy imaging technique. The leukemia cells were identified easily, clearly, and with high efficiency using these antibody-coated nanoparticles. The advantages of using small, uniform luminophore-doped nanoparticles are discussed.

Antibodies, Neoplasm↗
PubMed2026

Crucial role of telomere maintenance-related genes in survival prediction and subtype identification in colorectal cancer.

BACKGROUND: Telomere maintenance-related genes (TMRGs) are implicated in Colorectal cancer (CRC) development, but their prognostic value and clinical relevance remain insufficiently explored. This study aims to develop a TMRG-based prognostic model and elucidate its clinical utility in CRC management. METHODS: The Cancer Genome Atlas database was utilized to download RNA-seq data from 638 CRC and 51 control samples. Differential expressed genes were screened and intersected with 2086 TMRGs, resulting in the identification of 976 TMRGs. Through univariate and multivariate Cox regression analysis, a prognostic model comprising three telomere maintenance-related biomarkers (PDE1B, TFAP2B, and HSPA1A) was developed and validated using an external dataset. By integrating the model risk score with clinical features, a nomogram was constructed to predict the survival outcomes of CRC patients. Additionally, an in-depth investigation of the immuno-infiltration, functional variation and drug sensitivity analysis were performed in two risk subgroups defined by the prognostic model. Finally, the functional significance of PDE1B in CRC cell lines was investigated through MTT assays, cell colony formation assays, transwell assays and flow cytometry. RESULTS: A total of 976 DE-TMRGs were enriched in telomere/DNA replication pathways. A three-gene signature (PDE1B, TFAP2B, and HSPA1A) stratified patients into high- and low-risk groups with divergent survival (AUC >0.60, validated externally). High-risk patients had advanced N/M stages, elevated M0/M2 macrophages, reduced CD4+ memory T cells, and upregulated immune checkpoints. Nomogram integrating risk score, age, and N/M stage accurately predicted 1-/3-/5-year survival. Low-risk patients showed greater 5-fluorouracil sensitivity. PDE1B expression was significantly reduced in CRC tissues and correlated with advanced stages. Functional assays confirmed PDE1B overexpression suppressed proliferation, migration, invasion, and induced apoptosis in CRC cells. CONCLUSION: This study identifies a moderately predictive telomere maintenance-related gene signature as an independent prognostic predictor in CRC. The risk stratification model effectively discriminates patients with distinct survival patterns, tumor microenvironments, and therapeutic responses, while the integrated nomogram offers additional reference information for survival analysis, albeit with only moderate predictive accuracy. These findings indicate telomere maintenance-related gene signature could serve as a preliminary auxiliary risk stratification tool for postoperative CRC patients, PDE1B may also serve as a potential epithelial tumor-suppressor target for future preclinical studies.

PDE1B↗
PubMed2000

Molecular epidemiology.

The use of biomarkers in epidemiology is not new, but recent developments in molecular biology and genetics have increased the opportunities for their use. However, epidemiological studies based on biomarkers, which belong to the discipline defined as 'molecular epidemiology' are subject to the same problems of design and analysis as 'traditional' epidemiological studies. If biomarkers offer new opportunities to overcome some of the limitations of epidemiology, their added value over traditional approaches should be systematically assessed. Biomarkers should be validated though transitional studies; consideration to sources of bias and confounding in molecular epidemiology studies should be no less stringent than in traditional studies.

Bias↗
PubMed2005

Identification of mammaglobin as a novel serum marker for breast cancer.

PURPOSE: Early detection of breast cancer has implications for the management and treatment of patients with this disease. Currently, there exist no highly sensitive and specific serologic biomarkers for detection of breast cancer. Mammaglobin is predicted to be a secreted protein, and expression of this gene seems to be highly specific in breast cancer. The present studies were undertaken to develop the mammaglobin protein as a serum biomarker for detection of breast cancer. EXPERIMENTAL DESIGN: We characterized the mammaglobin protein as a secreted, 14- to 21-kDa species, which is likely post-translationally processed based on its predicted 7-kDa size. Immunostaining for mammaglobin was conducted. An ELISA was developed for the detection of the mammaglobin protein in serum, and levels were compared between women with and without breast cancer. A receiver operating characteristic curve was used to show sensitivity and specificity for cut points on the continuous mammaglobin scale. RESULTS: The protein was detectable by immunostaining in 72% of breast tumors and not in other tumor types. The ELISA was highly sensitive and specific for detection of mammaglobin protein in tissue culture fluids of breast cancer cells and sera of breast cancer patients. The ELISA differentiated healthy women from those with breast cancer with accurate, repeatable results across time and under varying storage conditions. CONCLUSION: Our results indicate that mammaglobin, as measured by the ELISA, holds significant promise for breast cancer screening with the realistic potential to impact management of this disease.

