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PubMed2004

Neonatal encephalopathy: association of cytokines with MR spectroscopy and outcome.

In term neonatal encephalopathy, little is known about the relationship between early inflammatory markers, neonatal brain injury, and long-term neurodevelopmental outcome. Our goal was to determine whether neonatal serum cytokine levels are associated with cerebral metabolism assessed by proton magnetic resonance spectroscopy (MRS), with magnetic resonance imaging (MRI) abnormalities, and with neurodevelopmental outcome at 30 mo of age. Levels of seven cytokines [IL-1 beta, IL-6, IL-8, IL-9, IL-12, IL-13, and tumor necrosis factor (TNF)-alpha] were measured in dried neonatal blood by immunoaffinity chromatography in a prospective cohort of 62 term newborns at risk of neonatal encephalopathy. MR images (n = 61) were scored and lactate/choline and N-acetyl-aspartate (NAA)/choline were measured by MRS (n = 42) on median day of life 6 in the deep gray nuclei (DGN) and in the watershed/cortical zone (WS). Neurodevelopmental outcome (n = 54) was considered abnormal if the infant died or if cognitive delay and/or functional motor deficit were detected at 30 mo. IL-1 beta, IL-6, IL-8 and TNF-alpha were significantly associated with lactate/choline in the DGN (p = 0.03, 0.02, 0.03, and 0.01 respectively), but not in the WS (all p > 0.1). Cytokines were not associated with NAA/choline in any region or with MRI scores. Children with abnormal neurodevelopmental outcome had higher neonatal levels of IL-1 beta, IL-6, IL-8, and lower levels of IL-12 (p = 0.04, 0.03, 0.01, 0.03 respectively). Elevated inflammatory cytokines were associated with impaired cerebral oxidative metabolism, but not with detectable MRI changes in the neonatal period. Understanding the link between elevated cytokines and outcome would inform novel strategies of cerebral protection.

Biomarkers↗
PubMed2005

Microdialysis of large molecules.

Microdialysis has been used in many tissues, including skin, brain, adipose tissue, muscle, kidney, and gastrointestinal tract, to recover low-molecular mass endogenous mediators, metabolites, and xenobiotics from the interstitial space. Recently, molecules of larger molecular mass, such as plasma proteins, cytokines, growth factors, and neuropeptides, have also been recovered successfully using larger-pore membranes. Microdialysis recovery of large molecules offers the opportunity to identify patterns of protein expression in a variety of tissue spaces and to evaluate clinically useful biomarkers of disease. From this may develop a better understanding of the disease process and its diagnosis and more targeted approaches to therapy.

Animals↗
PubMed2005

Urinary markers of adrenarche: reference values in healthy subjects, aged 3-18 years.

Information on the urinary excretion of dehydroepiandrosterone (DHEA) and its direct metabolites is scarce for healthy subjects during growth. We used gas chromatography-mass spectrometry urinary steroid profiling to noninvasively study adrenarchal metabolome in 400 healthy subjects, aged 3-18 yr. Urinary 24-h excretion rates of DHEA did not increase significantly before age 7-8 yr. However, DHEA together with its 16alpha-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 3beta,16alpha,17beta-androstenetriol (DHEA&M), as well as the DHEA metabolite, 5-androstene-3beta,17beta-diol (ADIOL), and the sum of major urinary androgen metabolites (C19) rose consistently from the youngest to the oldest age group. The significant increases (P < 0.01) observed for 24-h excretion rates of C19, ADIOL, and DHEA&M were 2- to 4-fold in boys and girls between age 3 and 8 yr. DHEA&M, for example, rose from about 20 to 80 microg/d (P < 0.0001) during this period. Until the age of 16 yr, DHEA&M excretion also increased to nearly 1000 microg/d. Patterns of steroidogenic enzyme activities were assessed (from definite ratios of urinary steroid metabolites) for 21-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and 5alpha-reductase. Our results indicate for healthy boys and girls that adrenarche is a gradual process starting much earlier than hitherto believed. Efficient metabolism of DHEA, especially to 16-hydroxylated steroids, may explain the almost constant levels seen for this steroid until age 7-8 yr. The established reference values for DHEA, DHEA&M, ADIOL, C19 (including androsterone and etiocholanolone), and urinary parameters of steroidogenic enzyme activities could be useful to identify nutritional, environmental, and pathophysiological interrelations with the progressive maturational process of adrenarche. Our data may also be used as reference data for the diagnosis of steroid-related disorders.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment.

