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PubMed2004

Context-specific memory and apolipoprotein E (ApoE) epsilon 4: cognitive evidence from the NIMH prospective study of risk for Alzheimer's disease.

The aim of the study was to determine whether the epsilon 4 allele of the apolipoprotein E (ApoE) gene was associated primarily with context-specific memory among individuals at genetic risk for developing Alzheimer's disease. The effect of ApoE status on comprehensive neuropsychological results was examined in 176 healthy adults during baseline cognitive testing in the NIMH Prospective Study of Biomarkers for Older Controls at Risk for Alzheimer's Disease (NIMH Prospective BIOCARD Study). The presence of the epsilon 4 allele was associated with significantly lower total scores on the Logical Memory II subtest of the Wechsler Memory Scale-Revised and percent of information retained after delay. Further analysis indicated the prose recall and retention effect was partially explained by a small subgroup of epsilon 4 homozygotes, suggesting a gradually progressive process that may be presaged with specific cognitive measures. The current results may represent an epsilon 4-associated breakdown between gist-related information and context-bound veridical recall. This relative disconnection may be understood in light of putative epsilon 4-related preclinical accumulation of Alzheimer pathology (tangles and plaques) in the entorhinal cortex (EC) and among frontal networks, as well as the possibility of less-efficient compensatory strategies.

Adult↗
PubMed2003

p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types.

Although recent studies have suggested that p16(INK4a) may be a useful surrogate biomarker of cervical neoplasia, Ki-67 and human papillomavirus testing have also been shown to be useful in detecting neoplasia. To help delineate the utility of p16(INK4a), biopsy samples (n = 569: negative, 133; reactive, 75; atypical, 39; low grade, 76; moderate, 80; and severe intraepithelial neoplasia, 113; also, squamous cell carcinoma, 46; adenocarcinoma, 7) were analyzed by immunohistochemistry for expression of p16(INK4a) and Ki-67 (n = 432), as well as by in situ hybridization for human papillomavirus Type 16 (n = 219). Testing for high-risk human papillomavirus types by polymerase chain reaction and HybridCapture2 was performed on concurrent cervical swab specimens. Recuts of the original blocks were reexamined (n = 198). Endometrial biopsies (n = 10) were also analyzed for p16(INK4a) expression. Degree of p16(INK4a) and Ki-67 expression correlated with degree of cervical neoplasia (P <.001) and with presence of high-risk human papillomavirus types (P <.001). There was no relationship between p16(INK4a) overexpression and inflammation or hormonal status. Ki-67 expression correlated with inflammation (P = 0.003) and was expressed in more reactive and atypical lesions than p16(INK4a) (P = 0.008). Probes for human papillomavirus 16 stained 54% of cervical neoplastic lesions; the degree of staining correlated significantly with degree of neoplasia (P <.001) and p16(INK4a) staining (P <.001). Interobserver reproducibility was substantial for p16(INK4a) and Ki-67 interpretation (weighted kappa: 0.74 and 0.70, respectively). Expression of p16(INK4a) was observed in all endometrial biopsies. Compared with Ki-67 expression and detection of high-risk human papillomavirus, p16(INK4a) was less likely to be positive in samples from women with negative, reactive, and atypical biopsies. Although expression of p16(INK4a) in endometrial epithelium may be problematic in terms of screening, the potential of p16(INK4a) as a screening test warrants investigation.

Adenocarcinoma↗
PubMed2006

Plasma proteome analysis reveals the geographical origin and liver tumor status of Dab (Limanda limanda) from UK marine waters.

