[Immunologic tests: Cryptosporidium].
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Animals↗
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Interleukin 6 and interleukin 8 as potential biomarkers for oral cavity and oropharyngeal squamous cell carcinoma.
BACKGROUND: Since morbidity and mortality rates due to oral cavity and oropharyngeal squamous cell carcinoma (OSCC) have improved little in the past 30 years, early detection or prevention of this disease is likely to be most effective. Using laser-capture microdissection, we have identified the expression of 2 cellular genes that are uniquely associated with OSCC: interleukin (IL) 6 and IL-8. These cytokines may contribute to the pathogenesis of this disease, and have been linked with increased tumor growth and metastasis. OBJECTIVES: To investigate whether IL-6 and/or IL-8 could serve as informative biomarkers for OSCC in saliva and/or serum and to determine if there is a role for saliva as a diagnostic medium for OSCC. PATIENTS AND METHODS: Patients with newly diagnosed T1 or T2 oral cavity or oropharyngeal histologically confirmed squamous cell carcinoma were recruited for the study. Age and sex-matched disease-free subjects were used as controls. Using quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay, we respectively assessed the expression of IL-6 and IL-8 in serum (controls, n = 32; patients with OSCC, n = 19) and saliva (controls, n = 32; patients with OSCC, n = 32) at the messenger RNA (mRNA) and protein levels. MAIN OUTCOME MEASURES: Specificity and sensitivity of these biomarkers for OSCC and their predictive value. RESULTS: Interleukin 8 was detected at higher concentrations in saliva (P<.01) and IL-6 was detected at higher concentrations in serum of patients with OSCC (P<.01). We confirmed these results at both the mRNA and the protein levels, and the results were concordant. The concentration of IL-8 in saliva and IL-6 in serum did not appear to be associated with sex, age, or alcohol or tobacco use (P>.75). Using statistical analysis, we were able to determine the threshold value, sensitivity, and specificity of each biomarker, as well as a combination of biomarkers, for detecting OSCC. CONCLUSIONS: Our findings indicate that IL-8 in saliva and IL-6 in serum hold promise as biomarkers for OSCC. A saliva-based test could be a cost-effective adjunctive tool in the diagnosis and follow-up of patients with OSCC.
Adult↗
Detecting a field gradient of PAH exposure in decapod crustacea using a novel urinary biomarker.
Norwegian coastal waters are subject to PAH contamination from electrochemical industries such as aluminium smelters. Evidence of PAH exposure has been established in fish and bivalves. The present study tests the applicability of a novel crustacean PAH exposure biomarker to a PAH contamination gradient in the field (Karmsund Strait, SW Norway). Fluorescence analysis of urine samples collected from crabs at each site revealed 1-OH pyrene "equivalent" levels (indicative of pyrogenic PAH contamination) decreased with increasing distance from a point source of pyrogenic PAH (a large aluminium works). The assay was shown to be suitable for the detection of PAH exposure in wild crustacean populations, for discriminating between contaminated and clean sites and is also sufficiently sensitive to detect gradients of PAH contamination. The method provides a rapid, inexpensive and non-destructive measure of biologically available PAH in crustaceans.
Animals↗
Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical.
Red meat consumption is associated with endogenous metabolic generation of mutagenic N-nitroso compounds (NOC) and may be implicated in causation of colorectal cancer. Assessment of a biologically relevant dose of NOCs is hampered by imperfect understanding of NOC interactions with other dietary components. This study tests the hypothesis that NOC effects upon mutational biomarkers in mouse colon may be modulated by a non-genotoxic diet-related compound. N-methyl-N-nitrosourea (MNU) and undegraded lambda carrageenan (lambdaCgN) were selected as test chemicals, representing a NOC and a non-genotoxic agent, respectively. Study end-points included (i) DNA adduct formation and (ii) metallothionein (MT) crypt restricted immunopositivity indices (MTCRII) which are considered representative of crypt stem cell mutations. Frequency and size of MT immunopositive foci as well as total number of MT immunopositive crypts were assessed. Biologically effective doses of MNU and lambdaCgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous lambdaCgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, lambdaCgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of lambdaCgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous lambdaCgN regimens had greater interactive effects with MNU upon MTCRII than short-term lambdaCgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound (lambdaCgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.
Alkylating Agents↗
[99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease.
BACKGROUND: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD). OBJECTIVE: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD. METHODS: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated. RESULTS: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant. CONCLUSIONS: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.
Agnosia↗
Perspective on RET proto-oncogene and thyroid cancer.