Baseline CSF amyloid beta-peptide-42 (Abeta42), tau, and phosphorylated tau (P-tau) levels from 46 control subjects and 78 patients with mild cognitive impairment (MCI) were measured. Twenty-three patients with MCI developed dementia during the study. Abnormal biomarkers were found early in the course of Alzheimer disease (AD). The most predictive assay for AD among the patients with MCI was the combination of Abeta42 and P-tau.

Aged↗
PubMed2002

Reductive activation with cysteine represents a chromium(III)-dependent pathway in the induction of genotoxicity by carcinogenic chromium(VI).

Induction of DNA damage by carcinogenic hexavalent chromium compounds [Cr(VI)] results from its reduction to lower oxidation states. Reductive metabolism of Cr(VI) generates intermediate Cr(V/IV)species, organic radicals, and finally Cr(III), which forms stable complexes with many biological ligands, including DNA. To determine the biological significance of different reaction products, we examined genotoxic responses and the formation of DNA damage during reduction of Cr(VI) by its biological reducer, cysteine. We have found that cysteine-dependent activation of Cr(VI) led to the formation of Cr-DNA and cysteine-Cr-DNA adducts as well as interstrand DNA cross-links. The yield of binary and ternary DNA adducts was relatively constant at different concentrations of Cr(VI) and averaged approximately 54 and 45%, respectively. Interstrand DNA cross-links accounted on average for 1% of adducts, and their yield was even less significant at low Cr(VI) concentrations. Reduction of Cr(VI) in several commonly used buffers did not induce detectable damage to the sugar-phosphate backbone of DNA. Replication of Cr(VI)-modified plasmids in intact human fibroblasts has shown that cysteine-dependent metabolism of Cr(VI) resulted in the formation of mutagenic and replication-blocking DNA lesions. Selective elimination of Cr-DNA adducts from Cr(VI)-treated plasmids abolished all genotoxic responses, indicating that nonoxidative, Cr(III)-dependent reactions were responsible for the induction of both mutagenicity and replication blockage by Cr(VI). The demonstration of the mutagenic potential of Cr-DNA adducts suggests that these lesions can be explored in the development of specific and mechanistically important biomarkers of exposure to toxic forms of Cr.

Biomarkers↗
PubMed1993

Complex mixtures of air pollutants: characterizing the cancer risk of polycyclic organic matter.

Complex mixtures of polycyclic organic matter (POM) are used to illustrate the scientific problems and issues associated with characterizing the comparative risk of related complex mixtures. The complexity of mixtures in which the active components are not well characterized present special challenges, which include identifying the critical components of mixtures, their sources, and the appropriate biomarker(s) of exposure and dose; developing the appropriate experimental models for dose-response assessment; species extrapolation; and developing a scientific basis for predicting from one mixture to another. Strategies for addressing these issues include bioassay-directed chemical characterization of bioactive components of complex mixtures, apportionment methods to determine the source of biological activity and risk, DNA adduct methods to determine tissue exposure and target dose of mixtures, and comparative approaches to determining the relative similarity, potency, and risk of complex mixtures. Epidemiological data are available for humans exposed to POM from coke ovens, coal roofing tar, coal smoke, aluminum smelters, and cigarette smoke. These emissions are characterized and compared to POM from automotive emissions (diesel and gasoline), woodstove emissions, residential oil furnace emissions, and ambient air particles. The tumor potency and estimated cancer risks for these POM mixtures ranges over nearly three orders of magnitude.

Air Pollutants↗
PubMed2006

RCA-enhanced protein detection arrays.

There are many instances in which it is desirable to generate profiles of the relative abundance of a multiplicity of protein species. Examples include studies in embryonic development, immunobiology, drug responses, cancer biology, biomarkers, and so on. Microarray formats provide a convenient, high-throughput vehicle for generating such profiles, and the repertoire of proteins that can be measured is growing continuously as larger panels of specific antibodies become available. Here we describe methods for the use of antibody microarrays, whereby the detection of specifically bound antigens is enhanced by rolling circle amplification (RCA). RCA-enhanced protein detection on antibody microarrays provides a means for rapid protein profiling at high sensitivity. The set of RCA reagents remains unchanged for different microarray formats and compositions, and signal readout is performed using standard fluorescent dyes and scanners. The method is sensitive enough for the most challenging applications, such as the detection of low-abundance components of human serum.

