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Results for “Biomarker variability”

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PubMed2001

Primary biliary cirrhosis: modalities of injury and death in biliary epithelium.

BACKGROUND/AIM: Despite the number of studies on primary biliary cirrhosis, contrasting data remain concerning modalities of cholangiocyte death. Liver biopsies obtained from 40 patients with anti mitochondrial antibody-positive primary biliary cirrhosis, at various stages of the disease, were examined, and special attention was paid to the expression of subcellular damage and evidence of apoptosis. METHODS: Liver sections were stained with haematoxylin/eosin or Sirius red. Ductular mass was evaluated on sections after cytokeratin 7 staining. Apoptosis was evaluated on haematoxylin/eosin stained material or after processing for terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling assay. In 16 patients, part of the biopsy was processed for electron microscopy. Twenty histologically normal liver biopsies were used for control purposes. RESULTS: According to Scheuer's classification, 29 patients were classified as stage I-II, and 11 as stage III-IV. A strong staining of bile ducts was evident after immunohistochemistry for cytokeratin 7, often associated with ductular metaplasia in lobular zone 1. Cytokeratin 7-positive cells occupied 3.0+/-1.3% of liver mass as compared to 0.25+/-0.03% in controls. Ductular metaplasia accounted for 1.4+/-0.07% of all cytokeratin 7-positive cells. Regardless of staging, apoptotic bodies were seen only exceptionally in epithelial wall of bile ducts, whereas cholangiocyte damage leading to extensive lytic necrosis appeared responsible for most of the bile duct mass loss, as also confirmed by ultrastructural studies. A few terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling-positive nuclei were occasionally associated with the inflammatory infiltrate and evidence of apoptosis in hepatocytes was frequent, especially in zone 1. CONCLUSION: Regardless of staging, lytic necrosis and not apoptosis accounts for most of the bile duct loss in primary biliary cirrhosis. Furthermore, ductular metaplasia appears as a late event with highly variable pattern being observed between patients.

Apoptosis↗

PubMed2004

Does urinalysis predict acute renal failure after heart surgery?

Acute renal failure (ARF) usually develops in 5% to 30% of patients undergoing heart surgery and is associated with a more complicated clinical evolution course and with an excessive mortality of up to 80%. The objective of this study was to verify the frequency of ARF in postoperative coronary artery bypass surgery with and without cardiopulmonary bypass, by the evaluation of renal function markers' performance [plasma creatinine, plasma urea, urinalysis, fractional excretion of sodium, creatinine clearance and Alpha-glutathione S-transferase (alpha-GST)], besides to verify possible relations between clinical variables involved in postoperative heart surgery and the occurrence of renal insufficiency.

Acute Kidney Injury↗

PubMed2001

Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients.

Protease genotype, as a variable in outcome to combination therapy for human immunodeficiency virus (HIV) type 1 infection, was evaluated among protease inhibitor-naive children and adolescents who had received extensive treatment with reverse-transcriptase inhibitors. After 24 weeks of combination therapy, 35% had viral and immune success (VSIS patients), 19% had viral and immune failure (VFIF patients), and 46% had viral failure but marked improvement in CD4 T cells (VFIS patients). Disease stage was the only pretherapy clinical variable associated with outcome (P=.02). Although reverse-transcriptase genotype was unrelated to outcome, pretherapy protease genotype was related significantly to therapy response (P=.005). Odds for immune or viral failure were 17.7 to 1 and 2.5 to 1, respectively, for protease genotype as a single variable. Protease genotype combined with disease stage and CD4 cell percentage predicted correct therapy response for 81% of patients (100% of VFIF, 78% of VSIS, and 75% of VFIS patiens). Naturally occurring amino acid polymorphisms in protease provide sensitive biomarkers for treatment response among inhibitor-naive patients with advanced HIV disease.

Adolescent↗

PubMed2003

Prognostic models in patients with non-small-cell lung cancer using artificial neural networks in comparison with logistic regression.

