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PubMed2005

The aromatase inhibitor anastrozole is associated with favorable embryo development and implantation markers in mice ovarian stimulation cycles.

OBJECTIVE: To investigate the embryonic and endometrial effects of anastrozole in preimplantation and implantation phases in FSH-induced cycles in mice. DESIGN: Blind randomized study. SETTING: University research laboratory. ANIMAL(S): Twenty-seven mature female mice. INTERVENTION(S): Single-dose anastrozole (25 mg/kg [0.75 mg]), recombinant FSH (5 IU/mL), and hCG (5 IU/mL) (n = 9); recombinant FSH (5 IU/mL) and hCG (5 IU/mL) (n = 9); or sterile saline (1 mL) (n = 9). The morning of finding the vaginal plug was designated as day 1 of embryonic development (E1). Three mice from each group were sacrificed on E1 and embryos aspirated from uterine tubes. The rest of the mice were sacrificed on E2.5-3 and uteruses removed. MAIN OUTCOME MEASURE(S): Embryo quality, endometrial histologic evaluation, and immunohistochemical analysis of tumor necrosis factor-alpha, leukemia inhibitory factor, laminin, and collagen IV staining. RESULT(S): Anastrozole use in FSH-induced cycles not only caused an increase in preimplantation receptivity and implantation but also supported release of implantation markers. The enhanced embryo development seen in this study would explain the higher implantation because embryo development is synchronized with endometrial development. CONCLUSION(S): In mice, the use of anastrozole in FSH-induced cycles has a positive effect on embryo quality and implantation. This effect might be species dependent, and human studies are needed.

Anastrozole↗
PubMed2003

Development of an immunoassay for serum caveolin-1: a novel biomarker for prostate cancer.

PURPOSE: Caveolin-1 (cav-1), the major protein component of caveolae, plays an important role in multiple signaling pathways, molecular transport, and cellular proliferation and differentiation. The specific functions of cav-1/caveolae are highly cell and context dependent. We have previously shown that cav-1 expression is increased in metastatic human prostate cancer and that cav-1 cellular protein expression is predictive of recurrence of the disease after radical prostatectomy. Recently, we reported that cav-1 is secreted by androgen-insensitive prostate cancer cells, and we detected, by Western blotting, cav-1 in the high-density lipoprotein(3) fraction of serum specimens from patients with prostate cancer. EXPERIMENTAL DESIGN: Using rabbit polyclonal antibodies with specificity for cav-1, we developed a direct sandwich immunoassay for the determination of cav-1 in serum. A recombinant human cav-1 fusion protein was overexpressed and purified from 293 PE cells and used as a calibrator. RESULTS: The assay was highly specific and had a minimum detection limit of 0.017 ng/ml (mean + 3 SD of zero calibrator) and measuring range of up to 200 ng/ml. Intra-assay coefficient of variation was 2.29-6.74% and inter-assay coefficient of variation was 2.81-6.43% over the serum concentration tested 0.04-31.89 ng/ml. The recovery limit of cav-1 by the assay was 89.55-100.28%. The median serum cav-1 level in 102 prostate cancer patients with clinically localized disease (0.463 ng/ml) was significantly higher than 81 healthy control men (0.324 ng/ml; P = 0.0446, Mann-Whitney test) or 107 men with benign prostatic hyperplasia (0.172 ng/ml; P = 0.0317, Mann-Whitney test). CONCLUSIONS: Our results indicate that serum cav-1 has the power to differentiate between prostate cancer and benign prostatic hyperplasia patients and the potential to be an important biomarker for prostate cancer. Additional studies to test the potential of serum cav-1 as a diagnostic and/or prognostic marker in prostate cancer are warranted.

Aged↗
PubMed1998

Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy.