Animals↗
PubMed1996

Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients.

Plasma total versus bone alkaline phosphatase as markers of bone turnover in hemodialysis patients. Plasma bone-specific alkaline phosphatase (bAP) has been demonstrated to be more reliable than total alkaline phosphatases (tAP) in providing information about bone turnover in patients with metabolic bone diseases. This study surveyed 42 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Plasma bAP was determined by using a new immunoassay (Tandem-R Ostase, Hybritech, Liège, Belgium). Plasma bAP values were compared with those of two other plasma markers of bone metabolism, namely tAP and intact parathyroid hormone (iPTH), for the correlations with bone histomorphometric parameters. Patients with high-turnover bone disease (HTBD) (N = 32) had significantly higher plasma bAP levels than patients with normal or low bone turnover (N/LTBD) (N = 10) (66.9 +/- 63.5 ng/mL versus 10.8 +/- 4.2 ng/mL, respectively). Bone formation and resorption were highly correlated in these patients, and plasma bAP levels were positively correlated with bone resorption parameters, including osteoclast surface (r = 0.39, P < 0.0001) and osteoclast number/mm2 (r = 0.36, P < 0.001), and with bone formation parameters, osteoblast surface (r = 0.50, P < 0.005), and bone formation rate (r = 0.91, P < 0.0001). The bone formation rate was better correlated with plasma bAP levels than with either plasma tAP or iPTH concentrations. Plasma bAP level equal or higher than 20 ng/mL, either alone or combined with plasma iPTH of 200 pg/mL, had the highest sensitivity, specificity, and predictability values for the diagnosis of high-turnover bone disease, and formally excluded patients with normal or LTBD. In conclusion, plasma bAP can be measured with a reliable immunoassay in hemodialysis patients. It represents a highly sensitive and specific biochemical marker of skeletal remodeling in these patients. Therefore, both serum iPTH and bAP are complementary in diagnoses of the type of renal osteodystrophy.

Alkaline Phosphatase↗
PubMed2005

Relationship between ethinylestradiol-mediated changes in endocrine function and reproductive impairment in Japanese medaka (Oryzias latipes).

Many biochemical endpoints currently are used to describe endocrine function in fish; however, the sensitivity of these parameters as biomarkers of impaired reproduction or sexual development is not well understood. In the present study, adult Japanese medaka (Oryzias latipes) were assessed for reproductive output and endocrine function, including circulating steroid concentrations, ex vivo steroidogenesis from the gonads, aromatase activity, hepatic estrogen receptor (ER), and plasma vitellogenin (VTG) after exposure to 0, 0.2, 5, 500, and 2,000 ng/L of 17alpha-ethinylestradiol (EE) for 14 d. The EE altered these biochemical responses at various sites along the hypothalamus-pituitary-gonadal axis at concentrations as low as 0.2 ng/L, but it only depressed reproductive function at concentrations of 500 ng/L or greater. Offspring also had reduced ability to hatch at 500 ng/L of EE, but this concentration did not produce any other observed changes in development or sexual phenotype. The reproductive parameters correlated well with VTG, ER, and gonadosomatic index (GSI) in both sexes of adult medaka, which could be indicative of the ER-mediated mode of action for EE. Vitellogenin and ER were elevated at higher concentrations of EE in both sexes, whereas GSI was decreased. Overall, most biochemical endpoints were more sensitive than reproduction or development to exposure, indicating that reproductive function may be relatively protected.

Animals↗
PubMed2004

Gene expression analysis for high throughput screening applications.