It is difficult to precisely predict the outcome of each individual patient with non-small-cell lung cancer (NSCLC) by using conventional statistical methods and ordinary clinico-pathological variables. We applied artificial neural networks (ANN) for this purpose. We constructed a prognostic model for 125 NSCLC patients with 17 potential input variables, including 12 clinico-pathological variables (age, sex, smoking index, tumor size, p factor, pT, pN, stage, histology) and 5 immunohistochemical variables (p27 percentage, p27 intensity, p53, cyclin D1, retinoblastoma (RB)), by using the parameter-increasing method (PIM). Using the resultant ANN model, prediction was possible in 104 of 125 patients (83%, judgment ratio (JR)) and accuracy for prediction of survival at 5 years was 87%. On the other hand, JR and survival prediction accuracy in the logistic regression (LR) model were 37% and 78%, respectively. In addition, ANN outperformed LR for prediction of survival at 1 or 3 years. In these cases, PIM selected p27 intensity and cyclin D1 for the 3-year survival model and p53 for the 1-year survival model in addition to clinico-pathological variables. Finally, even in an independent validation data set of 48 patients, who underwent surgery 10 years later, the present ANN model could predict outcome of patients at 5 years with the JR and accuracy of 81% and 77%, respectively. This study demonstrates that ANN is a potentially more useful tool than conventional statistical methods for predicting survival of patients with NSCLC and that inclusion of relevant molecular markers as input variables enhances its predictive ability.

Adenocarcinoma↗

PubMed2026

Spatial Proteomic Profiling, a Novel Method for Detecting Diagnostic and Prognostic Proteins in Pediatric Sarcoma.

Pediatric sarcomas comprise approximately 10% of all childhood solid malignancies and are characterized by distinct genetic and proteomic alterations that have potential diagnostic, prognostic, and therapeutic significance. We have utilized digital spatial profiling (DSP) to identify protein expression in pediatric Ewing sarcoma (ES), Osteosarcoma (OS), Alveolar rhabdomyosarcoma (ARMS), and Embryonal rhabdomyosarcoma (ERMS), in association with clinical outcomes. Formalin-fixed, paraffin-embedded sections from a tissue microarray block containing eight ES, eight OS, five ARMS, and three ERMS cases were subjected to proteomic DSP on a GeoMx NanoString platform yielding information on expression of 580 proteins. Proteins related to epigenetic regulation, signaling pathways, and mesenchymal differentiation were broadly expressed across all tumor types. Tumor-specific protein profiles were defined based on highly expressed proteins. Differentially expressed proteins include Cyclin D1 in ES, S100A4 in OS and IKKi/IKKe in ARMS and ERMS. Immunohistochemical validation confirmed variable expression of H3K27me3 across the tumors, and elevated expression of Cyclin D1 in ES and S100 in OS. These findings underscore the utility of DSP as a high-resolution proteomic tool for the identification of clinically relevant biomarkers in pediatric sarcomas. The results provide a foundation for further investigation of candidate proteins with potential diagnostic, prognostic, and therapeutic applications.

Humans↗

PubMed2002

Vascular endothelial growth factor expression in airways of patients with lung cancer: a possible diagnostic tool of responsive angiogenic status on the host side.

STUDY OBJECTIVE: We evaluated the expression of vascular endothelial growth factor (VEGF) in airways in patients with lung cancer. METHODS: BAL fluid (BALF) and plasma samples were obtained from 41 patients with primary lung carcinomas and 7 patients with noncancerous diseases, and were analyzed for VEGF by an enzyme-linked immunosorbent assay. After standardization with the albumin protein levels, the relative intensity (VEGF index) was determined as the ratio of VEGF expression on the disease side to that on the healthy side. RESULTS: In all cases, VEGF concentrations in BALF were greater than those in plasma samples. On the healthy side, the mean value of VEGF in BALF was significantly greater in lung cancer patients than in patients with noncancerous diseases (p = 0.0470). While age, gender, location of cancer (right vs left), histology (adenocarcinoma vs squamous cell carcinoma), and T factor (T1/2 vs T3/4) did not affect the VEGF levels in BALF, the VEGF index was inversely associated with distant metastasis and nodal involvement. The VEGF index of patients in stage I was significantly greater than that of patients in stage IV (p = 0.0308). CONCLUSIONS: The VEGF expression in airways is likely to reflect the response to tumor angiogenesis on the host side. Of direct clinical relevance is that the assessment of VEGF concentrations in airways may provide information concerning the dependency of tumor angiogenesis on VEGF, which is variable according to tumor progression.