OBJECTIVE: To study whether levothyroxine (LT4) suppressive therapy exposes patients with differentiated thyroid cancer (TC) to an increased risk of osteoporosis. DESIGN AND METHODS: Markers of bone formation (serum alkaline phosphatase (ALP), osteocalcin (OC), type I procollagen carboxyterminal (PICP) and aminoterminal (PINP) propeptide) and resorption (serum type I collagen carboxyterminal telopeptide (ICTP) and urine hydroxyproline (HOP)), as well as serum intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25(OH)2-D) were measured in 29 patients (25 women, 4 men) with a median age of 45 years, and in 38 age- and sex-matched controls. In a subgroup of 14 patients the measurements were repeated after 5 weeks' interruption of LT4 therapy. Since the primary treatment of TC the patients had used TSH suppressive doses of LT4 (a mean daily dose of 215 microg) for 9 to 11 years. The bone mineral density (BMD) of patients and controls was measured by dual energy X-ray absorptiometry. RESULTS: When on T4 therapy, patients had significantly higher mean levels of ALP (+21%, P < 0.05), OC (+35%, P < 0.01), PICP (+10%, P < 0.05), PINP (+46%, P < 0.001), ICTP (+21%, P < 0.05), and HOP (+37%, P < 0.001) compared with controls. After stopping treatment, OC (-42%, P < 0.001), PINP (-7%, P < 0.05), and ICTP (-54%, P < 0.001) decreased, whereas PICP (+24%, P < 0.001) and 1,25(OH)2D (+29%, P < 0.01) increased. BMD of the lumbar spine and the upper femur was similar in patients and controls. CONCLUSIONS: Patients with differentiated TC have high bone turnover when on LT4 suppressive therapy, After withdrawing treatment both bone formation and resorption decrease acutely. During development of hypothyroidism, serum PICP and PINP, which form from the same type I procollagen molecule and should change similarly, behaved differently. This may be due to different effects of hypothyroidism on their removal through separate receptors in the liver.

Adult↗
PubMed2005

Predictors of C-reactive protein in Tsimane' 2 to 15 year-olds in lowland Bolivia.

Infectious disease is a major global determinant of child morbidity and mortality, and energetic investment in immune defenses (even in the absence of overt disease) is an important life-history variable, with implications for human growth and development. This study uses a biomarker of immune activation (C-reactive protein) to investigate an important aspect of child health among the Tsimane', a relatively isolated Amerindian population in lowland Bolivia. Our objectives are twofold: 1) to describe the distribution of CRP by age and gender in a cross-sectional sample of 536 2-15-year-olds; and 2) to explore multiple measures of pathogen exposure, economic resources, and acculturation as predictors of increased CRP. The median blood-spot CRP concentration was 0.73 mg/l, with 12.9% of the sample having concentrations greater than 5 mg/L, indicating a relatively high degree of immune activation in this population. Age was the strongest predictor of CRP, with the highest concentrations found among younger individuals. Increased CRP was also associated with higher pathogen exposure, lower household economic resources, and increased maternal education and literacy. The measurement of CRP offers a direct, objective indicator of immune activation, and provides insights into a potentially important pathway through which environmental quality may shape child growth and health.

Acculturation↗
PubMedDate not supplied

Absolute quantification of the model biomarker prostate-specific antigen in serum by LC-Ms/MS using protein cleavage and isotope dilution mass spectrometry.