Adult↗
PubMed2001

Sexual characteristics are altered by 4-tert-octylphenol and 17beta-estradiol in the adult male guppy (Poecilia reticulata).

Endocrine-disrupting chemicals (EDCs) are believed to interfere with animal reproduction, but only few biomarkers above the cellular level have been developed to assess the adverse effects of these chemicals. Using the guppy (Poecilia reticulata) as a model organism, studies have been undertaken with the object of comparing biomarker responses to EDCs at increasing levels of biological complexity. Short-term exposure to the xenoestrogen 4-tert-octylphenol and the natural estrogen 17beta-estradiol (E2) changed important sexual characteristics in the adult male guppy. Both compounds increased the number of sperm cells in the ejaculates, reduced the area and color intensity of the sexually attractive orange spots, and inhibited testis growth. In the case of E2, the effects on sperm count and coloration were still evident after 3 months of recovery in clean water. Preliminary results on male reproductive capability demonstrated that treated males produced fewer offspring than untreated fish, indicating an impairment of reproduction itself.

Animals↗
PubMed2006

Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies.

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged.

Antineoplastic Agents↗
PubMed2000

Mutagen sensitivity as a biomarker for second primary tumors after head and neck squamous cell carcinoma.

The occurrence of second primary tumors after curative treatment of early stage head and neck squamous cell carcinoma negatively influences the overall survival. Our aim was to prospectively evaluate whether mutagen sensitivity (mean number of chromatid breaks per cell in cultured lymphocytes exposed to bleomycin) could be used as a biomarker to predict which patients will develop second malignancies in the respiratory or upper digestive tract. Patients treated for head and neck squamous cell carcinoma (n = 218) were followed for approximately 6 years. Nineteen patients developed a second primary tumor, and each of these patients was matched on age, gender, cumulative smoking, tumor site, and tumor stage to two patients who did not develop any second malignancy. No difference between the groups was found with respect to mutagen sensitivity. Smoking at the time of the index tumor had a significant influence on the occurrence of second primary tumors (log-rank, P = 0.019). There was a significantly (P = 0.005) higher mean breaks-per-cell value in those patients who had developed their second primary tumor > or = 3 years after the first tumor (0.97 +/- 0.24; n = 10) compared with early second primary tumor patients (0.69 +/- 0.09; n = 9). Conditional on a more than 3-year second primary tumor-free survival (n = 38), there is a significantly (log-rank, P = 0.036) higher probability of a second primary tumor for mutagen-sensitive patients [relative risk, 7.8 (95% confidence interval, 0.99-61.74; P = 0.05)]. Mutagen sensitivity is a potential biomarker for the occurrence of 'late' second malignancies (> 3 years between tumors), and additional studies on the inclusion of this biomarker in chemoprevention trials is commendable because it would greatly improve their efficiency.

Aged↗
PubMed2006

A novel scale including strabismus and 'cuspidal ear' for distinguishing schizophrenia patients from controls using minor physical anomalies.

The present study explored minor physical anomaly items relevant to schizophrenia in order to establish a scale that can distinguish schizophrenia from controls using newly identified items along with items from the refined Waldrop scale. Seven items were significantly more frequent among schizophrenia patients (N=218) than controls (N=226). Among these seven items, two novel features, strabismus and 'cuspidal ear' showed markedly different prevalence rates between schizophrenia and control groups. A six-item scale, including the newly identified strabismus and cuspidal ear, was selected for most accurately discriminating patients with schizophrenia from controls. This scale correctly classified 59.6% of patients and 78.9% of control subjects. This new scale is procedurally more exacting and quantitative, and more relevant to schizophrenia than the original Waldrop scale. The validity of this scale should be sound since it was tested on a larger number of cohorts than used in previous research. Our scale can be used as a biomarker for predicting risk for future development of schizophrenia. The scale may also facilitate the identification of schizophrenia susceptibility genetic/environmental factors by stratifying etiologically heterogeneous patients according to physical abnormalities.