Adenocarcinoma↗

PubMed1989

Quantitative relationship between plasma lipids and glycohemoglobin in type I patients. Longitudinal study of 212 patients.

Plasma cholesterol, triglycerides, glycohemoglobin, and other covariates were measured in 212 type I (insulin-dependent) diabetic subjects on entry into a longitudinal study of diabetes and again after an average interval of 3.7 yr. Changes in individual cholesterol and triglyceride values over time were significantly correlated with changes in glycohemoglobin. After adjustment for potentially confounding covariates, plasma cholesterol declined by 2.2% (0.1 mM) for each percentage-point reduction in glycohemoglobin and plasma triglycerides declined by 8% (0.08 mM) per percentage point glycohemoglobin. Increased insulin dose was independently associated with increased plasma triglycerides, after adjusting for glycohemoglobin level and other covariates. However, insulin dose diabetic metabolic control, measured as declining glycohemoglobin, is the variable most closely associated with reduced plasma lipids in a population of typical type I diabetic patients.

Biomarkers↗

PubMed1993

Postoperative course of functional and cellular variables in liver resection.

The determination of total serum bile acids (BA) is a sensitive variable for detection of altered liver function. This study investigated the course of serum bile acids in 44 liver-resected patients with different factors possibly compromising liver function. These factors were 1) amount of resected parenchyma; 2) duration of intraoperative ischemia; and 3) patient's age. The course of BA was compared with that of transaminases, bilirubin, lactate, and NH3. Serum BA showed a course correlated to the amount of resected liver parenchyma and differentiated between groups with < or = 35% and > 35% resected parenchyma. Whereas BA were more accurate in paralleling the resected tissue in the first postoperative days, a rise of bilirubin indicated complications in the postoperative course. As BA did not increase in a case of pulmonary-induced multiorgan failure, the specificity of this variable for liver function is implied. Different amounts of resection could not be distinguished by determination of transaminases. Different ischemic periods did not result in significant differences in the postoperative course of BA or bilirubin. However, marked elevations of transaminases depending on the duration of hepatic inflow occlusion were seen. None of the traced variables were related to the patient's age.

Adolescent↗

PubMed1999

Separation of distinct MUC2 mucin glycoforms using two anti-peptide monoclonal antibodies.

Two monoclonal antibodies (MAb996 and MAb994) were produced by immunisation with a synthetic peptide with a sequence based upon that of the protein core of the gastrointestinal MUC2 mucin. The epitopes were identified as T G T Q for MAb996 and P T G T Q for MAb994. Antibody competition tests also confirmed the overlapping nature of the epitopes for the two antibodies. MAb994 and MAb996 were employed in immunoadsorbent columns for the fractionation of human colorectal carcinoma tissue extracts. While the two antibodies displayed only relatively minor differences in immunological specificity and affinity for the immunising synthetic MUC2 mucin core related peptide, they had the capacity to separate antigenically distinct molecules when used as immunoadsorbents. The findings indicated that subfractions of MUC2 antibody-defined mucins exist in human carcinomas and that these may be distinguished by the differential exposure of determinants in the mucin protein core. The results are in accord with the view that aberrant patterns of glycosylation of mucins in human intestinal tumours produces a spectrum of variably glycosylated macromolecules.

Amino Acid Sequence↗

PubMed2002

Biological risk factors for deep vein trombosis.