Protein cleavage-isotope dilution mass spectrometry (PC-IDMS) can be used to quantify proteins, with an isotope-labeled analogue of the peptide fragment used as an internal standard. Here, we investigate use of a standard LC-MS/MS platform for quantifying a model biomarker directly from serum by this technique. We synthesized a peptide (IVGGWECEK) identical to the N-terminal tryptic fragment of PSA but with each glycine containing two 13C atoms and one 15N atom. PSA-free human serum was denatured with urea followed by the introduction of PSA standard and the stable isotope labeled internal standard peptide. The sample was then proteolyzed with trypsin and subjected to quantification using LC-MS/ MS on a triple quadrupole mass spectrometer. A linear least squares calibration curve made from five different concentrations of PSA added to serum and digested (each made in triplicate and randomly injected three times) had a mean slope of 0.973 (SE = 0.023), intercept of -0.003 (SE = 0.022), and R2 of 0.971. Recovery of calibrators ranged from 70 to 85% with a mean run-to-run CV of 13% and a mean within-run CV of 5.7%. PC-IDMS is a promising technique for quantifying proteins covering a broad range of applications from standardizing immunoassays to monitoring post-translational modifications to quantifying newly discovered biomarkers prior to the development and implementation of an immunoassay, just to name a few. Issues surrounding the application of PC-IDMS for the absolute quantification of proteins include selection of a proteolytic fragment for quantification that can be cleaved and isolated reproducibly over a broad dynamic range, stable isotope labeled synthetic peptide standards that give consistent results, and LC-MS/MS methods that provide adequate sensitivity and reproducibility without creating impractical analysis times. The results presented here show that absolute quantification can be performed on the model biomarker PSA introduced into denatured serum when analyzed by LC-MS/MS. However, concerns still exist regarding sensitivity compared to existing immunoassays as well as the reproducibility of PC-IDMS performed in different matrixes.

Humans↗
PubMed2005

Biochemical markers of bone metabolism and risk of dorsal metacarpal disease in 2-year-old Thoroughbreds.

REASONS FOR PERFORMING STUDY: Dorsal metacarpal disease (DMD) is a common problem in 2-year-old racehorses and results in loss of a significant number of days from training. Biochemical markers of bone cell activity measured early in the training season could have value for identifying 2-year-old Thoroughbred racehorses that develop DMD. OBJECTIVES: To determine the association between serum concentrations of osteocalcin, the carboxyterminal propeptide of type I collagen (PICP) and the carboxyterminal cross-linked telopeptide of type I collagen (ICTP) measured early in the training season and the risk of DMD. METHODS: Blood samples were collected from 165 two-year-old Thoroughbreds during late November/early December. Osteocalcin and PICP were measured as markers of bone formation, and ICTP as a marker of bone resorption. Training and veterinary records for each horse were monitored over the following training/racing season (10 months). Cases were defined as an episode where signs of DMD were sufficiently severe for a horse to miss at least 5 consecutive days of training. Classification tree and logistic regression analysis were used to identify the most important factors suitable for prediction of DMD risk. RESULTS: There were 24 cases of DMD during the season (14.6% cumulative incidence), with an average time to recognition of approximately 6 months (May). The earliest recognised case was in February and the latest in September. Osteocalcin and ICTP concentrations in the early stages of the training season were significantly higher in horses that subsequently developed DMD (P = 0.017 and 0.019, respectively). DMD cases were also significantly older compared to noncases (21.04 vs. 20.44 months, P = 0.023). Using a multivariable logistic regression model, it was possible to postulate a set of diagnostic rules to predict the likelihood of DMD injury during the season. This suggested that horses with ICTP concentrations above 12365 ug/l and older than 20.5 months are 2.6 times more likely to develop DMD. CONCLUSIONS: The measurement of the bone resorption marker ICTP could be useful for identification of 2-year-olds at increased risk of developing DMD. POTENTIAL RELEVANCE: These findings, together with other strategies such as modification of training regimens, e.g. early introduction of short distances of high-speed exercise into the training programme, could help reduce the days lost to training as a result of DMD.

Age Factors↗
PubMed2004

Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis.

