Biomedical subjects

Wendy A Wells

Publications and source records attributed to Wendy A Wells.

12 recordsLinked to original sources

PubMed2006

Spot 14: A marker of aggressive breast cancer and a potential therapeutic target.

Spot 14 (S14) is a nuclear protein that communicates the status of dietary fuels and fuel-related hormones to genes required for long-chain fatty acid synthesis. In mammary gland, S14 is important for both epithelial proliferation and milk fat production. The S14 gene is amplified in some breast cancers and is strongly expressed in most. High expression of S14 in primary invasive breast cancer is conspicuously predictive of recurrence. S14 mediates the induction of lipogenesis by progestin in breast cancer cells and accelerates their growth. Conversely, S14 knockdown impairs de novo lipid synthesis and causes apoptosis. We found that breast cancer cells do not express lipoprotein lipase (LPL) and hypothesize that they do not have access to circulating lipids unless the local environment supplies it. This may explain why primary breast cancers with low S14 do not survive transit from the LPL-rich mammary fat pad to areas devoid of LPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential target as well. Future effort will center on validation of S14 as a therapeutic target and producing antagonists of its action.

Animals↗

PubMed2006

Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker.

Most breast cancers are "lipogenic", defined by high fatty acid synthase (FAS) content and dependence on fatty acid synthesis for growth and survival. S14 (Spot 14; THRSP) is a nuclear protein that activates genes required for fatty acid synthesis. The S14 gene is amplified in approximately 15% of breast cancers, but clinical correlates of its expression were unknown. We analyzed 131 breast cancers by immunohistochemistry for S14 and FAS. Staining was graded 0, 1, or 2+, and scores were correlated with traditional tumor markers, histological features, and outcome. S14 and FAS staining were related to tumor size (p=0.05 for S14, p=0.038 for FAS), but not to stage. S14 but not FAS scores correlated with tumor grade in both DCIS (p=0.003) and invasive cases (p<0.001). Invasive cases (pooled node - and +) with weak S14 staining (n=21) showed no recurrence over 3000 d follow-up, including 10 cases with lymph node involvement, whereas 32% of 67 strongly-staining tumors recurred (log rank p<0.0001). S14 scores did not cosegregate with sex steroid receptors, Her2/neu, or cyclin D1. Low level S14 expression is associated with prolonged disease-free survival in invasive cases, including those with nodal metastasis. High-level expression of S14 identifies a subset of high-risk breast cancers that is not specified by analysis of sex steroid receptors, Her2/neu, or cyclin D1, and provides a molecular correlate to histologic features that predict recurrence.

Adult↗

PubMed2006

BRCA1 and BRCA2 mutation screening using SmartCycler II high-resolution melt curve analysis.

CONTEXT: Real-time polymerase chain reaction technologies have replaced many of the more labor-intense methods in the molecular diagnostics laboratory. Similarly, melt curve analysis can provide a rapid means of mutation screening. OBJECTIVE: To determine if real-time polymerase chain reaction and melt curve analysis using the SmartCycler II could be used as a screening tool for 3 common mutations in BRCA1 and BRCA2. DESIGN: Real-time polymerase chain reaction amplification with SYBR Green I detection was performed on DNA from cell lines known to carry the 185delAG or 5382insC mutation in BRCA1 or the 6174delT mutation in BRCA2. The melting temperatures and the melt curves were analyzed for differences between wild-type DNA and cell lines that were heterozygous for each mutation. RESULTS: Significant differences were present in the melt curves for each of the mutations compared with those of the wild-type sequences. The melt curve for the 185delAG mutation showed a separate peak at a lower temperature, which represented the melting temperature of the heteroduplex. For the 6174delT mutation, the melt curve had a shoulder at a lower temperature, while the melt curve for the 5382insC mutation was shifted to the left and was broader than that for the wild-type sequences. CONCLUSIONS: High-resolution melt curve analysis is a quick, reliable method for identifying mutations due to small deletions or insertions. As a proof of principle, we used this assay to identify the 3 most common BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population.