Abnormalities, Multiple↗
PubMed2006

Multiple sclerosis cerebrospinal fluid biomarkers.

Cerebrospinal fluid (CSF) is the body fluid closest to the pathology of multiple sclerosis (MS). For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP) and neurofilaments (NF) have advantages over intermittent inflammatory markers.

Biomarkers↗
PubMed2006

A serum glycomics approach to breast cancer biomarkers.

Because the glycosylation of proteins is known to change in tumor cells during the development of breast cancer, a glycomics approach is used here to find relevant biomarkers of breast cancer. These glycosylation changes are known to correlate with increasing tumor burden and poor prognosis. Current antibody-based immunochemical tests for cancer biomarkers of ovarian (CA125), breast (CA27.29 or CA15-3), pancreatic, gastric, colonic, and carcinoma (CA19-9) target highly glycosylated mucin proteins. However, these tests lack the specificity and sensitivity for use in early detection. This glycomics approach to find glycan biomarkers of breast cancer involves chemically cleaving oligosaccharides (glycans) from glycosylated proteins that are shed or secreted by breast cancer tumor cell lines. The resulting free glycan species are analyzed by MALDI-FT-ICR MS. Further structural analysis of the glycans can be performed in FTMS through the use of tandem mass spectrometry with infrared multiphoton dissociation. Glycan profiles were generated for each cell line and compared. These methods were then used to analyze sera obtained from a mouse model of breast cancer and a small number of serum samples obtained from human patients diagnosed with breast cancer or patients with no known history of breast cancer. In addition to the glycosylation changes detected in mice as mouse mammary tumors developed, glycosylation profiles were found to be sufficiently different to distinguish patients with cancer from those without. Although the small number of patient samples analyzed so far is inadequate to make any legitimate claims at this time, these promising but very preliminary results suggest that glycan profiles may contain distinct glycan biomarkers that may correspond to glycan "signatures of cancer."

Adult↗
PubMedDate not supplied

Development of hepatic CYP1A and blood vitellogenin in eel (Anguilla anguilla) for use as biomarkers in the Thames Estuary, UK.

The potential of eel (Anguilla anguilla) as a monitoring species for the Thames Estuary, UK, was examined. Hepatic cytochrome P4501A [7-ethoxyresorufin O-deethylase (EROD) activity] and blood vitellogenin (Western analysis) were investigated as biomarkers of exposure to, respectively, organic contaminants and to contaminants showing estrogenic activity. Hepatic microsomal EROD activities in A. anguilla from seven sites in the Thames Estuary in May 1998 varied three-fold (111 +/- 24 to 355 +/- 42 pmol min-1 mg protein-1) (mean +/- S.E.M.) and showed correlation with salinity; however, the latter relationship was not maintained at other times of the year. The range of EROD activities was two- to eight-fold higher than the 37 +/- 8 pmol min-1 mg-1 for A. anguilla from the relatively clean Tamar Estuary. beta-Naphthoflavone treatment (5 mg kg-1 wet wt.; 2 days) of Thames A. anguilla produced a two-fold increase in hepatic microsomal EROD activity. Comparing the Thames EROD data with those for A. anguilla from well-characterised contaminated sites in the Netherlands (Van der Oost, R., Goksøyr, A., Celander, M., Heida, H., & Vermeulen, N. P. E. 1996. Aquatic Toxicology, 36, 189-222), the Thames is suggested to be moderately impacted by polycyclic aromatic hydrocarbons and related contaminants. 17-beta-Estradiol treatment produced the appearance of a plasma protein of 211 Kd app. mol. wt. (recognised by antibodies to vitellogenin of Morone saxatilis), but putative vitellogenin could not be detected in A. anguilla from selected sites in the Thames Estuary.

Anguilla↗