Much is yet to be learned about cancer and its genetic basis. The discovery of the RET proto-oncogene and its role in tumorigenesis have improved our understanding of thyroid cancer. It is clear that RET is responsible for MEN 2A, MEN 2B, FMTC, and PTC. Although the physical and genetic map of the RET proto-oncogene has been elucidated, the precise mechanism of neoplastic transformation and how it affects phenotypic variability is not completely understood. From the precise mapping of RET arose a highly reliable method of DNA analysis for presymptomatic detection of disease allele carriers. The understanding of the role of the RET proto-oncogene in MEN syndromes has led to a new paradigm in surgical practice: the recommendation for surgery based solely on genetic testing.
Biomarkers↗
Breast cancer prevention trials using retinoids.
Retinoids have been studied as chemopreventive agents in clinical trials. Given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide has extensively been investigated because of its favorable toxicological profile in humans. In a phase III secondary prevention trial, fenretinide showed a trend to a reduction of second breast malignancies in premenopausal women but not in postmenopausal women. This pattern was associated with a similar modulation of circulating IGF-I. A trend towards a reduction of ovarian cancer was also noted. Biomarker studies of fenretinide or novel selective retinoids alone and in combination with different nuclear receptor ligands are being conducted. These studies provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women, and offer clues as to both the pathophysiology of carcinogenesis and the drug mechanisms of action, and help select new compounds and doses for testing in large randomized studies.
Anticarcinogenic Agents↗
Neurotoxicity of active compounds--establishment of hESC-lines and proteomics technologies for human embryo- and neurotoxicity screening and biomarker identification.
Pharmaceutical and chemical industries are facing new challenges for hazard and risk assessment from regulatory agencies. Especially for potential embryotoxicity of active compounds, conclusions from animal testing remain problematic due to numerous species-specific effects. Developmental toxicity screening preferentially should be performed with human material. Appropriate models are scarce or missing, and the development of a human in vitro model for the molecular characterisation of embryotoxic effects appears to be highly desirable. The outstanding advantages of a human embryonic stem cell (hESC) based in vitro screening model for embryonic neurotoxicity become clear from corresponding results from a murine ESC-screening system. This in vitro test system is based on neuronal differentiated murine embryonic stem cells and quantitative differential proteomic display techniques to identify biomarkers for neurotoxicity. Results are superior to those of conventional array technologies (nucleic acids), because the proteomic analysis covers posttranslational modifications. Under the new strict guidelines for stem cell importation of the German Ministry of Health and a Central Ethics Commission for Stem Cell Research, it is now possible for the first time to exploit the outstanding features of human embryonic stem cells to establish an innovative screening method for embryo- and neurotoxicity and to identify toxicity biomarkers without using animal-based in vitro or in vivo systems.
Animal Testing Alternatives↗
Changes in serum alpha2u-globulin levels in castrated male rats treated with testosterone propionate in a Hershberger assay.
The Hershberger assay has been proposed as a candidate screening test method for the detection of androgenic and anti-androgenic chemicals and is being validated presently under the test guideline programme of the Organization for Economic Cooperation and Development (OECD). Rat alpha2u-globulin is male rat-specific protein appearing in their serum and urine, and the protein is known to be induced by androgens. We investigated the usefulness of measuring serum alpha2u-globulin levels as a parameter for the androgenic activity of chemicals tested in the Hershberger assay. The serum alpha2u-globulin level was measured after the administration of testosterone propionate at dosages of 0, 20, 100 or 500 microg kg(-1) day(-1) for ten consecutive days in the castrated male rats. The ventral prostate, balbocavernosus/levator ani muscles, glans penis and Cowper's gland were collected and weighed. Although all the androgen-responsive organ weights were increased significantly at dosages of 100 and 500 microg kg(-1) day(-1), the serum alpha2u-globulin level was increased significantly only at a dosage of 500 microg kg(-1) day(-1). These results show that the serum alpha2u-globulin level may be a useful biomarker for detecting androgenic activity caused by test chemicals, but it is less sensitive than the organ weights of androgen-responsive tissues in the Hershberger assay.
Alpha-Globulins↗
Proteomics for hepatocellular carcinoma marker discovery.
Refinements of serological markers and screening of patients at high risk for developing hepatocellular carcinoma (HCC) may lead to better HCC detection, earlier intervention, and successful treatment, improving long-term outcomes. Proteomics promises the discovery of biomarkers for early HCC detection and diagnosis. Proteomic-based profiling uniquely allows delineation of global changes in expression patterns resulting from transcriptional and posttranscriptional control, posttranslational modifications, and shifts in proteins between cellular compartments. Approaches to that effect include direct serum protein profiling and comparative analysis of protein expression in normal, precancerous, and early-stage tumor tissues. Identification of panels of tumor antigens that elicit a humoral response also may contribute to the discovery of new markers for HCC screening and diagnosis. Today, 2-dimensional polyacrylamide gel electrophoresis, multidimensional liquid chromatography, mass spectrometry, and protein microarrays are among the proteomic tools available for biomarker and drug target discovery. We review these technologies and their application to the study of HCC. Our objective is to provide a framework for appreciating the promise, while at the same time understanding the challenges behind translating proteomics discovery into novel diagnostic tests.