Hypercoagulable states due either to inherited or acquired thrombotic risk factors are only present in approximately half of cases of DVT, but the causes in the other half, remain unknown. The importance of biological risk factors such as hyperlipidemia, hypofibrinolysis and hemorheological alterations in the pathogenesis of DVT has not been well established. In order to ascertain whether the above mentioned biological factors are associated with DVT and could constitute independent risk factors, we carried out a case-control study in 109 first DVT patients in whom inherited or acquired thrombophilic risk factors had been ruled out and 121 healthy controls age (42+/-15 years) and sex matched. From all the biological variables analyzed (cholesterol, triglycerides, glucose, fibrinogen, erythrocyte aggregation, hematocrit, plasma viscosity and PAI-1) only fibrinogen concentration reached a statistically significant difference on the comparison of means (290+/-73 mg/dl in cases vs 268+/-58 mg/dl in controls, p<0.05). After this continuous variables were dichotomized according to our reference values, the percentage of cases with cholesterolemia >220 mg/dl, hematocrit >45% and fibrinogen >300 mg/dl was higher in cases than in controls: 38% vs 22%; p<0.01; 43% vs 27%; p<0.05; 36% vs 23%; p<0.05, respectively. The percentage of cases with PAI-1 values >30 ng/ml, 37% vs 25% was borderline significant; p=0.055. Multivariate logistic regression analysis showed that cholesterolemia >220 mg/dl and fibrinogen >300 mg/dl constitute independent predictors of venous thrombotic risk. The adjusted OR's were 2.03 (95% CI; 1.12-3.70) for cholesterolemia and 1.94 (95% CI; 1.07-3.55) for fibrinogen. When these two variables combined DVT risk rose about fourfold (3.96; p<0.05). Our results suggest that hypercholesterolemia and hyperfibrinogenemia should be added to the list of known DVT risk factors and we recommend adopting measures to decrease these variables in the population with a high risk of DVT.

Biomarkers↗

PubMedDate not supplied

Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome.

The elevated RNase L enzyme activity observed in some Chronic Fatigue Syndrome (CFS) patients may be linked to the low exercise tolerance and functional impairment that typify this disease. The purpose of this investigation was to determine if specific indicators of physical performance can predict abnormal RNase L activity in CFS patients. Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. This measure was employed as the dependent variable in a discriminant function analysis, with peak V02, exercise duration and Karnofsky Performance Scores (KPS) serving as the independent variables. All three variables entered the single significant function (p < 0.001). The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. The results suggest that both exercise testing and the RNase L biomarker have potential to aid in the diagnosis of CFS.

2',5'-Oligoadenylate Synthetase↗

PubMed2004

Prognostic significance of nm23 gene product expression in patients with colorectal carcinoma treated with radical intent.

Reports of the relationship between the putative metastasis suppressor NM23 and metastasis and/or survival in colorectal cancer patients are conflicting. This study aimed to investigate whether nm23 immunostaining is correlated with established prognostic variables (Dukes' stage, degree of tumour differentiation, T stage and nodal involvement) in colorectal carcinomas for the patients treated with radical intent using Kruskal chi(2) analysis. The rates of survival at five years were estimated with the use of the Kaplan-Meier product-limit method with 95% confidence intervals derived by Greenwood's formula and the curves were compared with the use of the log-rank test. Cox proportional-hazard regression model was used to identify multivariate predictors and the corresponding outcome. The staining was performed on 112 paraffin-embedded surgical specimens collected between 1989-1992 using a monoclonal anti-nm23 antibody. Follow-up of patients was until time of death or for at least 5 years. There was not a significant correlation between tumour staging, degree of tumour differentiation, nodal involvement and nm23 status. Furthermore, there was no significant association with overall 5-year survival, disease recurrence, tumour site, age or sex. Although nm23 may be involved in suppressing tumour metastasis, nm23 immunohistochemistry has no prognostic value in colorectal cancer. For these reasons nm23 does not contribute further to the prognostic information provided by established prognostic variables.

Adenocarcinoma↗

PubMed1991

Individual differences in aging: behavioral and neural analyses.