To meet growing needs for high throughput gene expression profiling, we established a new automated high throughput TaqMan RT-PCR method for quantitative mRNA expression analysis. In this method, the Allegro( trade mark ) (Zymark) system conducts all sample tracking and liquid handling steps, and ABI PRISM 7900 HT (Applied Biosystems) is used to conduct real-time determination of the C(t) value when amplification of PCR products is first detected and accumulation of inhibitory PCR products is unlikely to occur. The ABI PRISM 7900 HT Sequence Detection System features a real-time PCR instrument with 384-well-plate compatibility and robotic loading, and continuous wavelength detection, which enables the use of multiple fluorophores in a single reaction. The Allegro System offers an assembly line approach with a modular design that allows reconfiguration of the components to accommodate variations in the assay flow. In the present study, we have established and validated a new automated High Throughput (HT) TaqMan RT-PCR- based method for quantitative mRNA expression analysis. The data demonstrate that HT-Taqman PCR is a powerful tool that can be used for measuring low concentrations of mRNA, and is highly accurate, reproducible, and amenable to high throughput analysis. Results suggest that HT-TaqMan is a reliable method for the quantification of low-expression genes and a powerful tool with HT capability for target identification/validation, structure-activity relationship (SAR) study, compound selection for efficacy studies, and biomarker identification in drug discovery and development.

Drug Design↗
PubMed2026

Tumor-Intrinsic Blood and Imaging Correlatives in Advanced Prostate Cancer Treated with Combination Radiopharmaceutical Therapy and Immunotherapy.

The PRINCE trial showed the clinical activity for 177Lu-PSMA-617 in combination with pembrolizumab for metastatic castration-resistant prostate cancer. To refine patient selection and improve response monitoring strategies to this combination, we investigated candidate tumor-intrinsic biomarkers of treatment response and resistance. Methods: We performed circulating tumor DNA (ctDNA), circulating tumor cell (CTC), and PET imaging analyses at baseline, 12 wk on-treatment, and disease progression in participants enrolled in PRINCE (n = 37). We performed targeted sequencing for ctDNA quantification and genomic analysis of more than 70 prostate cancer genes. CTC enumeration was performed on the EpicSciences platform and was combined with selective single-cell whole-genome sequencing. PET imaging included serial PSMA PET as well as 18F-FDG PET imaging at baseline. Results: A low baseline ctDNA fraction and high PSMA avidity in metastatic lesions were linked to superior treatment responses and may have composite biomarker value. Genomic alterations in tumor suppressor genes TP53, RB1, or PTEN were associated with higher 18F-FDG avidity and metabolic tumor volume on 18F-FDG PET imaging and worse prognosis. At 12-wk on-treatment, both ctDNA detection and PSMA PET imaging were strong indicators of response depth and durability. At disease progression, PSMA expression on PET imaging was lower compared with baseline and supported by subclonal remodeling of ctDNA and CTC copy number profiles and by clonal expansions of tumor suppressor gene mutations. Conclusion: We provide the first integrated molecular and imaging insights into determinants of response and resistance to combined radiopharmaceutical therapy and immunotherapy in prostate cancer and propose biomarker strategies to inform future clinical development.

177Lu-PSMA-617↗
PubMed2002

An evidence-based approach to cancer prevention clinical trials.

Research on carcinogenesis and its inhibition has made significant progress in the last 30 years, providing an impressive body of evidence that supports various strategies for cancer prevention. Innovative studies have helped to identify potential causes of cancer, including environmental factors such as diet, and provided valuable information about their mechanisms of action. Hundreds of epidemiologic and experimental studies have focused on possible associations between dietary factors and different types of cancer. During the same period, potential inhibitors of cancer that appeared able to prevent, arrest or reverse cancer development by interfering with one or more steps in the process of carcinogenesis were identified, and the term 'chemoprevention' was coined for this pharmacological approach to cancer prevention. Promising compounds were systematically evaluated for their potential as chemopreventive agents. Numerous agents were determined to be safe and effective in preclinical trials, including naturally occurring vitamins, minerals and phytochemicals as well as synthetic compounds. Based on preclinical results, selected agents have been and are now being evaluated in phase I, II and III clinical interventions for various cancers. Development of valid surrogate end point biomarkers for clinical disease that can be modulated by interventions is essential to accelerate progress in cancer prevention clinical trials.

Anticarcinogenic Agents↗
PubMed2002

Predictors of response to systemic therapy in breast cancer.