The flatfish species dab (Limanda limanda) is the sentinel for offshore marine monitoring in the United Kingdom National Marine Monitoring Programme (NMMP). At certain sites in the North and Irish Seas, the prevalence of macroscopic liver tumors can exceed 10%. The plasma proteome of these fish potentially contains reporter proteins or "biomarkers" that may enable development of diagnostic tests for liver cancer and further our understanding of the disease. Following selection of sample groups by quality-assured histopathology ("phenotype anchoring"), we used surface-enhanced laser desorption/ionization (SELDI) time-of-flight mass spectrometry to produce proteomic profiles of plasma from 213 dab collected during the 2004 UK NMMP. The resulting protein profiles were compared between fish from the North and Irish Seas and between fish with liver neoplasia or nondiseased liver. Significant differences were found between the plasma proteomes of dab from the North Sea and Irish Sea, which in conjunction with artificial neural networks can correctly determine from which sea dab were captured in 85% of the cases. In addition, the presence of liver tumors is associated with significant changes in the plasma proteome. We conclude that SELDI-based plasma profiling is potentially of use in nonlethal marine monitoring using wild sentinels such as dab. Furthermore, accurate selection of sample groups is critical for avoiding effects of confounding factors such as age, gender, and geographic origin of samples.

Adenoma, Liver Cell↗
PubMed1992

Tumor markers in prostate cancer.

Prostatic specific antigen (PSA) is a tissue specific marker that is now the most widely used biochemical test for the assessment and follow-up of prostate cancer. The levels of PSA rise with tumor stage, but there is considerable overlap of their distribution between stages. PSA measurement now forms a part of the workup of a suspected carcinoma of the prostate, with a level of more than 4 ng/ml being an indication for further investigation. The sensitivity of PSA makes it an essential test for the postoperative assessment of radical prostatectomy and curative radiation therapy. The rates of change of PSA levels in locally advanced and metastatic disease treated by hormone manipulation can provide prognostic information. Low levels of PSA (less than 10 ng/ml) 6 months after treatment are a sign that the response will be prolonged. However, the sensitivity of PSA often results in a rising level preceding clinical evidence of progression by several months and is not necessarily an indication to change treatment. Alkaline phosphatase and prostatic acid phosphatase provide a less sensitive test for the bone response to skeletal metastases and tumor activity in advanced disease, respectively.

Acid Phosphatase↗
PubMed2001

Elevated tissue expression of hyaluronic acid and hyaluronidase validates the HA-HAase urine test for bladder cancer.

PURPOSE: We examined the expression of 2 bladder tumor markers, hyaluronic acid (HA) and hyaluronidase (HAase), in bladder tissues and correlated tissue staining with the inferences of the HA-HAase urine test, which detects bladder cancer. MATERIALS AND METHODS: A biotinylated HA binding protein and an antiHYAL1 antibody were used to localize HA and HYAL1 type HAase, respectively, in 83 bladder tissues. Immunoblot analysis was performed using an antiHYAL1 antibody to detect HYAL1. RESULTS: A total of 12 normal bladder tissues showed no (66%) to 1+ (34%) HA staining and 0 (83%) to 1+ (17%) HYAL1 staining. The staining intensity of HA and HYAL1 increased in 71 bladder tumor specimens on chi-square analysis (p <0.001). Grade 1 tumors demonstrated 1+ (50%) to 2+ (50%) staining for HA and 1+ to 3+ staining for HYAL1 (37%, 37% and 26%, respectively). Grades 2 and 3 tumors showed 2+ to 3+ HA (94%) and HYAL1 (79%) staining. HA was expressed in tumor associated stroma and in tumor cells, whereas only tumor cells expressed HYAL1. In bladder tumor tissues HYAL1 expression was confirmed by immunoblot analysis. In 33 of the 34 patients (97%) with bladder cancer from whom urine and tumor tissue specimens were obtained at the same time 2+ to 3+ staining of HA and/or HYAL1 in 12 and 21, respectively, constituted a positive HA-HAase urine test (kappa = 0.945). CONCLUSIONS: To our knowledge this is the first report of HA localization in bladder tissues and of HYAL1 in any normal or tumor tissue. A close correlation of elevated HA and HYAL1 levels in tumor tissues with a positive HA-HAase urine test indicates that in patients with bladder cancer tumor associated HA and HYAL1 are secreted in urine, causing the HA-HAase test to be positive.

