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PubMed1997

Bone biomarkers as tools in osteoporosis management.

Biochemical tests that can index bone turnover rate in the patient are increasingly being used in the study and management of osteoporosis. Markers of bone formation and resorption are reviewed here, including their molecular basis, relative strengths and weaknesses in clinical performance, and future potential. A bone mass measurement (e.g., by dual-energy x-ray absorptiometry) and a biochemical index of bone turnover provide different but complementary information that can aid in predicting risk of future bone loss and osteoporotic fracture. A specific and responsive bone resorption marker can also be used to monitor and establish the short-term effectiveness of an antiresorptive therapy in the patient. Bone-specific alkaline phosphatase (an osteoblast enzyme) and osteocalcin (a bone matrix protein) levels in serum are the best markers of bone formation. Collagen degradation products in urine, particularly cross-linked telopeptides and pyridinolines, have the highest specificity to bone resorption activity. The telopeptide markers (NTx and CTx) appear to be the most specific and responsive markers of systemic osteoclast activity.

Alkaline Phosphatase↗
PubMed2006

Application of a suite of biomarkers in Posidonia oceanica (L.) delile to assess the ecotoxicological impact on the coastal environment.

The main aim of this study was to develop and validate a suite of sensitive responses (biomarkers) for monitoring conservation status and ecotoxicological impact in Posidonia oceanica meadows. Analytical methods were developed for NADPH cytochrome c reductase, ethoxycoumarin-o-deethylase (ECOD), guaiacol peroxidase (GPOX) and superoxide dismutase (SOD) assays. A preliminary proteomic approach using 2-D electrophoresis was also proposed as a biomarker. These techniques were initially tested on samples of posidonia exposed experimentally to various contaminants. Once validated, this approach was applied to posidonia in a field study. Samples of the seagrass were collected at four sites with potentially different environmental impact along the northern Tyrrhenian coast. The results showed that reductase activity was significantly induced in the various sampling areas with respect to the reference site. GPOX and SOD showed a similar trend; the highest activities were found in samples collected off a chlor-alkali plant and near a river estuary. Analysis of trace elements, polycyclic aromatic hydrocarbons (PAHs) and organochlorine compounds (OCs) in posidonia leaves showed differences between sites. A significant correlation was found between Hg concentrations and GPOX activity and between Cr, Al and As concentrations and reductase activity. The results validated these biomarkers in posidonia for the assessment of ecotoxicological impact on the coastal ecosystem.

Alismatales↗
PubMed2005

Prevention of bladder cancer: a review.

INTRODUCTION: Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention. MATERIALS AND METHODS: A literature review of peer-reviewed articles which address bladder cancer prevention was performed. RESULTS: Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects. CONCLUSIONS: While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Use of multiple biomarkers for a molecular diagnosis of prostate cancer.

The identification of biomarkers capable of providing a reliable molecular diagnostic test for prostate cancer (PCa) is highly desirable clinically. We describe here 4 biomarkers, UDP-N-Acetyl-alpha-D-galactosamine transferase (GalNAc-T3; not previously associated with PCa), PSMA, Hepsin and DD3/PCA3, which, in combination, distinguish prostate cancer from benign prostate hyperplasia (BPH). GalNAc-T3 was identified as overexpressed in PCa tissues by microarray analysis, confirmed by quantitative real-time PCR and shown immunohistochemically to be localised to prostate epithelial cells with higher expression in malignant cells. Real-time quantitative PCR analysis across 21 PCa and 34 BPH tissues showed 4.6-fold overexpression of GalNAc-T3 (p = 0.005). The noncoding mRNA (DD3/PCA3) was overexpressed 140-fold (p = 0.007) in the cancer samples compared to BPH tissues. Hepsin was overexpressed 21-fold (p = 0.049, whereas the overexpression for PSMA was 66-fold (p = 0.047). When the gene expression data for these 4 biomarkers was combined in a logistic regression model, a predictive index was obtained that distinguished 100% of the PCa samples from all of the BPH samples. Therefore, combining these genes in a real-time PCR assay represents a powerful new approach to diagnosing PCa by molecular profiling. (Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)

Adenocarcinoma↗
PubMed2005

Molecular epidemiology of physical activity and cancer.

