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Results for “Biomarker Profiling”

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At least 1,729 records · Page 96Linked to original sources
PubMed2005

Evaluation of a panel of tumor markers for molecular detection of circulating cancer cells in women with suspected breast cancer.

PURPOSE: We examined the feasibility of using molecular characterization of circulating tumor cells as a method for early detection of breast cancer. RESEARCH DESIGN: Women without a prior history of cancer who had a breast abnormality detected on imaging followed by a breast biopsy were enrolled in this study. Density gradient centrifugation and immunomagnetic capture were used to enrich for epithelial cells from approximately 20 mL of blood. Real-time reverse transcription-PCR was used to quantitate the expression levels of the highly breast-specific genes, mammaglobin, gamma-aminobutyric acid type A receptor pi subunit (GABA A(pi)), B305D-C, and B726P in the epithelial cell-enriched samples. RESULTS: The assay was technically feasible in 154 of 199 accrued patients. From their clinical assessment, 100 patients had benign breast disease, 10 patients had ductal carcinoma in situ, and 44 patients had invasive breast cancer. We constructed a diagnostic test that classified patients with mammaglobin levels of at least 32.2 copies/pg beta-actin (units) in their circulating epithelial cells as positive for invasive breast cancer. This resulted in a sensitivity and specificity of 63.3% and 75.0%, respectively. A diagnostic test that classified patients as positive for invasive breast cancer when either mammaglobin levels were >46.3 units or B305D-C levels were >11.6 units increased the sensitivity and specificity to 70.5% and 81.0%, respectively. In the latter test, 12 of the 14 node-positive breast cancer patients were correctly identified. Including GABA A(pi) and B726P in the test did not increase its diagnostic potential. CONCLUSIONS: These results suggest that molecular characterization of circulating epithelial cells using mammaglobin and B305D-C offers potential for early detection of invasive breast cancer.

Adult↗
PubMed2005

Tumor dose response to the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid, using in vivo magnetic resonance spectroscopy.

PURPOSE: To use (31)P and (1)H magnetic resonance spectroscopy (MRS) to assess changes in tumor metabolic profile in vivo in response to 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with a view to identifying biomarkers associated with tumor dose response. EXPERIMENTAL DESIGN: In vivo (31)P and (1)H MRS measurements of (a) tumor bioenergetics [beta-nucleoside triphosphate/inorganic phosphate (beta-NTP/Pi)], (b) the membrane-associated phosphodiesters and phosphomonoesters (PDE/PME), (c) choline (mmol/L), and (d) lactate/water ratio were made on murine HT29 colon carcinoma xenografts pretreatment and 6 or 24 hours posttreatment with increasing doses of DMXAA. Following in vivo MRS, the tumors were excised and used for high-resolution (31)P and (1)H MRS of extracts to provide validation of the in vivo MRS data, histologic analysis of necrosis, and high-performance liquid chromatography. RESULTS: Both beta-NTP/Pi and PDE/PME decreased in a dose-dependent manner 6 hours posttreatment with DMXAA, with significant decreases in beta-NTP/Pi with 15 mg/kg (P < 0.001) and 21 mg/kg (P < 0.01). A significant decrease in total choline in vivo was found 24 hours posttreatment with 21 mg/kg DMXAA (P < 0.05); this was associated with a significant reduction in the concentration of the membrane degradation products glycerophosphoethanolamine and glycerophosphocholine measured in tissue extracts (P < 0.05). CONCLUSIONS: The reduction in tumor energetics and membrane turnover is consistent with the vascular-disrupting activity of DMXAA. (31)P MRS revealed tumor response to DMXAA at doses below the maximum tolerated dose for mice. Both (31)P and (1)H MRS provide biomarkers of tumor response to DMXAA that could be used in clinical trials.

Animals↗
PubMedDate not supplied

Surface expression of Hsp25 and Hsp72 differentially regulates tumor growth and metastasis.