Adult↗
PubMed2006

Reduced Pms2 expression in non-neoplastic flat mucosa from patients with colon cancer correlates with reduced apoptosis competence.

Pms2 protein is a component of the DNA mismatch repair complex responsible both for post-replication correction of DNA nucleotide mispairs and for early steps in apoptosis. Germline mutations in DNA mismatch repair genes give rise to hereditary non-polyposis colon cancer, which accounts for about 4% of colon cancers. However, little is known about the expression of mismatch repair proteins in relation to sporadic colon cancer, which accounts for the great majority of colon cancers. Multiple samples were taken from the non-neoplastic flat mucosa of colon resections from patients with no colonic neoplasia, a tubulovillous adenoma, or an adenocarcinoma. Expression of Pms2 was assessed using semiquantitative immunohistochemistry. Apoptosis was assessed in polychrome-stained epoxy sections using morphologic criteria. Samples from patients without colonic neoplasia had moderate to strong staining for Pms2 in cell nuclei at the base of crypts, while samples from 2 of the 3 colons with a tubulovillous adenoma, and from 6 of the 10 colons with adenocarcinomas, showed reduced Pms2 expression. Samples from patients with an adenocarcinoma that had reduced Pms2 expression also exhibited reduced apoptosis capability in nearby tissue samples, evidenced when this paired tissue was stressed ex vivo with bile acid. Reduced Pms2 expression in the colonic mucosa may be an early step in progression to colon cancer. This reduction may cause decreased mismatch repair, increased genetic instability, and/or reduced apoptotic capability. Immunohistochemical determination of reduced Pms2 expression, upon further testing, may prove to be a promising early biomarker of risk of progression to malignancy.

Adenosine Triphosphatases↗
PubMedDate not supplied

Chemoprevention by difluoromethylornithine: correlation of an in vitro human cell assay with human clinical data for biomarker modulation.

The efficacy of difluoromethylornithine (DFMO) as a chemopreventive agent has been tested in vitro using a human epidermal cell (HEC) assay with growth inhibition and involucrin induction as endpoints. Suppression of polyamine content is currently being utilized as a biomarker in clinical trials for the chemopreventive efficacy of DFMO against colon cancer formation. We have now examined the effects of DFMO on suppression of polyamine content in the HEC assay. The findings indicate 1) the % change in spermidine to spermine ratio and the depletion of putrescine show excellent correlation with chemopreventive efficacy in vitro; 2) the effective concentrations in vitro overlap the plasma concentrations in the clinical trial. These observations serve as further validation of the usefulness of the HEC assay as a screen for chemopreventive efficacy.

Antineoplastic Agents↗
PubMed1997

Candidate biomarkers of aging: age-sensitive indices of immune and muscle function covary in genetically heterogeneous mice.

A longitudinal experiment was designed to test the hypothesis that individual mice differ in their aging rate and to validate candidate biomarkers proposed to measure the rate of aging. Mice were bred as the genetically heterogeneous progeny of a cross between CB6F1 mothers and C3D2F1 fathers. Half of the mice were fed ad libitum (AL group), and the other half were subjected to 60% calorie restriction (CR group). Each mouse was tested at about 9 months of age using age-sensitive tests of immune status, and then again at about 12 months of age using age-sensitive tests of muscle function. The data were then analyzed using the method of partial least squares to determine the combinations of test weights that maximize the covariance of the weighted sum of immune measures with the weighted sum of muscle function measures. Both AL and CR mice exhibited a statistically significant relation between the immune status tests and the muscle function tests. Maximal covariance was obtained with a set of weighting coefficients consistent with our working hypothesis: mice with high levels of CD4 memory T cells (which increase with age) also had relatively low levels of muscle strength and endurance. Low strength was associated with low CD8 cells in the AL mice, with high numbers of CD8 memory cells in the CR mice and with low CD3 cells in both diet groups. The partial least squares method generates composite indices of immune status and muscle function that can be evaluated as biomarkers of aging rate in these mice. Further work will be needed to assess whether these tests predict either longevity or the trajectory of change in other age-sensitive molecular and physiological traits.