Biomarkers, Tumor↗
Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.
Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.
Acute Kidney Injury↗
Volatile biomarkers of pulmonary tuberculosis in the breath.
Pulmonary tuberculosis may alter volatile organic compounds (VOCs) in breath because Mycobacteria and oxidative stress resulting from Mycobacterial infection both generate distinctive VOCs. The objective of this study was to determine if breath VOCs contain biomarkers of active pulmonary tuberculosis. Head space VOCs from cultured Mycobacterium tuberculosis were captured on sorbent traps and assayed by gas chromatography/mass spectroscopy (GC/MS). One hundred and thirty different VOCs were consistently detected. The most abundant were naphthalene, 1-methyl-, 3-heptanone, methylcyclododecane, heptane, 2,2,4,6,6-pentamethyl-, benzene, 1-methyl-4-(1-methylethyl)-, and cyclohexane, 1,4-dimethyl-. Breath VOCs were assayed by GC/MS in 42 patients hospitalized for suspicion of pulmonary tuberculosis and in 59 healthy controls. Sputum cultures were positive for Mycobacteria in 23/42 and negative in19/42 patients. Breath markers of oxidative stress were increased in all hospitalized patients (p<0.04). Pattern recognition analysis and fuzzy logic analysis of breath VOCs independently distinguished healthy controls from hospitalized patients with 100% sensitivity and 100% specificity. Fuzzy logic analysis identified patients with positive sputum cultures with 100% sensitivity and 100% specificity (95.7% sensitivity and 78.9% specificity on leave-one-out cross-validation); breath VOC markers were similar to those observed in vitro, including naphthalene, 1-methyl- and cyclohexane, 1,4-dimethyl-. Pattern recognition analysis identified patients with positive sputum cultures with 82.6% sensitivity (19/23) and 100% specificity (18/18), employing 12 principal components from 134 breath VOCs. We conclude that volatile biomarkers in breath were sensitive and specific for pulmonary tuberculosis: the breath test distinguished between "sick versus well" i.e. between normal controls and patients hospitalized for suspicion of pulmonary tuberculosis, and between infected versus non-infected patients i.e. between those whose sputum cultures were positive or negative for Mycobacteria.
Adult↗
Insights from changes in NDEV biomarkers of metabolism: effects of PPARγ and GLP1 receptor agonists on brain metabolism.
BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD). METHODS: We analyzed biological samples from two cohorts of clinical trial participants: (1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and (2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups. RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all P ≤ .02) compared with placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; P = .04 and P = .025, respectively) compared with placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test. DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.
Humans↗
Nanoparticles: potential biomarker harvesters.
A previously untapped bank of information resides within the low molecular weight proteomic fraction of blood. Intensive efforts are underway to harness this information so that it can be used for early diagnosis of diseases such as cancer. The physicochemical malleability and high surface areas of nanoparticle surfaces make them ideal candidates for developing biomarker harvesting platforms. Given the variety of engineering strategies afforded through nanoparticle technologies, a significant goal is to tailor nanoparticle surfaces to selectively bind a subset of biomarkers, sequestering them for later study using high sensitivity proteomic tests. To date, applications of nanoparticles have largely focused on imaging systems and drug delivery vectors. As such, biomarker harvesting is an underutilized application of nanoparticle technology and is an area of nanotechnology research that will likely undergo substantial growth.
Biomarkers↗
Sensitivity and specificity of mass screening for gastric cancer using the measurment of serum pepsinogens.
The aim of this study was to estimate the validity of mass screening for gastric cancer using serum pepsinogens (PG test). The study subjects were 4876 workers aged from 40 to 61 years old. Sera were obtained at the time of the health checkup and serum pepsinogen levels (PG I and PG II) were measured at the same time. PG I < 50 ng/ml and PG I/PG II ratio < 3.0 were adopted as the criteria for a positive result for the PG test. PG test-positive subjects were examined, in principle, by endoscopy. Furthermore, all subjects were followed up for a year to check for occurrence of gastric cancer. Among the total subjects, 911 (18.7%) were positive for the PG test and 650 (71.4%) among the positive subjects underwent further examinations, which revealed 11 cases of gastric cancer. Seven gastric cancer cases were diagnosed during the follow-up period within one year after the PG test. When the results of one years's follow-up from the time of screening were defined as the gold standard, the sensitivity and specificity of the PG test were estimated at 66.7% and 81.5%, respectively. The authors conclude that the validity of the PG test as a mass screening method may be comparable to that of X-ray screening, if optimum criteria of a positive test are selected.