The expression of unique surface structures on tumors that allow for recognition and activation of host immunocompetent cells plays an important role in determining tumor growth and/or metastasis. Recent studies have identified an important role for heat shock proteins (Hsp) in antitumor surveillance; however, the exact role of Hsp expressed on the surface of tumors has not been fully addressed. In this study, we show that 4T1 mammary adenocarcinoma cells sorted for high Hsp25 surface expression (Hsp25(high)) grow significantly faster than cells sorted for intermediate Hsp25 surface expression (Hsp25(intermediate)) or wild-type 4T1 cells implanted into the abdominal breast gland of female BALB/c mice (p < 0.05). In addition, histological examination of lung tissues revealed that Hsp25(high) 4T1 cells metastasized to the lungs more aggressively than either Hsp25(intermediate) or wild-type 4T1 cells (p < 0.05). Exposure of 4T1 cells to nonlethal heat shock (43 degrees C, 30 min) induced the surface expression of Hsp72 and a concomitant reduction in Hsp25 surface expression. The growth and metastastic potential of Hsp72(+) 4T1 cells was significantly less than that of Hsp25(high), Hsp25(intermediate) or wild-type 4T1 cells (p < 0.05). Taken together, these studies identify an important role for expression of Hsp25 and Hsp72 during tumor growth and metastatic spread which might be helpful in the design of antimetastatic therapies.

Adenocarcinoma↗
PubMed2003

Expression of interleukin-5- and granulocyte macrophage-colony-stimulating factor-responsive genes in blood and airway eosinophils.

Because interleukin (IL)-5 family cytokines are critical regulators of eosinophil development, recruitment, and activation, this study was initiated to identify proteins induced by these cytokines in eosinophils. Using oligonucleotide microarrays, numerous transcripts were identified as responsive to both IL-5 and granulocyte macrophage-colony-stimulating factor (GM-CSF), but no transcripts were markedly affected by one cytokine and not the other. Expression of several gene products were seen to be increased following in vitro stimulation of human blood eosinophils, including the IL-3 receptor alpha subunit, lymphotoxin beta, Pim-1, and cyclin D3. Given that eosinophils recovered from the bronchoalveolar lavage fluid of allergic patients after antigen challenge are exposed to IL-5 or GM-CSF in the airway prior to isolation, the hypothesis was tested that selected IL-5- and GM-CSF-responsive genes are upregulated in airway eosinophils relative to the expression in blood cells. Airway eosinophils displayed greater cell surface expression of the IL-3 receptor alpha subunit, CD44, CD25, and CD66e, suggesting that these proteins may be markers of eosinophil activation by IL-5 family cytokines in airway eosinophils. Other genes that were induced by both IL-5 and GM-CSF showed protein expression at similar or decreased levels in airway eosinophils relative to their circulating counterparts (i.e., lymphotoxin beta and CD24). These studies have identified several transcriptional targets of IL-5 and GM-CSF in human eosinophils and suggest that a number of protein products are critical to the responsiveness of airway eosinophils.

Biomarkers↗
PubMed2005

Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in diffuse large B-cell lymphoma: a tissue microarray and clinico-pathological analysis.

BACKGROUND: Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis. METHODS: Immunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics. RESULTS: Mcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424). CONCLUSION: Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL.

Biomarkers, Tumor↗
PubMed2005

Proliferation marker Ki-67 in early breast cancer.

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer. Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67. The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake. High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios. However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs.

Antineoplastic Agents↗
PubMed2006

Novel prognostic immunohistochemical biomarker panel for estrogen receptor-positive breast cancer.