Aging↗
PubMed2002

Deoxyribonucleic acid damage in human lymphocytes after percutaneous transluminal coronary angioplasty.

UNLABELLED: OBJECTIVES; We investigated the presence of oxidative deoxyribonucleic acid (DNA) damage in the peripheral lymphocytes of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) by using the micronucleus test and comet assay, which are sensitive biomarkers of DNA damage. BACKGROUND; Although it has recognized that ischemia-reperfusion can induce oxidative DNA damage, its occurrence in patients undergoing PTCA has not yet been demonstrated. METHODS: Three groups of patients were enrolled: 30 patients with documented coronary heart disease who underwent elective PTCA (group I); 25 patients who underwent elective coronary angiography for diagnostic purpose (group II); and 27 healthy, age- and gender-matched subjects (group III). For each subject, the frequency of micronucleated binucleated (MNBN) cells, DNA single-strand breaks (SSBs), endonuclease III-sensitive sites, and sites sensitive to formamidopyrimidine glycosylase (FPG) were analyzed before and after diagnostic procedures. RESULTS: The mean basal values of MNBN cells (p = 0.04), DNA-SSBs (p = 0.001), endonuclease III-sensitive sites (p = 0.002), and FPG sites (p < 0.0001) were significantly higher in groups I and II than in group III. A high significant increase of MNBN cell frequency was observed in group I after the PTCA procedure (11.0 +/- 1.3 vs. 19.8 +/- 1.6, p < 0.0001), whereas no significant difference was observed in group II (10.2 +/- 1.3 vs. 12.9 +/- 1.4, p = 0.18). A significant positive correlation was observed between the increase in the MNBN cell rate and total inflation time during PTCA (R = 0.549, p = 0.0017). The levels of DNA-SSBs (11.7 +/- 1.4 vs. 26.5 +/- 3.0, p = 0.0003) and FPG sites (13.8 +/- 1.8 vs. 22.5 +/- 2.4, p = 0.01) were also higher after PTCA. CONCLUSIONS: Our results provide evidence for oxidative DNA damage after PTCA, likely related to ischemia-reperfusion injury.

Angioplasty, Balloon, Coronary↗
PubMed2002

Markers for early detection of cancer: statistical guidelines for nested case-control studies.

BACKGROUND: Recently many long-term prospective studies have involved serial collection and storage of blood or tissue specimens. This has spurred nested case-control studies that involve testing some specimens for various markers that might predict cancer. Until now there has been little guidance in statistical design and analysis of these studies. METHODS: To develop statistical guidelines, we considered the purpose, the types of biases, and the opportunities for extracting additional information. RESULTS: The following guidelines: (1) For the clearest interpretation, statistics should be based on false and true positive rates - not odds ratios or relative risks (2) To avoid overdiagnosis bias, cases should be diagnosed as a result of symptoms rather than on screening. (3) To minimize selection bias, the spectrum of control conditions should be the same in study and target screening populations. (4) To extract additional information, criteria for a positive test should be based on combinations of individual markers and changes in marker levels over time. (5) To avoid overfitting, the criteria for a positive marker combination developed in a training sample should be evaluated in a random test sample from the same study and, if possible, a validation sample from another study. (6) To identify biomarkers with true and false positive rates similar to mammography, the training, test, and validation samples should each include at least 110 randomly selected subjects without cancer and 70 subjects with cancer. CONCLUSION: These guidelines ensure good practice in the design and analysis of nested case-control studies of early detection biomarkers.

Bias↗
PubMed2006

Relations among questionnaire and laboratory measures of rhinovirus infection.