As in other areas of epidemiology, researchers studying physical activity and cancer have begun to include laboratory analyses of biological specimens in their studies. The incorporation of these "biomarkers" into epidemiology has been termed molecular epidemiology and is an approach primarily developed to study chemical carcinogens. Thus far, there has been no discussion in the field on how the established molecular epidemiologic framework might be adapted for research into physical activity, what methodologic needs exist, what the goals of such an approach might be, and what limitations exist. This article relates the literature on molecular epidemiology to the needs of physical activity research and tries to set research priorities for the field as it moves in this new direction. Although this approach will be very useful for investigating the mechanisms through which physical activity exerts effects, there are several challenges for physical activity epidemiologists in adapting molecular epidemiologic approaches. Primarily, there are currently no available biomarkers that might be considered measures of exposure or biologically effective dose. In addition, most available biomarkers of intermediate effects have been tested in training studies at activity levels much higher than those seen in population-based epidemiologic studies. Thus, it is not clear whether these biomarkers are valid at lower activity levels. Furthermore, the nature of the relationship between activity and many available biomarkers depends very much on the context of the activity. Addressing these issues should be a priority if we are to develop a molecular epidemiologic paradigm for studying physical activity.

Biomarkers, Tumor↗
PubMed2003

Genotyping for polymorphic drug metabolizing enzymes from paraffin-embedded and immunohistochemically stained tumor samples.

OBJECTIVES: Paraffin-embedded tumor samples are valuable in the study of cancer for routine staging, tumor marker analysis, and in retrospective studies to test new prognostic and predictive biomarkers. Their utility in retrospective pharmacogenetic analysis of clinical trials has yet to be evaluated. We set out to establish genotyping methods for relevant genes from archival tumor samples and determine if fixation, processing or somatic changes in the tumor might affect our ability to identify germ-line polymorphisms. METHODS AND RESULTS: To establish the assays, paraffin blocks were made using pellets prepared from eight tumor cell lines. DNA was isolated from viable cells and from sections from these blocks, and genotyped for polymorphisms in CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5 and MDR1 using conventional PCR-RFLP assays. This demonstrated that fixation and processing did not alter the genotypes obtained (100% concordance). Next, sections were obtained from paraffin-embedded archival breast samples from 10 patients for whom gDNA isolated from peripheral blood was available for comparison. Concordance was complete with the same genotype being obtained for 100% of the samples tested. Attempts to extend these methods for the study of hematoxylin/eosin or immunohistochemically stained sections were not successful since the staining inhibited the PCR reactions. Only 25 of 50 samples were successfully amplified and of those only 14 produced accurate genotypes. CONCLUSIONS: Accurate genetic testing for polymorphisms in several genes of pharmacogenetic importance can be obtained from archival paraffin-embedded tumor samples. Thus, pharmacogenetic analysis can be applied to existing cancer therapy trials to test associations between these polymorphisms and treatment response.

Base Sequence↗
PubMed1998

Heterogeneity of guanylyl cyclase C expressed by human colorectal cancer cell lines in vitro.

In humans, guanylyl cyclase C (GCC) is expressed by mucosal cells lining the intestine, from the duodenum to the rectum, but not by extraintestinal tissues. Expression of GCC persists after mucosal cells undergo neoplastic transformation, and this protein has been identified in all primary and metastatic colorectal tumors examined to date, suggesting that GCC may be a highly specific biomarker for colorectal cancer. The utility of GCC as a diagnostic biomarker and therapeutic target is predicated, in part, on defining the variability of its expression in colorectal cancer cells. Similarly, the utility of this biomarker to define tumor burden in diagnosing, staging, and postoperative surveillance of patients is predicated on quantifying GCC expression in cancer cells in tissues and blood. The present studies examined the heterogeneity of GCC expression in eight human colorectal carcinoma cell lines in vitro representing the full spectrum of cytological differentiation. Quantification of GCC expression by ligand binding and stimulation of cGMP accumulation demonstrated that functional GCC expression is heterogeneous in different colorectal cancer cell lines. Qualitative reverse transcription (RT)-PCR demonstrated that all colorectal cancer cells examined expressed GCC mRNA. However, GCC expression varied 100-fold in different colorectal cancer cell lines, determined by a novel quantitative RT-PCR assay. Functional and molecular expressions of GCC were unrelated to the differentiation state of cancer cells. These studies suggest that GCC is heterogeneously expressed by colorectal cancer cells in vitro and suggest a role for quantitative RT-PCR analysis in the development of diagnostic tests using GCC as a biomarker for metastatic colorectal cancer.

Biomarkers, Tumor↗
PubMed2006

Chemical safety and health conditions among Hungarian hospital nurses.