PURPOSE: Patients with breast cancer experience progression and respond to treatment in diverse ways, but prognostic and predictive tools for the oncologist are limited. We have used gene expression data to guide the production of hundreds of novel antibody reagents to discover novel diagnostic tools for stratifying carcinoma patients. PATIENTS AND METHODS: One hundred forty novel and 23 commercial antisera, selected on their ability to differentially stain tumor samples, were used to stain paraffin blocks from a retrospective breast cancer cohort. Cox proportional hazards and regression tree analysis identified minimal panels of reagents able to predict risk of recurrence. We tested the prognostic association of these prospectively defined algorithms in two independent cohorts. RESULTS: In both validation cohorts, the Kaplan-Meier estimates of recurrence confirmed that both the Cox model using five reagents (p53, NDRG1, CEACAM5, SLC7A5, and HTF9C) and the regression tree model using six reagents (p53, PR, Ki67, NAT1, SLC7A5, and HTF9C) distinguished estrogen receptor (ER)-positive patients with poor outcomes. The Cox model was superior and distinguished patients with poor outcomes from patients with good or moderate outcomes with a hazard ratio of 2.21 (P = .0008) in validation cohort 1 and 1.88 (P = .004) in cohort 2. In multivariable analysis, the calculated risk of recurrence was independent of stage, grade, and lymph node status. A model proposed for ER-negative patients failed validation in the independent cohorts. CONCLUSION: A panel of five antibodies can significantly improve on traditional prognosticators in predicting outcome for ER-positive breast cancer patients.

Algorithms↗
PubMed2004

Detection of melanoma cells in the lymphatic drainage after lymph node dissection in melanoma patients by using two-marker reverse transcriptase-polymerase chain reaction assay.

BACKGROUND: The aim of this study was to evaluate the role of melanoma gene expression as a marker of the presence of melanoma cells in lymphatic drainage routinely collected after lymphadenectomy and to correlate reverse transcriptase-polymerase chain reaction (RT-PCR) assay results with recurrence, survival, and prognostic factors. METHODS: We collected 24-hour postoperative lymphatic drainage samples (between days 2 and 4) from 93 patients with stage III melanoma who underwent radical lymphadenectomy between May 2002 and November 2003. We used RT-PCR assays with primers specific for the tyrosinase and MART-1 (Melan-A) genes. The samples were considered positive if at least one marker was expressed. Median follow-up time was 12.8 months. RESULTS: In 18 (19.4%) of 93 patients, the RT-PCR assay results were positive: in 8 of 18 for tyrosinase only, in 7 of 18 for MART-1 only, and in 3 of 18 for both markers. We observed a significantly higher recurrence rate in patients with positive RT-PCR results (15 of 18; 83%) than negative results (26 of 75; 35%; P = .0001). Positive results of RT-PCR correlated with the number of involved lymph nodes (P = .0001) and extracapsular extension of nodal metastases (P = .03). We observed significant differences in overall and disease-free survival for RT-PCR-positive and -negative patients in univariate and multivariate analyses. CONCLUSIONS: We observed positive RT-PCR assay results for melanoma cells in the lymphatic drainages of approximately 20% of patients after lymphadenectomy. This correlated significantly with early recurrence and shorter survival. These results may suggest that the RT-PCR assay could be useful for routinely analyzing postoperatively collected lymphatic drainage in stage III melanoma patients and for predicting disease progression.

Adult↗
PubMed2006

Tissue detection of biomolecular predictors in breast cancer.

