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PubMed2005

Biomarkers of space radiation risk.

Radiation risk estimates are based on epidemiological data obtained on Earth for cohorts exposed predominantly to acute doses of gamma rays, and the extrapolation to the space environment is highly problematic and error-prone. The uncertainty can be reduced if risk estimates are compared directly to space radiation-induced biological alterations, i.e. by detecting biomarkers in astronauts. Chromosomal aberrations in peripheral blood lymphocytes are the only biomarker that can provide simultaneous information on dose, dose equivalent and risk, and they have been measured extensively in astronauts during the past 10 years. Individual relative risks calculated from chromosomal aberration measurements in crew members after single space missions in low-Earth orbit fall in the same range as the estimates derived from physical dosimetry, suggesting that the current system for radiogenic risk evaluation is essentially sound. However, the output of the biomarker test is dependent upon the sampling time. Recent results show a fast time-dependent decay of chromosomal aberrations in blood lymphocytes after space flight and a lack of correlation between translocations and cumulative dose in astronauts involved in two to five space missions. This "time factor" may reflect individual variability and time dependence in the risk produced by exposure to cosmic radiation during the flight. Biomarkers may be superior to dose in predicting space radiation risk, pending technical improvements in sensitivity, and validation by epidemiological studies.

Biomarkers↗

PubMed2002

A phase II breast cancer chemoprevention trial of oral alpha-difluoromethylornithine: breast tissue, imaging, and serum and urine biomarkers.

PURPOSE: A double-blind randomized Phase II chemoprevention trial of alpha-difluoromethylornithine (DFMO) was conducted in a group of women at high risk for development of breast cancer. DFMO is an irreversible inhibitor of ornithine decarboxylase, the limiting enzyme of polyamine synthesis that is often up-regulated in breast cancer. EXPERIMENTAL DESIGN: Study entrants were required to have random periareolar fine-needle aspiration cytology prior to entry that exhibited hyperplasia or hyperplasia with atypia, as well as a mammogram and clinical breast exam judged as not suspicious for breast cancer and no clinical hearing loss. Subjects were randomized to 6 months of oral DFMO (0.5 g/m(2)/day) or placebo, followed by repeat fine-needle aspiration and biomarker assessment. The main study end point was an improvement in cytologic pattern. RESULTS: Of 119 subjects entered, 96% completed the study and were evaluable for the main study end point. A modest reduction (28%) in average total urine polyamines was obtained in the DFMO group, but there was no reduction in the spermidine:spermine ratio. There was no difference in cytologic improvement between DFMO and placebo. Likewise, there was no difference between DFMO and placebo for the secondary end points of breast molecular marker changes (immunocytochemical expression of proliferating cell nuclear antigen, p53, and epidermal growth factor receptor), mammographic breast density, serum insulin-like growth factor I: insulin-like growth factor binding protein 3 ratio, adverse events, quality of life indices, or subsequent cancer development. CONCLUSIONS: DFMO at a dose level of 0.5 g/m(2)/day administered for 6 months does not modulate breast risk biomarkers tested in this study.

Administration, Oral↗

PubMed1997

[Biomarkers in diagnosis of kidney diseases caused by chemical toxins].

As yet there has been no evidence produced that nephrotoxic chemicals damage nephron in sites, characteristic of a given toxin. A number of nephrotoxic effects result rather from changes induced by these substances mostly in the peripheral circulatory system than from a direct effect of chemical toxin on the kidneys. In many cases the morbid process in the kidneys does not emerge until a considerable number of nephrons is already damaged. Therefore, it is essential that doctors, attending patients exposed to nephrotoxins, have at their disposal, during periodical examinations, appropriate laboratory tests (biomarkers) able to detect subclinical forms of chemical damage of the kidneys. These biomarkers should also help to identify which of the functional parts of the kidneys have been damaged. It seems that determination of protein excreted with urine is one of the best biomarkers most frequently used to detect the dysfunction of renal glomerulus. It is recommended that the relationship between urine concentration of total protein and urine concentration of creatinine be determined. In the group of biomarkers of tubule dysfunction the measurement of substances usually reabsorbed from glomal filtrate (low-molecular protein) in proximal tubule or determination of enzymes' activity in urine (e.g. N-acetylo-glucosoaminidase) and those cellular components which are not excreted with normal urine are recommended. In the assessment of distal renal tubule dysfunction it is advised to examine urine osmolarity and/or determination of Thamm-Horsfall glycoprotein.