In the present study genotoxicological and immunotoxicological follow-up investigations were made on 811 donors including 94 unexposed controls and 717 nurses with various working conditions from different hospitals (The Hungarian Nurse Study). The nurses were exposed to different chemicals: cytostatic drugs, anesthetic, and sterilizing gases, such as ethylene oxide (ETO) and formaldehyde. The measured biomarkers were: clinical laboratory routine tests, completed with genotoxicological (chromosome aberrations [CA], sister chromatid exchange [SCE]), and immune-toxicological monitoring (ratio of lymphocyte subpopulations, lymphocyte activation markers, and leukocyte oxidative burst). The highest rate of genotoxicologically affected donors (25.4%) was found in the group of cytostatic drug-exposed nurses. Comparing geno- and immunotoxicological effect markers, we found that among genotoxicologically affected donors the frequency of helper T cell (Th) lymphocytes, the ratio of activated T and B cells increased, whereas the oxidative burst of leukocytes decreased. In hospitals with lack of protective measures increased CA yields were observed compared to those with ISO 9001 quality control or equivalent measures. Anemia, serum glucose level, thyroid dysfunctions, benign, and malignant tumors were more frequent in the exposed groups than in controls. The hygienic standard of the working environment is the basic risk factor for the vulnerability of nurses. On the basis of these results, it is suggested, that the used cytogenetic and immunological biomarkers are appropriate to detect early susceptibility to diseases. The Hungarian Nurse Study proved that the use of safety measures could protect against occupational exposure at work sites handling cytostatic drugs, anesthetic, and sterilizing gases.

Flow Cytometry↗
PubMed2001

Biological markers and the treatment of Alzheimer's disease.

Disease-modifying approaches are being developed to treat Alzheimer's Disease (AD). These are expected to slow the clinical progression of AD or delay the onset of AD. Biological markers, measured in cerebrospinal fluid (CSF) or in the periphery, may be useful adjuncts to clinical assessment methods for AD, especilly when applied to these types of treatment approaches. Markers related to beta-amyloid and tau, components of AD lesions, can be quantified in CSF and show a stable and predictable pattern over time in AD. Biomarkers related to oxidation, such as isoprostanes, and to inflammation may provide information regarding mechanisms leading to neuronal damage. Biomarkers could be used during early clinical testing of drugs that affect key pathogenic steps inAD, such as amyloid production or clearance, to assess drug action and dose-responserelationships. In large-scale clinical trials or in clinical practice, biomarkers that are easy to access, such as blood or urine tests, could help in evaluating effects of treatment.

Alzheimer Disease↗
PubMed2000

[A clinical evaluation of three different quantitative fibrin D-dimer analyses in the diagnosis of deep venous thrombosis].

The trial included ninety-five consecutive outpatients admitted with symptoms and signs suggesting deep venous thrombosis. Blood samples were collected on admission and analysed when the trial was ended. The three different D-dimer methods were BC D-dimer, Tinaquant D-dimer (both quantitative latex agglutination methods) and VIDAS D-dimer, based on the ELISA principle. Ultrasound was used as the reference method, but the outcome evaluated at three month follow up was the gold standard. The sensitivities of the three different methods were 66% (95% confidence interval 55-75%), 93% (88-98%) and 98% (94-100%) respectively. The negative predictive values were respectively 71% (62-80%), 88% (81-95%) and 95% (91-99%). This trial confirms that VIDAS D-dimer has a high sensitivity and negative predictive value that makes it suitable for clinical use. The same conclusion can be drawn for the Tinaquant D-dimer. The trial also emphasizes the importance of testing new methods under routine clinical conditions.

Adult↗
PubMedDate not supplied

Oestrogenic markers and reduced population fertile egg production in a sand goby partial life-cycle test.

Understanding the ecological significance of oestrogenic biomarker responses, seen in field surveys of some UK estuarine fish, requires a suitable model to link biochemical and reproductive effects. The sand goby (Pomatoschistus minutus) is a common inshore fish that has been successfully bred in laboratory aquaria. Juvenile sand goby were continuously exposed to 17beta-oestradiol (E2) during gonadal maturation, and their subsequent reproductive success investigated. Exposure endpoints included hepatic vitellogenin (VTG) mRNA expression and maturation (male nuptial colouration, sperm duct gland- and gonado-somatic indices (SDGSI, GSI)). Reproductive endpoints included spawning behaviour, brood size, fertility and population-level fertile egg production. Measured E2 exposure concentrations were <5 (controls), 17, 71 and 530 ngl(-1). Male maturation decreased with increasing E2 concentration. VTG mRNA expression increased with E2 concentration, but not with duration of exposure. Reproductive endpoints showed progressive impairment with increasing E2 concentration. For most endpoints, the lowest observed effect concentration (LOEC) was 71 ngl(-1), and EC50s were in the range 87-165 ngl(-1). Pre-breeding male colouration, VTG expression and SDGSI were good predictors of subsequent population-level fertile egg production, but GSI was not. The sensitivity of oestrogenic markers in sand goby are comparable to those used in other species, and feral fish populations exhibiting such oestrogenic responses at molecular and organ levels are likely to have reduced fertile egg production.