OBJECTIVES: We sought to evaluate the association between plasma levels of monocyte chemoattractant protein (MCP)-1 and the risk for subclinical atherosclerosis. BACKGROUND: Monocyte chemoattractant protein is a chemokine that recruits monocytes into the developing atheroma and may contribute to atherosclerotic disease development and progression. Plasma levels of MCP-1 are independently associated with prognosis in patients with acute coronary syndromes, but few population-based data are available from subjects in earlier stages of atherosclerosis. METHODS: In the Dallas Heart Study, a population-based probability sample of adults in Dallas County </=65 years old, plasma levels of MCP-1 were measured in 3,499 subjects and correlated with traditional cardiovascular risk factors, high-sensitivity C-reactive protein (hs-CRP), and coronary artery calcium (CAC) measured by electron beam computed tomography. RESULTS: Higher MCP-1 levels were associated with older age, white race, family history of premature coronary disease, smoking, hypertension, diabetes, hypercholesterolemia, and higher levels of hs-CRP (p < 0.01 for each). Similar associations were observed between MCP-1 and risk factors in the subgroup of participants without detectable CAC. Compared with the subjects in the lowest quartile of MCP-1, the odds of prevalent CAC (CAC score >/=10) for subjects in the second, third, and fourth quartiles were 1.30 (95% confidence interval [CI] 0.99 to 1.73), 1.60 (95% CI 1.22 to 2.11), and 2.02 (95% CI 1.54 to 2.63), respectively. The association between MCP-1 and CAC remained significant when adjusted for traditional cardiovascular risk factors, but not when further adjusted for age. CONCLUSIONS: In a large population-based sample, plasma levels of MCP-1 were associated with traditional risk factors for atherosclerosis, supporting the hypothesis that MCP-1 may mediate some of the atherogenic effects of these risk factors. These findings support the potential role of MCP-1 as a biomarker target for drug development.

Adult↗
PubMed1995

Increased bone resorption and decreased bone formation in Chinese patients with hip fracture.

Biochemical markers of bone formation (bone-specific alkaline phosphatase and osteocalcin) and bone resorption (hydroxyproline excretion and bone isoenzyme of acid phosphatase) were measured in 30 patients (15 M and 15 F) with hip fracture and 30 healthy subjects matched for age and sex. Bone isoenzyme of tartrate-resistant acid phosphatase (TRACP) was measured by a recently developed specific immunoassay. Serum osteocalcin concentration and bone-specific alkaline phosphatase activity were significantly lower and serum TRACP concentration and urinary hydroxyproline excretion were elevated in patients compared with healthy subjects. We suggest that there is reduced bone formation and increased bone resorption in patients with hip fracture.

Acid Phosphatase↗
PubMed2006

Physiological and reproductive effects of beta adrenergic receptor antagonists in Daphnia magna.

Although pharmaceuticals are increasingly found in surface waters, environmental levels of many of these compounds are not acutely toxic to model test organisms. Prior to conducting appropriate ecological risk assessments of pharmaceuticals, the mode of action-based biomarkers needs to be developed for non-target species. To evaluate toxicity of the beta-adrenergic blockers propranolol and metoprolol on non-target biota, we assessed standard ecotoxicological endpoints after 9 days of subchronic exposure in a transgenerational study with Daphnia magna. On day 9 of exposure, the lowest observed effects concentration (LOEC) for growth were 0.44 mg L(-1) for propranolol and 12 mg L(-1) for metoprolol. Total fecundity LOECs for the 9-day exposure were 0.11 mg L(-1) and 6 mg L(-1) for propranolol and metoprolol, respectively. In addition to typical ecotoxicological endpoints, we evaluated the utility of employing the physiological biomarkers of heart rate and metabolic rate following subchronic and acute exposures to propranolol and metoprolol. Propranolol and metoprolol LOECs for heart rate were 0.055 mg L(-1) and 3.1 mg L(-1), significantly lower than the LOECs for growth and reproduction. At these concentrations, heart rate was significantly lower than the control values for both compounds. Daphnia magna endpoint sensitivity to chronic propranolol and metoprolol exposure was mortality < growth < fecundity < heart rate. Second generation D. magna were less sensitive to both compounds. Responses of the physiological biomarkers heart rate and metabolic activity suggest that propranolol and metoprolol exerts sublethal toxicity to D. magna at lower concentrations than observed in the classical endpoints.

Adrenergic beta-Antagonists↗
PubMed2006

The process chain for peptidomic biomarker discovery.