Aged populations have remarkable variability in recent memory and cognitive mapping. Although some individuals may have substantial age-related impairments, others perform almost as well as young individuals. This paper reviews the relevant data on aged rats and indicates two challenges for biomarkers of aging. The first is to provide an appropriate quantitative description of these individual differences. The second is to use them effectively as markers for age-related changes in psychological functions and their neural substrates.

Aging↗

PubMed1989

Interlaboratory variability of immunohistochemical stains. Results of the cell markers survey of the College of American Pathologists.

Immunohistochemical techniques have become commonplace adjunctive aids in anatomic pathology. Although much has been written describing modifications of the basic techniques, sensitivity, and specificity of reagents, little has been published regarding the interlaboratory variability in immunostain results on a given test sample. The Cell Markers Survey of the College of American Pathologists was organized to address this question of interlaboratory variability and to disseminate information on the techniques and reagents currently available.

Biomarkers↗

PubMed1998

Exfoliated ductal epithelial cells in human breast milk: a source of target tissue DNA for molecular epidemiologic studies of breast cancer.

Studies of biomarkers of putative breast carcinogens, such as DNA adducts, have been limited by the difficulty in obtaining representative ductal epithelial cells (DECs) from breast tissue. In this feasibility study, we sought to ascertain if exfoliated DECs in breast milk could be a source of DNA for biomarker studies. Specimens (n = 38) were collected over 24 h from nursing women, and a questionnaire was administered. Cell pellets were isolated by repeated centrifugation and washing. Pellets were resuspended and incubated for 2 h, with glass adherence used to remove monocytes, resulting in an enrichment of DECs of >80%. Nonadherent cells were removed, washed, and homogenized for DNA isolation. Accurate DNA quantification was performed by 32P-postlabeling of normal nucleotides under conditions of excess ATP. Although there was wide variability in the amounts of DNA recovered, DNA yield was significantly associated with the number of weeks postpartum (P < 0.01), with optimal yield between 6 and 8 weeks after birth. There were no significant associations (P < 0.05) between the number of cells recovered and milk volume, method of collection, or the number of samples in a 24-h period per individual. This study demonstrates that breast milk can be used as a source of DECs for biomarker studies of gene-environment interaction and that sufficient DNA can be recovered to evaluate carcinogen-DNA adducts and to perform genotyping assays. Using this approach, exfoliated DECs may serve as a source of representative cells for studies of breast carcinogenesis and biomarkers of exposure, susceptibility, and effect.

Biomarkers, Tumor↗

PubMed2005

Mean corpuscular volume and ADH1C genotype in white patients with alcohol-associated diseases.

BACKGROUND: Alcohol abuse is associated with several gastrointestinal diseases, such as esophageal carcinoma, chronic alcoholic pancreatitis, and liver cirrhosis. Increased mean corpuscular volume (MCV) has been recognized as a biomarker for alcohol abuse and heavy drinkers. Recent studies from Japan revealed that macrocytosis is related to ALDH-2/2 genotype, leading to increased acetaldehyde accumulation. It has also demonstrated that increased MCV values could also be an independent biomarker for esophageal cancer in Asians. Therefore, the aim of the current study was to investigate possible associations of MCV value with polymorphisms of ADH1C in white patients with alcohol-associated esophageal carcinoma, chronic alcoholic pancreatitis, and alcoholic cirrhosis as well as in heavy drinkers without organ damage. METHODS: In this study, a total of 510 alcoholic patients were enrolled with esophageal cancer (n = 98), chronic pancreatitis (n = 98), alcoholic liver cirrhosis (n = 151), and alcohol abuse without gastrointestinal disease (n = 163). ADH1C genotyping was performed by PCR-based restriction fragment length polymorphism (PCR-RFLP) analysis from whole blood. The relation between MCV and ADH1C gene polymorphisms (ADH1C*1 and 1C*2) controlled for the amount of drinking, smoking, and age were investigated using both univariate and multivariate analysis. RESULTS: In univariate analysis, higher alcohol consumption was associated with increased MCV. Other variables were not associated with macrocytosis. In multiple linear regression analysis, after adjustment for age and smoking, higher alcohol consumption and female sex were independently associated with higher MCV values. No other variables, including which alcohol-associated disease the patient had, had an independent effect. Adding ADH genotype rendered no independent significant effect on MCV value. CONCLUSIONS: In a white population, MCV values were not associated with genotype polymorphisms of ADH1C. In contrast to findings in Asians, macrocytosis does not seem to be an independent biomarker for esophageal cancer. The role of ADH1C polymorphism in increasing MCV and the potential use of MCV as a marker for esophageal carcinoma are still pending.