Animals↗
PubMed2006

Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum.

BACKGROUND: We investigated the potential of proteomic fingerprinting with mass spectrometric serum profiling, coupled with pattern recognition methods, to identify biomarkers that could improve diagnosis of tuberculosis. METHODS: We obtained serum proteomic profiles from patients with active tuberculosis and controls by surface-enhanced laser desorption ionisation time of flight mass spectrometry. A supervised machine-learning approach based on the support vector machine (SVM) was used to obtain a classifier that distinguished between the groups in two independent test sets. We used k-fold cross validation and random sampling of the SVM classifier to assess the classifier further. Relevant mass peaks were selected by correlational analysis and assessed with SVM. We tested the diagnostic potential of candidate biomarkers, identified by peptide mass fingerprinting, by conventional immunoassays and SVM classifiers trained on these data. FINDINGS: Our SVM classifier discriminated the proteomic profile of patients with active tuberculosis from that of controls with overlapping clinical features. Diagnostic accuracy was 94% (sensitivity 93.5%, specificity 94.9%) for patients with tuberculosis and was unaffected by HIV status. A classifier trained on the 20 most informative peaks achieved diagnostic accuracy of 90%. From these peaks, two peptides (serum amyloid A protein and transthyretin) were identified and quantitated by immunoassay. Because these peptides reflect inflammatory states, we also quantitated neopterin and C reactive protein. Application of an SVM classifier using combinations of these values gave diagnostic accuracies of up to 84% for tuberculosis. Validation on a second, prospectively collected testing set gave similar accuracies using the whole proteomic signature and the 20 selected peaks. Using combinations of the four biomarkers, we achieved diagnostic accuracies of up to 78%. INTERPRETATION: The potential biomarkers for tuberculosis that we identified through proteomic fingerprinting and pattern recognition have a plausible biological connection with the disease and could be used to develop new diagnostic tests.

Adolescent↗
PubMedDate not supplied

Evaluation of genotoxic potential of chromium (VI) in Channa punctata fish in terms of chromosomal aberrations.

Chromium, a widely recognized carcinogenic, mutagenic and redox active metal, is released into aquatic environments by electroplating, tannery and textile industries. Elevated concentrations in sediments and interstitial waters are well documented. Fishes dwelling in chromium waste infested waters are presumed to be affected by its deposits. To evaluate the genotoxic potential of chromium [Cr(VI)] on aquatic bio-system, bottom feeding fishes, Channa punctata, as model fish, were exposed to [Cr(VI)]. The chromosomal aberration test (CAT) was used as biomarker of [Cr(VI)] induced toxicity. The fish were divided into three groups:Group I non-treated controls; group II positive controls, treated with an intra-muscular injection of mitomycin-C at 1 mg/kg body wt; group III exposed to a sublethal concentration (7.689 mg/l) of [Cr(VI)], dissolved in the water. For CAT estimation, short term static bioassays were conducted and samples were collected from the kidneys of fish after 24, 48, 72, 96 and 168 hrs of exposure. The remarkable chromosomal aberrations recorded in the present investigation included chromatid breaks, chromosome breaks, chromatid deletions, fragments, acentric fragments, and ring and di-centric chromosomes, along with chromatid and chromosome gaps. A significant increase in chromosomal aberrations was observed after 72 hrs of [Cr(VI)] exposure. The present study, thus reveals that even for acute exposure, [Cr(VI)] is a genotoxic agent for C. punctata.

Animals↗
PubMed2004

Phagocyte-specific calcium-binding S100 proteins as clinical laboratory markers of inflammation.

The EF-hand homolog family of S100 proteins comprises the largest group of calcium-binding proteins. Within this S100 family, the phagocyte-specific calcium-binding proteins are pro-inflammatory molecules expressed and secreted by phagocytes, which play a pivotal role within the innate immune system. Although the exact biological functions of these proteins still remain to be defined in greater detail, there is evidence that they are involved in a pro-inflammatory axis associated with various inflammatory conditions. The three members of this group, S100A8, S100A9 and S100A12 are overexpressed at local sites of inflammation. High concentrations are found in synovial fluid, sputum, stool and blood plasma/serum during inflammation. Both the S100A8/S100A9 complex and S100A12 have been proven to be useful as diagnostic markers of inflammation especially in non-infectious inflammatory diseases such as arthritis, chronic inflammatory lung and bowel disease. They indicate phagocyte activation more sensitively than conventional parameters of inflammation. As a consequence, there is a strong correlation to the inflammation of various acute and chronic disorders, making these proteins sensitive parameters for the monitoring of disease activity and response to treatment in individual patients. The phagocyte-specific S100 proteins are able to indicate minimal residual inflammation, which is not detected by other diagnostic tests, and they may even be prospective markers for the outcome of patients. In this review, pro-inflammatory functions of S100 proteins and their usefulness as biomarkers of inflammation are presented.