Over the last few years the interest in diagnostic markers for specific diseases has increased continuously. It is expected that they not only improve a patient's medical treatment but also contribute to accelerating the process of drug development. This demand for new biomarkers is caused by a lack of specific and sensitive diagnosis in many diseases. Moreover, diseases usually occur in different types or stages which may need different diagnostic and therapeutic measures. Their differentiation has to be considered in clinical studies as well. Therefore, it is important to translate a macroscopic pathological or physiological finding into a microscopic view of molecular processes and vice versa, though it is a difficult and tedious task. Peptides play a central role in many physiological processes and are of importance in several areas of drug research. Exploration of endogenous peptides in biologically relevant sources may directly lead to new drug substances, serve as key information on a new target and can as well result in relevant biomarker candidates. A comprehensive analysis of peptides and small proteins of a biological system corresponding to the respective genomic information (peptidomics(R)methods) was a missing link in proteomics. A new peptidomic technology platform addressing peptides was recently presented, developed by adaptation of the striving proteomic technologies. Here, concepts of using peptidomics technologies for biomarker discovery are presented and illustrated with examples. It is discussed how the biological hypothesis and sample quality determine the result of the study. A detailed study design, appropriate choice and application of technology as well as thorough data interpretation can lead to significant results which have to be interpreted in the context of the underlying disease. The identified biomarker candidates will be characterised in validation studies before use. This approach for discovery of peptide biomarkes has potential for improving clinical studies.

Biomarkers↗
PubMed2004

Exploiting natural peptide diversity: novel research tools and drug leads.

During the course of evolution, nature has developed a vast number of peptides in all living and past species that display an exceeding diversity of structure and biological effects, such as hormonal and enzyme-controlling activity, communication between cells, and participation in host defence. Sensitive mass spectrometric technologies have been introduced and facilitate access to new natural peptides, even in trace amounts, and allow the quantitative determination of the peptide status of cells, organs and whole organisms (peptidomics). Among the large number of new biologically active peptides identified from an increasing variety of natural sources, regulators of ion channels, chemoattractants, protease inhibitors, metabolism-related hormones, cytotoxins, and antimicrobials have been found. These novel peptides serve as research tools and have potential as diagnostic biomarkers and for the development of peptide and peptidometic drugs.

Animals↗
PubMed2000

Biochemical markers of bone formation.

The procollagen peptides, ALP and osteocalcin evaluate a different osteoblastic function. With increased understanding of the precise functions of these markers and the factors that govern their biosynthesis and metabolic clearances, abnormalities in specific osteoblast activities may be discerned. It is hoped that further advances in research and development will provide assays with increased specificity, sensitivity, and availability. Clearly, measurement of bone markers does not substitute for bone mass measurement, the latter giving, at this time, the most useful information about fracture risk. The combined use of BMD and marker measurements, however, has the potential to be valuable in individual risk assessment. It is not clear whether a combination of markers or a single marker will gain the highest predictive results in this context.

Alkaline Phosphatase↗
PubMed2006

Drug-induced phospholipidosis: issues and future directions.

Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of potential phospholipogenic candidate compounds are available. In contrast, a clear need exists for the identification of valid biomarkers to assess the development of phospholipidosis in preclinical and clinical studies.

Animals↗
PubMed2005

Contribution of studies on renal effects of heavy metals and selected organic compounds to our understanding of the progression of chronic nephropathies towards renal failure.

Risk assessment for a number of workplace or environmental chemicals, especially heavy metals and industrial organic compounds, relies mostly on clinical and epidemiologic findings. The low incidence of chronic nephropathies raises methodological issues in carrying out and interpreting human data on the progression of early changes towards end-stage renal disease. To overcome such limitations of epidemiological studies, two main approaches have been explored: (i) human studies relying on biomarkers and (ii) experimental animal models. Animal experiments have been useful to characterize early changes, such as hyperfiltration, eventually leading to chronic renal failure. Animal studies provided insights into the mechanisms underlying microalbuminuria and microproteinuria. Such biomarkers of early changes, developed for use at the workplace, have then been used to monitor such chronic disorders and multifactorial diseases as diabetes and arterial hypertension. Another area where occupational medicine has provided evidence is the effectiveness of primary prevention over other possible approaches. Avoidance of exposure to heavy metals and volatile hydrocarbons and their derivatives, mainly in individuals with diagnosed renal disorders, remains the best approach towards a substantial reduction in the burden of renal diseases.