The most appropriate systemic therapy for a population of patients with breast cancer is determined from clinical trial data. However, the heterogeneity of breast cancer is such that within a population individual patients derive variable benefit. There is therefore a need for predictive molecular factors in order that treatment can be individualised. This review describes the roles of HER-2, epidermal growth factor receptor (EGFR), oestrogen receptor (ER)/progesterone receptor (PgR), Ki67, Bcl-2, p53 and gene expression profiling in predicting responses to endocrine, cytotoxic and biological therapies. ER and PgR remain the only well-established predictive markers of responses to endocrine therapy, although HER-2/neu has an emerging role in this area and in choice of adjuvant chemotherapy. There are considerable methodological difficulties in identifying useful predictive factors but on the basis of current evidence other biomarkers add little additional information. The development of targeted therapies means that the molecular targets themselves may become useful predictive factors for directing use of these therapies. HER-2 already has an established role in this area, but the role of EGFR requires further elaboration. The use of DNA microarrays to assess gene expression profiles may revolutionise our ability to predict responses to therapy.

Antibodies, Monoclonal↗
PubMed2003

Transcriptional profiling of targets for combination therapy of lung carcinoma with paclitaxel and mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor.

A combination of paclitaxel (Taxol) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK/Erk) inhibitor represents a rational new approach to chemotherapy. We performed Affymetrix microarray analysis to understand the global effects of this combination in lung carcinoma. Genes involved in cell cycle control, apoptosis, adhesion, proliferation, invasion, and metastasis were modulated. We observed similar patterns of gene modulation in ovarian and melanoma cell lines, indicating the general applicability of these findings. Functional genomic analysis identified two genes as new targets of drug-induced tumor apoptosis. The MGSA/Gro1 gene, important in melanoma growth, was induced by paclitaxel and reduced by MEK inhibition. Blockage of paclitaxel-induced melanoma growth stimulatory activity significantly reduced melanoma growth. Additionally, the expression of topoisomerase III beta, which exhibited a clear pattern of gene reduction by a combination of the two drugs, was significantly increased (5.7-fold) in primary lung cancers but not adjacent tissues. These findings provide potential new biomarkers and gene targets for the development of improved cancer treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Bioinformatics: towards new directions for public health.

OBJECTIVES: Epidemiologists are reformulating their classical approaches to diseases by considering various issues associated to "omics" areas and technologies. Traditional differences between epidemiology and genetics include background, training, terminologies, study designs and others. Public health and epidemiology are increasingly looking forward to using methodologies and informatics tools, facilitated by the Bioinformatics community, for managing genomic information. Our aim is to describe which are the most important implications related with the increasing use of genomic information for public health practice, research and education. To review the contribution of bioinformatics to these issues, in terms of providing the methods and tools needed for processing genetic information from pathogens and patients. To analyze the research challenges in biomedical informatics related with the need of integration of clinical, environmental and genetic data and the new scenarios arisen in public health. METHODS: Review of the literature, Internet resources and material and reports generated by internal and external research projects. RESULTS: New developments are needed to advance in the study of the interactions between environmental agents and genetic factors involved in the development of diseases. The use of biomarkers, biobanks, and integrated genomic/clinical databases poses serious challenges for informaticians in order to extract useful information and knowledge for public health, biomedical research and healthcare. CONCLUSIONS: From an informatics perspective, integrated medical/biological ontologies and new semantic-based models for managing information provide new challenges for research in areas such as genetic epidemiology and the "omics" disciplines, among others. In this regard, there are various ethical, privacy, informed consent and social implications, that should be carefully addressed by researchers, practitioners and policy makers.

Computational Biology↗
PubMedDate not supplied

Frequency of antitoxoplasma antibodies in patients with ocular pathology.

BACKGROUND: Toxoplasmosis is a worldwide disease caused by toxoplasma gondii. This disease is prevalent in many parts of the world including Pakistan. Besides other conditions, ocular diseases are also caused by it. Immune response is mounted against this protozoon in the form of antibodies which are detectable in patient's serum. The present study estimated the seroprevalence of antitoxoplasma antibodies in patients with ocular diseases. METHODS: One hundred patients of either sex and age were studied at the ophthalmology units of Jinnah Postgraduate Medical Centre and Lyari General Hospital Karachi. Antitoxoplasma antibodies, both immunoglobulin G and M (IgG & IgM) were detected in the sera of these patients by the recommended methods. RESULTS: Seroprevalence of antitoxoplasma antibodies was highest (60%) in age groups 21 to 40 years. It was seen in either sex but was found to be more common in females. CONCLUSIONS: Further studies with improved diagnostic techniques on larger samples are needed to diagnose and treat toxoplasmosis in acute stage in order to minimize the deleterious effects it has on different tissues and organs of the body.

Adolescent↗