Biomarkers↗
PubMed1998

Advances in periodontal diagnosis. 4. Potential microbiological markers.

The potential of bacterial markers for the detection of periodontal disease activity is discussed. Chronic periodontitis has been associated with subgingival bacteria. Techniques are available to detect and distinguish different bacteria. In subgingival plaque, bacterial proteases can be detected. Commercial diagnostic tests based on bacterial factors are described.

Bacteria, Anaerobic↗
PubMed1999

Contribution of carbohydrate deficient transferrin to gamma glutamyl transpeptidase in evaluating progress of patients in treatment for alcoholism.

Eight previous investigations have suggested that conjoint consideration of findings on tests for gamma glutamyl transpeptidase (GGT) and carbohydrate deficient transferrin (CDT) substantially enhances sensitivity of screening for alcohol problems while minimally diminishing specificity. Using results from a large clinical trial, the current study evaluated the two tests singly and in combination as measures of three clinically important treatment outcome criteria: any drinking, at least one day of heavy drinking, and at least three consecutive days of heavy drinking during the past month. When scored by quartile, CDT is slightly better at screening for alcohol problems in males than GGT. However, CDT seems less accurate in females than GGT. Use of the two tests in consort moderately improves the individual test accuracy in predicting drinking status for both genders.

Adult↗
PubMed2001

[Pancreatic lipase].

Although "lipase" contains various lypolytic enzymes, the main object of lipase measurement is pancreatic lipase. Recent advances in pancreatic lipase research clarified its unique structure, and two novel pancreatic proteins, PLRL 1 and 2, were added to the pancreatic lipase gene family. In pancreatic lipase measurement, several new specific, sensitive, and reproducible assay methods were developed, and they have been widely adapted as routine tests. With these modern assays, pancreatic lipase has a good diagnostic utility for pancreatic disease.

Animals↗
PubMed2005

Ischemia-modified albumin levels in cord blood: a case-control study in uncomplicated and complicated deliveries.

BACKGROUND: In the past few years ischemia modified albumin (IMA) has emerged as a new biomarker of ischemia in the area of monitoring acute coronary syndromes. We hypothesized that reduced blood flow, such as that resulting from vascular compression in complicated labors or placental ischemia, may increase IMA. IMA level in cord blood could then serve as an indicator of fetal hypoxia and fetal tissue ischemia and serve as a biomarker of the severity of these conditions. METHODS: We performed a case-control study with 26 newborns (12 normal term deliveries, Apgar 8-9; and 14 complicated labors or pre-term deliveries, Apgar 5-8). Complications were: prematurity (3), fetal distress (6), premature rupture of membranes (6), intrauterine growth retardation (3), pre-eclampsia (1). We also studied 30 healthy adults. IMA was measured in serum from cord blood (or venous blood for adults) by the decrease in cobalt 2+ binding. RESULTS: IMA levels in neonates from non-complicated deliveries are significantly higher (45%, p < 0.005) than those of an adult control population, suggesting that IMA may increase as a consequence of labor. This increased IMA in neonates could not be accounted for by the changes in albumin concentration. It is conceivable that a transient increase in IMA reflects, in part, transient localized tissue ischemia due to the external forces exerted on the fetus during the mechanism of labor. IMA levels in cord blood from neonates from complicated deliveries are 50% higher than in neonates from uneventful deliveries (p < 0.05) while their albumin values are not significantly different (32 +/- 3 vs. 33 +/- 2 g/l). Moreover, IMA seems to be responsive to hypoxic fetal distress, showing values more than 300% higher in cases of severe fetal hypoxia (Apgar 5 n = 2: 2.19 +/- 0.01 AU vs. 0.64 +/- 0.24 for controls). IMA values did not correlate significantly with either lipoperoxides or CRP levels. CONCLUSIONS: This is the initial reporting of IMA levels in cord blood from normal deliveries compared to healthy adult ranges and neonates from complicated deliveries. Cord blood IMA levels may be an indicator of fetal ischemia and/or hypoxia. This test could become an additional biomarker to be used in conjunction with other markers and/or clinical scores aimed at determining risk of neurological complications of fetal distress.

Adult↗