Animals↗
PubMed2006

[Biochemical markers for Alzheimer disease].

It is estimated that approximately 40,000 people in Denmark suffer from Alzheimer's disease (AD), a neurodegenerative dementia. Symptomatic treatment now exists which can temporarily inhibit the loss of brain function. Unfortunately, AD is difficult to diagnose, especially early in the disease course, and a definite diagnosis is possible only post-mortem. To develop improved diagnostic methods, several biomarkers have been examined for their ability to differentiate AD from normal aging and other dementias. Their measurement in blood samples has not yet been developed, but analyses may now be routinely performed using cerebrospinal fluid (CSF). The CSF biomarkers include amyloid-beta 1-42 (Abeta1-42), which is decreased in AD patients, as well as total tau (t-tau) and hyperphosphorylated tau (p-tau), which are elevated. While a decreased Abeta1-42 level in CSF has no independent value in the diagnostic differentiation, t-tau and p-tau add more specificity to the differentiation of AD from other dementias while retaining a reasonable degree of sensitivity.

Aged↗
PubMed2001

Human placenta as a 'dual' biomarker for monitoring fetal and maternal environment with special reference to potentially toxic trace elements. Part 3: toxic trace elements in placenta and placenta as a biomarker for these elements.

The human placenta as a body component is exposed to several harmful substances, depending upon the environmental conditions encountered. In the case of toxic metals, placental tissue can be regarded as a dual biomarker to assess maternal and fetal health. The average range of concentrations for toxic trace elements in placenta based on wet weight are found to be: cadmium 1-6 ng/g; total mercury 2-13 ng/g; methyl mercury 1-14 microg/g; and lead 5-60 ng/g. The placenta appears to be at least a partial barrier for Cadmium. Cadmium transport includes a broad variety of mechanisms. Once in circulation, it mainly interferes with Ca and Zn transportation. On the other hand, placenta appears to be a weaker harrier for Pb than for Cd. In the case of Hg, predominantly the organic form is absorbed and readily crosses the placenta. In fetal blood, the organic mercury content is equal or even greater than in maternal blood, raising questions on normal fetal development. Placenta as a biomarker could be taken as an alternative to repeated maternal blood sampling for assessing lead exposure in utero. Placenta samples are usually obtained at the time of parturition, a one-time event. Hence, each pregnancy has to be looked upon as an RTM (real time monitoring) process since the affected species is exposed to the placental source of pollutants only during the course of that particular pregnancy.

Adult↗
PubMed2006

Specific peptide patterns of follicular fluids at different growth stages analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Human follicular fluid (HFF) has been suggested to influence oocyte development potential, and some of HFF proteins may be potential markers for oocyte maturation during follicular development. Using matrix-assisted laser desorption /ionization-time of flight mass spectrometry (MALDI-TOF MS), the presence of specific peptide peaks in HFF which could represent the follicle development potential was evaluated. HFF from different developmental stages were first digested and the resultant peptide mixtures were directly analyzed by MALDI-TOF MS. It was shown that the frequencies of specific peaks demonstrated higher reproducibility than peak intensities after multiple measurements (>or=6 times) per sample. Using this approach, a reliable peak list for each different sample could be generated by combining the information from multiple measurements. By comparing the peak lists from different samples at different growth stages, we found that 5 specific peaks appeared in the 100% frequency category of 6 replicates in all the HFF samples containing mature oocyte. Similarly, such 25 peptide peaks were also identified for HFF containing immature oocyte. These specific peaks could be used to distinguish HFF from different stages as biomarkers related to follicle development and maturation. After searching the protein database, some proteins that are known to be involved in the development and maturation of oocyte were identified, such as apolipoprotein A-I, collagen type IV, integrin, et al. Identification of such proteins in our experiment further proved that the direct analysis of tryptic digests could be of practical value.

Female↗