Biomarkers↗

PubMed2006

Increased ventricular ectopic activity in relation to C-reactive protein, and NT-pro-brain natriuretic peptide in subjects with no apparent heart disease.

BACKGROUND: Subjects with frequent ventricular premature complexes (VPC) and no apparent heart disease make a heterogenic group with regard to prognosis. Some biomarkers have recently proved useful in risk stratification in different heart diseases. We examined prognostic impact of NT-Pro-brain natriuretic peptide (NT-Pro BNP), and C-reactive protein (CRP) in relation to frequent VPC in subjects with no apparent heart disease. METHODS: Six hundred seventy-eight healthy subjects between 55 and 75 years of age with no history of cardiovascular disease were included in the study. All were tested with fasting laboratory testing and 48-hour ambulatory ECG monitoring. Frequent VPC was defined as VPC > or =30/hour. RESULTS: In 56 subjects (8%) with frequent VPC the prognosis was much poorer compared to those without frequent VPC (Hazard ratio and 95% CI: 2.3;1.2-4.4, P = 0.01), after adjustment for conventional risk factors. In subjects with frequent VPC increased levels of CRP (above 2.5 microg/mL) was the only factor among the tested biomarkers, which was associated with a poor prognosis. Taking subjects without frequent VPC as reference, the hazard ratio and 95% CI for subjects with frequent VPC and increased CRP was 3.6;1.8-7.1, P = 0.0004, and for those with frequent VPC and normal CRP 0.8;0.2-3.5, P = 0.83, after correction for conventional risk factors. CONCLUSIONS: Among middle-aged and elderly subjects with no apparent heart disease and frequent VPCs, a CRP value > or =2.5 microg/mL is associated with a significantly higher risk of death and acute myocardial infarction. These subjects deserve primary prevention measures and further work up for structural heart disease.

Aged↗

PubMed2006

Heart-type fatty acid-binding protein permits early risk stratification of pulmonary embolism.

AIMS: We investigated the value of a novel early biomarker, heart-type fatty acid-binding protein (H-FABP), in risk stratification of patients with acute pulmonary embolism (PE). METHODS AND RESULTS: We prospectively included 107 consecutive patients with confirmed PE. The endpoints were (i) PE-related death or major complications and (ii) overall 30-day mortality. Overall, 29 patients (27%) had abnormal (>6 ng/mL) H-FABP levels at presentation. Of those, 12 (41%) had a complicated course, whereas all patients with normal baseline H-FABP had a favourable 30-day outcome (OR, 71.45; P<0.0001). At multivariable analysis, H-FABP (P<0.0001), but not cardiac troponin T (P=0.13) or N-terminal pro-brain natriuretic peptide (P=0.36), predicted an adverse outcome. Evaluation of a strategy combining biomarker testing with echocardiography revealed that patients with a negative H-FABP test had an excellent prognosis regardless of echocardiographic findings. In contrast, patients with a positive H-FABP test had a complication rate of 23.1% even in the presence of a normal echocardiogram, and this rose to 57.1% if echocardiography also demonstrated right ventricular dysfunction (OR vs. a negative H-FABP test, 5.6 and 81.4, respectively). CONCLUSION: H-FABP is a promising early indicator of right ventricular injury and dysfunction in acute PE. It may help optimize risk stratification algorithms and treatment strategies.

Biomarkers↗

PubMed1998

Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer.

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.

Antibiotics, Antineoplastic↗

PubMed2005

Ischemia-modified albumin improves the usefulness of standard cardiac biomarkers for the diagnosis of myocardial ischemia in the emergency department setting.

We studied the role of ischemia-modified albumin (IMA) with standard biomarkers (myoglobin, creatine kinase-MB [CK-MB], troponin I [TnI]) in assessment of 200 patients with suspected myocardial ischemia admitted to the emergency department. Every case was reviewed by a cardiologist. A clinical diagnosis of ischemia was assigned and correlated with biomarker test results. Of the patients, 25 (13.0%) had myocardial ischemia. Receiver operating characteristic curves demonstrated IMA as highly sensitive but somewhat poorly specific for the presence of ischemia (area under curve, 0.63; P = .01). With a cut point of 90 U/mL, the Albumin Cobalt Binding Test had 80% sensitivity and 31% specificity for diagnosing ischemia and a negative predictive value of 92%. IMA was positive in 4 of 5 patients with electrocardiographic (ECG) evidence of ischemia and 16 of 20 patients with coronary ischemia but negative ECG. Among the same patients, the myoglobin-CK-MB-TnI triad had a sensitivity of 57%. The combination of IMA-myoglobin-CK-MB-TnI increased the sensitivity for detecting ischemia to 97%, with a negative predictive value of 92%. IMA is highly sensitive and has a high negative predictive value, which might improve the usefulness of standard biomarkers of myocardial ischemia.