Adult↗
Enhanced Prediction of Peripheral Artery Disease Using Plasma Proteomics Among Individuals Without Diabetes.
BACKGROUND: Although peripheral artery disease (PAD) is an important diabetes complication, a substantial proportion of cases occur among individuals without diabetes. This study aimed to assess the predictive value of plasma proteomics in the long-term risk of PAD among individuals initially free of diabetes. METHODS: Included were 46 508 participants (6046 with prediabetes) without diabetes or major cardiovascular disease at recruitment of the UK Biobank. Using multivariable Cox regression models, a total of 2923 unique plasma proteins were assessed for the associations with incident PAD. Significant proteins were subsequently processed by a trained light gradient boosting machine classifier to determine important proteins. Using receiver operating characteristic analyses, the performance of these important proteins in predicting incident PAD were evaluated, in the whole sample and by glycemic status (normoglycemia and prediabetes). RESULTS: During a median follow-up of 12.7 years, 461 participants developed PAD. There were 107 proteins associated with incident PAD, with 103 positive associations. The LGBM approach identified 9 proteins (eg, WFDC2 [WAP 4-disulfide core domain protein 2], MMP12 [macrophage metalloelastase], and GDF15 [growth differentiation factor 15]) as the top-ranked proteins based on their importance ordering. Whereas glycated hemoglobin showed very modest predictive accuracy, a panel incorporating these top proteins showed good performance in the prediction of PAD risk (area under the curve 0.820), and it significantly enhanced the prediction beyond traditional risk factors (raising area under the curve from 0.803 to 0.837, DeLong test P=5.21×10-3). These observations were consistent for participants with normoglycemia or prediabetes. CONCLUSIONS: Plasma protein biomarkers enhance the prediction of long-term risk for PAD among individuals without diabetes, regardless of glycemic status.
Humans↗
Monitoring clinical changes in patients with heart failure: a comparison of methods.
BACKGROUND: Although monitoring the clinical status of patients with heart failure rests at the core of clinical medicine, the ability of different techniques to reflect clinical change has not been evaluated. This study sought to describe changes in various measures of disease status associated with gradations of clinical change. METHODS: A prospective, 14-center cohort of 476 outpatients was assessed at baseline and 6 +/- 2 weeks to compare changes in 7 heart failure measures with clinically observed change. Measures included health status instruments (the Kansas City Cardiomyopathy Questionnaire [KCCQ], Short Form-12, and EQ-5D), physician-assessed functional class (New York Heart Association [NYHA]), an exercise test (6-minute walk), patient weight, and a biomarker (B-type natriuretic peptide). Cardiologists, blinded to all measures except weight and NYHA, categorized clinical change ranging from large deterioration to large improvement. RESULTS: The KCCQ, NYHA, and 6-minute walk test were most sensitive to clinical change. For patients with large, moderate, and small deteriorations, the KCCQ decreased by 25 +/- 16, 17 +/- 14, and 5.3 +/- 11 points, respectively. For patients with small, moderate, and large improvements, the KCCQ increased by 5.7 +/- 16, 10.5 +/- 16, and 22.3 +/- 16 points, respectively (P < .01 for all compared with the no change group). New York Heart Association and 6-minute walk distance were significantly different for those with moderate and large changes (P < .05) but neither revealed a difference between those with small versus no clinical deterioration. The KCCQ had the highest c statistic for monitoring individual patients, followed by NYHA and 6-minute walk. CONCLUSION: The KCCQ, followed by the NYHA and the 6-minute walk test, most accurately reflected clinical change in patients with heart failure.
Diagnostic Tests, Routine↗
New laboratory tests in acute pancreatitis.
Acute pancreatitis (AP) is a common disease with wide variation of severity. The diagnosis of AP is usually based on high serum amylase or lipase values but the accuracy of these methods is considered unsatisfactory. One in five of the patients develops a severe disease and carries a considerable risk of development of organ failure and high mortality. Early detection of patients with severe AP and especially those with increased risk of organ failure is importance since such patients seem to benefit from treatment in an intensive care unit started as soon as possible after presentation. In addition to enzymological methods, increasing interest has been focused on laboratory markers reflecting the level of inflammatory response in AP. At present, in routine clinical work the most commonly used severity marker is serum C-reactive protein, the concentration of which rises too slowly to be used for early prediction of severity. New therapies aiming at modifying the course of systemic inflammation in AP are being developed and therefore monitoring the patient's immune inflammatory status is needed. In this review article we present the current knowledge of laboratory tests, which has been evaluated for diagnostic and prognostic purposes in AP.
Biomarkers↗