Adult↗

PubMed2005

Clinicopathologic and biological significance of kallikrein 6 overexpression in human gastric cancer.

PURPOSE: Human kallikrein genes (KLK) have been reported to be involved in human malignancies and several KLKs are promising biomarkers of prostate, ovarian, testicular, and breast cancers. Herein, we investigated the clinicopathologic and biological significance of KLK6 gene expression in human gastric cancer. PATIENTS AND METHODS: Using real-time reverse transcription-PCR, we analyzed the KLK6 expression status with respect to various clinicopathologic variables in 66 patients with gastric cancer. In addition, we established a KLK6 stably suppressed gastric cancer cell line (MKN28) using small interfering RNA-mediated gene silencing, and investigated its effects on the cell proliferation rate, cell cycle, and invasiveness. RESULTS: The KLK6 gene expression in cancerous tissue (0.37 +/- 0.53) was significantly (P < 0.000001) higher than that in noncancerous tissue (0.026 +/- 0.060). Elevated KLK6 expression was significantly associated with lymphatic invasion (P = 0.03). Furthermore, patients with a high KLK6 expression had a significantly poorer survival rate than those with a low KLK6 expression (P = 0.03). Therefore, we showed that KLK6 gene silencing with KLK6 small interfering RNA effectively suppressed the cell proliferation rate (P = 0.002), cell population in the S phase (P < 0.01), and invasiveness (P < 0.01) in comparison to mock-transfected cells. CONCLUSIONS: The KLK6 gene is markedly overexpressed in gastric cancer tissue and its expression status may be a powerful prognostic indicator for patients with gastric cancer. Our findings also suggest that KLK6 may possibly be a novel target for gastric cancer therapy by gene-silencing procedures.

Biomarkers, Tumor↗

PubMed2001

Validation of the Healthy Eating Index with use of plasma biomarkers in a clinical sample of women.

BACKGROUND: The Healthy Eating Index (HEI) is a 100-point analytic scoring tool used to measure compliance with dietary recommendations and guidelines. OBJECTIVE: The objective was to calculate HEI scores for a sample of women and to link the HEI scores to plasma biomarkers of dietary exposure. DESIGN: Respondents were 340 women aged 21-80 y who were enrolled in a case-control study of diet and breast cancer. The sample included 172 patients with newly diagnosed cancer (case subjects), 149 cancer-free control subjects, and 19 women at high risk of breast cancer. Dietary intake assessment was based on 3-d food records. HEI scores were calculated for all respondents. Venous blood was collected for measurements of plasma carotenoids, vitamin C, and folate. CONCLUSIONS: Higher HEI scores were associated most strongly with greater dietary variety (r = 0.71), higher intakes of fruit (r = 0.57), and lower intakes of fat and saturated fat. HEI scores were also associated with higher intakes of energy, carbohydrates, fiber, folate, and vitamin C. Higher HEI scores were associated with higher plasma concentrations of alpha-carotene (r = 0.40), beta-carotene (r = 0.28), beta-cryptoxanthin (r = 0.41), lutein (r = 0.23), and vitamin C (r = 0.26) after age and vitamin supplement use were controlled for in a regression model. There was a further association between HEI scores and socioeconomic variables. Women with higher HEI scores were more likely to be older, married, and better educated and to have higher household incomes.

Adult↗