Adult↗

PubMed2002

Detection of environmental androgens: a novel method based on enzyme-linked immunosorbent assay of spiggin, the stickleback (Gasterosteus aculeatus) glue protein.

We report the development and validation of a novel in vivo biomarker test for waterborne androgens. During breeding, male sticklebacks (Gasterosteus aculeatus) manufacture a glue protein, spiggin, in their kidneys that they use to build their nests. Spiggin production is under the control of androgens. Until now, however, it has only been possible to quantify its production by measurement of the height of kidney epithelial cells. In the present study, we report the development of an enzyme-linked immunosorbent assay (ELISA) for spiggin and demonstrate its application to the measurement of spiggin in the kidneys of female sticklebacks that have been exposed to androgens in water. Results from the ELISA procedure revealed a strong correlation with measurement of kidney epithelial cell height (r2 = 0.93). However, the ELISA was much quicker and had a considerably higher response range (100,000-fold vs fourfold). Clear, graded responses in spiggin production were obtained by exposing intact females to increasing concentrations of 17a-methyltestosterone and 5alpha-dihydrotestosterone over three-week test periods. The lowest effective concentrations for these two steroids were 100 ng/L and 3 micorg/L, respectively. Female sticklebacks that were exposed to pulp mill effluent also produced spiggin in their kidneys. Possession of an androgen-regulated protein by the female stickleback makes it a unique bioassay organism for detecting androgenic contamination in the aquatic environment.

Agglutinins↗

PubMed2004

Impact of antiseptics on radical metabolism, antioxidant status and genotoxic stress in blood cells: povidone-iodine versus octenidine dihydrochloride.

No sufficient data are available of the of antiseptics' influence on human blood cells. Effects of two antiseptics, povidone-iodine (PVD-I) versus octenidine dihydrochloride (OD), were tested on antioxidant status, radical formation, antioxidant defence enzymes and genotoxic stress in blood cells, in vitro. Human blood was taken by venipuncture, enriched with PVD-I or OD (0.0001-20% final concentration) and incubated at 37 degrees C between 30 and 120 min. alpha-Tocopherol was assessed in erythrocytes and granulocytes. Superoxide-dismutase (SOD) and glutathione (GSH) were determined in erythrocytes, the total anti-oxidative capacity (TAC) and malondialdehyde (MDA) in their ghosts. In granulocytes status of hydrogen peroxide (H(2)O(2)), superoxide anions and MDA was observed. Genotoxic stress was determined by counting sister chromatide exchanges (SCE) in lymphocytes after enrichment within 0.05-0.4% of antiseptics. Based on all biomarker tested, concentrations up to 0.05% incubated for 30 min did not affect cell metabolism. 1% and 10% PVD-I reduced the activity of SOD (-40%), GSH (-62%) and the content of alpha-tocopherol more than OD (p<0.05). No significant differences between the antiseptics were observed for TAC and MDA. H(2)O(2) and superoxide anions were significantly reduced after the 10% addition for both substances independent on the exposure. Without having changes in lipid oxidation, the reduction of antioxidative defence mechanisms must be due to the oxidation caused by the antiseptics, mainly PVD-I. An increased SCE rate was neither observed with PVD-I nor with OD within an enrichment with 0.05-0.4%. Higher concentrations (1% and more) could not be tested on SCE formation because they caused cell bursts. The results presented indicate that concentrations up to 0.05% incubated for 30 min are safe for exposing blood cells of healthy subjects.