One of the promises of modern biotechnology is to improve medical care by providing accurate diagnosis and targeted treatment to patients who will derive the maximum benefit. Delivery of this promise in the 21st century is the result of major advances in biotechnology over the past 20 years. Sequencing of the human genome and other high-volume data discovery has become possible, owing to relatively inexpensive computation power and automation. The same forces that drove the human genome project are now being focused on cataloging various disease processes at the DNA, RNA and protein levels. As these high-throughput technologies are entering the clinical care environment, the major task at hand is to integrate the complex data and derive clinically useful information. In spite of major breakthroughs in molecular approaches to the diagnosis and prognostication of cancer, there remain significant obstacles in applying these technologies to clinical samples. The time-honored conventional histopathology, for example, is still the backbone of tumor diagnosis and prognostication. The traditional fixation and processing methods are, however, rapidly losing ground, as they do not protect important tissue macromolecules. Formalin, the common universal fixative, is losing its place in histopathology. In addition to its toxicity, it alters macromolecules and renders the tissue unfit for most advanced molecular studies. This has prompted the use of fresh or fresh-frozen biopsy material for most biomolecular discoveries and clinical assays. This of course is impractical, or even impossible, in most clinical settings, particularly since tumors are being detected earlier and smaller. Also, many preneoplastic conditions are impossible to triage for freezing since their accurate diagnosis requires the use of the entire sample for detailed microscopic examination. The focus in this report is on breast cancer, where the value of the innovative approaches of the tissue detection of biomolecular predictors is examined. To this end, novel tissue handling platforms are introduced that are not only suitable for histological diagnosis, but allow the detection of tumor proteome and expression profiles on the same biopsy sample.

BRCA2 Protein↗
PubMed2005

Analysis of estrogenic effects by quantification of green fluorescent protein in juvenile fish of a transgenic medaka.

TheChgH-GFP strain of the teleost medaka contains a regulatory region of the estrogen-responsive choriogenin H (chgH) gene fussed to the green fluorescent protein (GFP) gene. The strain was developed for the identification of environmental estrogens by noninvasive analysis of GFP fluorescence. In the present study, a quantification method for GFP by image analysis was establishedand applied to the analysis of time- and concentration-dependent GFP fluorescence in juvenile fish. Concentration-response analyses were performed with fish exposed for 14 d to 17beta-estradiol (0.37-367 pM), genistein (0.37-367 nM), or p-nonylphenol (0.367-1,835 nM). By means of image analysis, it was shown that ChgH-GFP was induced at 183.5 pM or greater 17beta-estradiol. Time-course and recovery experiments indicated a strong accumulation of GFP in the liver. Results of reverse transcriptase-polymerase chain reaction analysis of choriogenin H and vitellogenin demonstrated induction of gene expression for the same rangeof concentrations as that for GFP analysis. Neither expression of these genes nor GFP fluorescence was induced by genistein and p-nonylphenol. Although the ChgH-GFP strain failed to detect these weakly estrogenic compounds, the simplicity of the GFP quantification during early life stages of fish offers promising possibilities for further developments of transgenic strains using different target regulatory sequences.

Animals↗
PubMed2006

Utilization of a one-dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database.

A large-scale toxicogenomcis database has now been constructed in the Toxicogenomics Project in Japan (TGP). To facilitate the analytical procedures for such large-scale microarray data, we developed a simple one-dimensional score, named TGP1 which expresses the trend of the changes in expression of biomarker genes as a whole. To evaluate the usefulness of the TGP1 score, microarray data of rat liver and rat hepatocytes deposited in the TGP database were scored for three biomarker gene sets, i.e., carcinogenesis-related, PPARalpha-regulated and glutathione depletion-related gene sets. The TGP1 scoring system gave reasonable results, i.e., the scores for carcinogenesis-related genes were high in omeprazole-, chlorpromazine-, hexachlorobenzene-, sulfasalazine- and Wy-14,643-treated rat livers, that for PPARalpha-regulated genes were high in clofibrate-, Wy-14,643-, gemfibrozil-, benzbromarone- and aspirin-treated rat livers as well as rat hepatocytes, and for glutathione deficiency-related genes were high in omeprazole-, bromobenzene-, acetaminophen- and coumarin-treated rat liver. We concluded that the TGP1 score is useful for surveying the expression changes in multiple biomarker gene sets for a large-scale toxicogenomics database, which would reduce the time of doing conventional multivariate statistical analysis. In addition, the TGP1 score can be applied to screening of compatible biomarker gene sets between rat liver and rat hepatocytes, like PPARalpha-regulated gene sets, which will allow us to develop an appropriate in vitro system for drug safety assessment in vivo.

Animals↗