Due to high incidence and quality-of-life impact, upper respiratory infection substantially impacts on population health. To test or compare treatment effectiveness, a well-designed and validated illness-specific quality-of-life instrument is needed. Data reported in the current study were obtained from a trial testing echinacea for induced rhinovirus infection. Laboratory-assessed biomarkers included interleukin (IL)-8, nasal neutrophil count (polymorphonuclear neutrophils (PMN)), mucus weight, viral titre and seroconversion. The questionnaires used included the general health short form (SF)-8 (24-h recall version), the eight-item Jackson cold scale, and the 44-item Wisconsin Upper Respiratory Symptom Survey (WURSS). In total, 399 participants were inoculated with rhinovirus and monitored over 2,088 person-days. Statistically significant associations were found among nearly all variables. Between-questionnaire correlations were: WURSS-Jackson = 0.81; WURSS-SF-8 = 0.62; and Jackson-SF-8 = 0.60. Correlations with laboratory values were as follows: WURSS-mucus weight = 0.53; Jackson-mucus weight = 0.55; WURSS-viral titre = 0.37; Jackson-viral titre = 0.46; WURSS-IL-8 = 0.31; Jackson-IL-8 = 0.36; WURSS-PMN = 0.31; and Jackson-PMN = 0.28. Neither WURSS nor Jackson yielded satisfactory cut-off scores for diagnosis of infection. Symptomatic and biological outcomes of upper respiratory infection are highly variable, with only modest associations. While Wisconsin Upper Respiratory Symptom Survey and Jackson questionnaires both correlate with biomarkers, neither is a good predictor of induced infection. The inclusion of functional and quality-of-life items in the Wisconsin Upper Respiratory Symptom Survey does not significantly decrease the strength of association with laboratory-assessed biomarkers.

Adult↗
PubMed2006

Proteomics: a new diagnostic frontier.

BACKGROUND: Analysis of proteins has been an integral part of the field of clinical chemistry for decades. Recent advances in technology and complete identification of the human genome sequence have opened up new opportunities for analysis of proteins for clinical diagnostic purposes. METHODS: Content of a recent conference of proteomics is summarized. RESULTS: New analytical methods allow the simultaneous analysis of a large number of proteins in biological fluids such as serum and plasma, offering partial views of the complete set of proteins or proteome. Plasma presents many analytical challenges, such as the complexity of components, predominance of a few major components, and the large concentration range of components, but the number of proteins that can be detected in plasma has expanded dramatically from hundreds to thousands. At the same time, there is increased capability to detect structural variations of proteins. Recent studies also identified the presence of complex sets of small protein fragments in plasma. This set of protein fragments, the fragmentome or peptidome, is potentially a rich source of information about physiologic and disease processes. CONCLUSIONS: Advances in proteomics offer great promise for the discovery of markers that might serve as the basis for new clinical laboratory tests. There are many challenges, however, in the translation of newly discovered markers into clinical laboratory tests.

Biomarkers↗
PubMed2005

Statistical and computational methods for comparative proteomic profiling using liquid chromatography-tandem mass spectrometry.

The combined method of LC-MS/MS is increasingly being used to explore differences in the proteomic composition of complex biological systems. The reliability and utility of such comparative protein expression profiling studies is critically dependent on an accurate and rigorous assessment of quantitative changes in the relative abundance of the myriad of proteins typically present in a biological sample such as blood or tissue. In this review, we provide an overview of key statistical and computational issues relevant to bottom-up shotgun global proteomic analysis, with an emphasis on methods that can be applied to improve the dependability of biological inferences drawn from large proteomic datasets. Focusing on a start-to-finish approach, we address the following topics: 1) low-level data processing steps, such as formation of a data matrix, filtering, and baseline subtraction to minimize noise, 2) mid-level processing steps, such as data normalization, alignment in time, peak detection, peak quantification, peak matching, and error models, to facilitate profile comparisons; and, 3) high-level processing steps such as sample classification and biomarker discovery, and related topics such as significance testing, multiple testing, and choice of feature space. We report on approaches that have recently been developed for these steps, discussing their merits and limitations, and propose areas deserving of further research.

Animals↗