Anti-Infective Agents, Local↗

PubMed2026

AI-driven diagnostic and prognostic models for metabolic dysfunction-associated steatotic liver disease: insights from clinical, imaging, and multi-omics studies-a scoping review.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common chronic liver disease around the world, affecting 33.6% of the adult population (95% CI: 28.1%-39.5%; I 2 = 99.9%), or roughly one in three. The extent of the liver damage is variable, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), cirrhosis and hepatocellular carcinoma (HCC). Early diagnosis is essential to prevent serious liver damage. Traditional diagnostic techniques such as liver biopsy, imaging, and biomarker testing are all invasive, costly, reduced sensitive to early-stage disease, and they also have variability among observers. Modern diagnostic and prognostic approaches based on the principles of Artificial Intelligence (AI) and specifically on machine learning (ML) and deep learning (DL) have enabled multimodal approaches integrating clinical, imaging and molecular data. This scoping review conducted per PRISMA-ScR guidelines, synthesizes findings from 73 studies (search window 2020-2026) across three dimensions: clinical data driven models, imaging-based classifiers (ultrasound, CT and MRI), and multi-omics (genomics, transcriptomics and proteomics) techniques. Moreover, emergence of models such as U-Net and LiverNet 2.x, classification models like DeepLiverNet and BiLSTM models, as well as transformer frameworks and the identification of biomarkers models are also described. This study also investigates challenges such as data heterogeneity, data interpretability, fairness and real-world clinical application. Finally, important areas of research opportunities and future directions are highlighted to present a developing clinically applicable, explainable and ethical AI solutions to manage MASLD.

MASLD↗

PubMed2002

Vitellogenin induction in Cyprinus carpio treated with 17beta-estradiol and 4-nonylphenol.

The aim of the present study was to demonstrate induction of vitellogenin in the common carp (Cyprinus carpio) as a biomarker for monitoring freshwater ecosystems. Sexually undifferentiated specimens of common carp were treated experimentally with 17beta-estradiol and increasing doses of 4-nonylphenol and levels of plasma Vtg were measured in order to: 1) validate an ELISA assay for plasma Vtg in the common carp using the polyclonal rabbit anti-salmon Vtg antibody AA1 (Biosense, Norway); 2) check the sensitivity of carp juveniles in producing Vtg in response to estrogen stimulation. The group treated with 17beta-estradiol showed high induction (156%) with respect to controls, also groups treated with 4-nonylphenol showed induction of Vtg. The group treated with 100 mg kg(-1) b.wt showed an induction of 61%. A statistically significant correlation was found between dose and response. This preliminary study demonstrate a response to the ELISA assay for Vtg in the common carp using rabbit anti-salmon antibody AA1. With further evidence the tested biomarker might be proposed for large scale monitoring of estrogenic effects caused by pollution in urban and industrial effluents.

Animals↗

PubMed2005

Biomarker response and biomass change of earthworms exposed to chlorpyrifos in microcosms.

Background levels of chlorpyrifos and earthworm abundance were determined in an orchard and adjacent areas on a farm in the Western Cape, South Africa before these areas were again sprayed with this organophosphate. The background concentrations ranged from 0.2 microg/kg dm in the spray drift area adjacent to the orchard to 10.18 microg/kg dm on the slope in the run off area. In the target area the chlorpyrifos concentrations varied from a mean of 15.25 +/- 10.0 microg/kg directly after spraying to a mean of 7.0 +/- 0.9 microg/kg 6 months later and in the nontarget area they varied from a mean of 55.0 +/- 35 microg/kg to 12.0 +/- 5 microg/kg after 6 months. Chlorpyrifos was therefore still present in the field soils, but at lower concentrations, up to 6 months after the last spraying event. Earthworm abundance and population densities were very low. Only Aporrectodea caliginosa was found and the densities were much lower in the orchards (22 per m(2)) than in the nontarget areas (98.3 per m(2)). Microcosm studies were undertaken to relate biomarker responses to chlorpyrifos with biomass changes. Microcosms were filled with soil from the same areas and earthworms of the species A. caliginosa were introduced. The microcosms were treated with a series of concentrations of chlorpyrifos in the laboratory under controlled conditions. These concentrations were chosen to fall within the background ranges found in the soils. The biomass of the worms was determined regularly for a period of 5 weeks and worms in a state of estivation were noted. Earthworms were removed from the microcosms for biomarker tests: for cholinesterase (ChE) inhibition assays every week and for a neutral red retention determination 2 weeks after the exposures started. The most prominent biomass loss was noted in earthworms exposed to the highest pesticide concentration of 8.0 microg/kg. Estivation was higher among earthworms exposed to higher exposure concentrations. Inhibition of ChE increased with higher exposure concentrations and with time but there was no clear dose-related response. A clear dose-related response with exposure concentration was established for the neutral red retention assay. A correlation between ChE inhibition and biomass change existed directly after the second application of chlorpyrifos.

Animals↗

PubMed2026

Genomic Analysis and Clinical Correlation of Non-Small Cell Lung Cancer with Special Reference to Brain Metastasis.

BACKGROUND: Next-generation sequencing (NGS) has improved genomic analysis depth in precision oncology. This study analyzed genomic biomarker testing in stage IV NSCLC, focusing on brain metastasis and clinicopathological correlations. OBJECTIVE: To study molecular markers and clinicopathological correlations in stage IV NSCLC patients, with and without brain metastasis. METHODS: A total of 169 stage IV NSCLC patients were studied from April 2023 to May 2025. Demographic data, clinical presentations, and mutation analyses were assessed using NGS on tissue blocks or liquid biopsies. RESULTS: Among 169 patients, 41.42% (n = 70) had brain metastasis (NSCLC-BM), while 58.58% (n = 99) had no brain metastasis (mNSCLC). Median ages were 51.5 and 56 years, respectively. Adenocarcinoma comprised 95.27% (n = 161) of cases. The cerebral hemisphere was the most common intracranial metastatic site, while skeletal involvement was the most common extracranial site. Headache was the predominant neurological symptom. EGFR mutations were the most common overall. EGFR > TP53 > ALK > other mutations were observed in NSCLC-BM, while EGFR > TP53 > KRAS > other mutations were seen in mNSCLC. Mutation analysis stratified by smoking history (χ²(1) = 1.347, p = 0.245) and sex (χ²(1) = 0.0302, p = 0.862) was not statistically significant. The benefit of gefitinib plus chemotherapy in EGFR exon 19 and exon 21 L858R mutations was greater in mNSCLC (log-rank χ²(1) = 10.813, p = 0.001) than in NSCLC-BM (log-rank χ²(1) = 3.100, p = 0.078). Median survival was 11 months (95% CI: 7.506-14.494) for NSCLC-BM versus 21 months (95% CI: 8.365-33.635) for mNSCLC, with a statistically significant difference (log-rank χ²(1) = 8.639, p = 0.003). CONCLUSION: NSCLC-BM showed higher genomic biomarker enrichment (80% vs. 68.68%) but poorer outcomes than mNSCLC. EGFR was the most common targetable mutation, followed by ALK in NSCLC-BM and KRAS in mNSCLC.

Humans↗

PubMed2006

[Alcohol use disorder: risks in anesthesia and intensive care medicine].

Approximately 20% of medical and surgical patients in hospital have an alcohol use disorder (AUD). Diagnosis of chronic alcohol abuse is performed by specific medical history, examination and validated tests. Biomarkers are a means of diagnosing chronic alcoholism in sedated, intubated and emergency patients. Chronic alcohol consumption damages the central nervous and cardiovascular system, the liver and the immune system. In medical ICUs more than 50% of liver injuries and chronic pancreatitis are due to chronic alcohol abuse. The alcohol withdrawal syndrome is emerging in 25% of AUD patients in intensive care after reduction of sedative drugs. Long term alcohol abuse also leads to cardiac arrhythmias, dilatative cardiomyopathy and hypotonic circulatory dysregulation. Bleeding complications are two-fold increased during and after surgery. Immune suppression results in an increased incidence of infectious complications like pneumonia, wound infection and urinary tract infection. In particular, septic encephalopathy is often misinterpreted as alcohol withdrawal syndrome. Due to the fact that AUD patients show a two to five-fold higher rate of postoperative complications they require increased attention to avoid latency of treatment and the development of multiple organ failure. Prophylaxis in terms of drug therapy or abstinence intervals and brief intervention strategies can help to prevent or ease some of these complications and can decrease the rate of long-term injuries.

Alcohol-Induced Disorders↗

PubMed2006

Therapeutic drug monitoring assay development to improve efficacy and safety.

The development of therapeutic drug management (TDM) utilizing diagnostic assays as biomarker tests is described. TDM can be useful in establishing an individual patient's optimal blood concentration range, and benchmarking blood concentrations at which seizures are controlled, as well as those associated with AED-specific adverse effects. TDM requires the application of pharmacokinetic, pharmacodynamic, pharmacogenomic, pathophysiological and clinical principles to the management of patients in order to achieve safe and effective therapy. Optimal therapy requires rational application of all these principles to personalize patient care.

Anticonvulsants↗

PubMed2005

N-Methylenvaline in a group of subjects occupationally exposed to formaldehyde.

Aim of this pilot study was to correlate the human exposure to formaldehyde (F) with N-methylenvaline, a molecular adduct formed by addiction of F to the N-terminal valine in hemoglobin. A group of 21 subjects employed in a plywood factory and a laminate factory, and occupationally exposed to F, together with a group of 30 controls, were recruited as volunteers to test this biomarker. Each subject received a questionnaire and a passive personal F sampler. Exposure to F vapors and occurrence of N-methylenvaline in blood were measured. Integrated F concentrations always proved lower than threshold limit value as a ceiling (TLV-TWA) (0.37 mg/m(3), 0.3 ppm). N-Methylenvaline distribution in blood, as measured by GC/MS upon derivatization, showed direct positive relationship to F exposure, with r=0.465. Prevalence of the molecular adduct expressed in nmol/g of globin was significantly higher in the exposed group (p<0.04) than in the control group. However, the N-methylenvaline marker was unable to provide significant distinction between the subjects exposed to F through tobacco smoke habit and the non smokers. Despite this interference, in this pilot study the usefulness of N-methylenvaline as a biomarker for testing occupational exposure to F was demonstrated.

Adult↗

PubMed2000

Inter- and intra-individual variation of faecal water - genotoxicity in human colon cells.

Exogenous nutritional factors modulate the faecal contents leading to an enhanced or reduced burden with toxic and cancerogenic factors. These factors are thought to contribute to colon cancer by inducing mutations or enhancing proliferation in colon cells. Faecal water more or less causes these effects in model systems and thus could be the basis for valuable biomarker approaches. Our investigations are aimed at determining geno- and cytotoxicity of faecal water in human colon cell lines in vitro. We are developing techniques for their applicability as biomarker tests during dietary intervention studies. Faecal water is isolated by centrifugation of the faeces at 25000xg and added to cultured human colon cells (HT29). Membrane damage as assessed by trypan blue exclusion is determined as a measure for cytotoxicity. Semiquantitative analysis of inducible DNA damage (breaks and alkali labile sites) are analysed with the single cell microgelelectrophoresis assay (comet-assay) and oxidised DNA bases by the additional use of repair specific enzymes. We have now determined baseline toxic activities and calculated inter- and intra-individual and -experimental coefficients of variation for faecal water from different subjects consuming similar or different diets. Most faecal water induced DNA damage and oxidised DNA bases in HT29 clone 19a cells (0.9-9.14 fold and 1.7-4.9 fold, respectively in comparison to the NaCl controls). Intra- and inter-experimental coefficients (CV) of variation, were in a similar order of magnitude and ranged from 6.9 to 31.4. In contrast both intra- and inter-individual variability were considerably higher (CV-ranges of 29.7-76.6 and 21.3-64.0, respectively). Interestingly, these inter-individual values were not lowered when subjects consumed identical diets (CV-ranges of 28.4-126.0). However, following intervention with certain protective dietary regimens (e.g. lignan containing bread) significant reductions of faecal water-induced genotoxicity can be observed. Therefore, in spite of the expected and observed degrees of variation in this methodology, effective experimental protocols may still lead to detectable modulations of the level of toxic and genotoxic effects.

Adult↗

PubMed2001

Accumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats.

Although a number of increased CSF proteins have been correlated with brain damage and outcome after traumatic brain injury (TBI), a major limitation of currently tested biomarkers is a lack of specificity for defining neuropathological cascades. Identification of surrogate biomarkers that are elevated in CSF in response to brain injury and that offer insight into one or more pathological neurochemical events will provide critical information for appropriate administration of therapeutic compounds for treatment of TBI patients. Non-erythroid alpha II-spectrin is a cytoskeletal protein that is a substrate of both calpain and caspase-3 cysteine proteases. As we have previously demonstrated, cleavage of alpha II-spectrin by calpain and caspase-3 results in accumulation of protease-specific spectrin breakdown products (SBDPs) that can be used to monitor the magnitude and temporal duration of protease activation. However, accumulation of alpha II-spectrin and alpha II-SBDPs in CSF after TBI has never been examined. Following a moderate level (2.0 mm) of controlled cortical impact TBI in rodents, native alpha II-spectrin protein was decreased in brain tissue and increased in CSF from 24 h to 72 h after injury. In addition, calpain-specific SBDPs were observed to increase in both brain and CSF after injury. Increases in the calpain-specific 145 kDa SBDP in CSF were 244%, 530% and 665% of sham-injured control animals at 24 h, 48 h and 72 h after TBI, respectively. The caspase-3-specific SBDP was observed to increase in CSF in some animals but to a lesser degree. Importantly, levels of these proteins were undetectable in CSF of uninjured control rats. These results indicate that detection of alpha II-spectrin and alpha II-SBDPs is a powerful discriminator of outcome and protease activation after TBI. In accord with our previous studies, results also indicate that calpain may be a more important effector of cell death after moderate TBI than caspase-3.

Animals↗