Cell Line, Tumor↗

PubMed2005

Measurement error and confidence intervals for ROC curves.

Measurement error in a continuous test variable may bias estimates of the summary properties of receiver operating characteristics (ROC) curves. Typically, unbiased measurement error will reduce the diagnostic potential of a continuous test variable. This paper explores the effects of possibly heterogenous measurement error on estimated ROC curves for binormal test variables. Corrected estimators for specific points on the curve are derived under the assumption of known or estimated measurement variances for individual test results. These estimators and associated confidence intervals do not depend on normal assumptions for the distribution of the measurement error and are shown to be approximately unbiased for moderate size samples in a simulation study. An application from a study of emerging imaging modalities in breast cancer is used to demonstrate the new techniques.

Computer Simulation↗

PubMed2005

Near-infrared characterization of breast tumors in vivo using spectrally-constrained reconstruction.

Multi-wavelength Near-Infrared (NIR) Tomography was utilized in this study to non-invasively quantify physiological parameters of breast tumors using direct spectral reconstruction. Frequency domain NIR measurements were incorporated with a new spectrally constrained direct chromophore and scattering image reconstruction algorithm, which was validated in simulations and experimental phantoms. Images of total hemoglobin, oxygen saturation, water, and scatter parameters were obtained with higher accuracy than previously reported. Using this spectral approach, in vivo NIR images are presented and interpreted through a series of case studies (n=6 subjects) having differing abnormalities. The corresponding mammograms and ultrasound images are also evaluated. Three of six cases were malignant (infiltrating ductal carcinomas) and showed higher hemoglobin (34-86% increase), a reduction in oxygen saturation, an increase in water content as well as scatter changes relative to surrounding normal tissue. Three of six cases were benign, two of which were diagnosed with fibrocystic disease and showed a dominant contrast in water, consistent with fluid filled cysts. Scatter amplitude was the main source of contrast in the volunteer with the benign condition fibrosis, which typically contains denser collagen tissue. The changes monitored correspond to physiological changes associated with angiogenesis, hypoxia and cell proliferation anticipated in cancers. These changes represent potential diagnostic indicators, which can be assessed to characterize breast tumors.

Adult↗

PubMed2004

Allele-specific loss of heterozygosity at the DAL-1/4.1B (EPB41L3) tumor-suppressor gene locus in the absence of mutation.

DAL-1/4.1B (EPB41L3)is a member of the protein 4.1 superfamily, which encompasses structural proteins that play important roles in membrane processes via interactions with actin, spectrin, and the cytoplasmic domains of integral membrane proteins. DAL-1/4.1B localizes within chromosomal region 18p11.3, which is affected by loss of heterozygosity (LOH) in various adult tumors. Reintroduction of this protein into DAL-1/4.1B-null lung and breast tumor cell lines significantly reduced the number of cells, providing functional evidence that this protein possesses a growth suppressor function not confined to a single cell type. For characterization of the mutational mechanisms responsible for loss of DAL-1/4.1B function in tumors, the exon-intron structure of DAL-1/4.1B was examined for mutations in 15 normal/tumor pairs of non-small cell lung carcinoma by single-strand conformation polymorphism analysis. These studies revealed that small intragenic mutations are uncommon in DAL-1/4.1B. Furthermore, LOH analysis on 129 informative early-stage breast tumors utilizing a new intragenic C/T single-nucleotide polymorphism in exon 14 revealed that LOH resulted in preferential retention of the C-containing allele, suggesting that allele-specific loss is occurring. These studies indicate that mechanisms such as imprinting or monoallelic expression in combination with loss of heterozygosity may be responsible for loss of the DAL-1/4.1B protein in early breast disease.

Adult↗

PubMed2004

Electromagnetic breast imaging: average tissue property values in women with negative clinical findings.

Representative data are provided for three electromagnetic breast imaging techniques-near-infrared spectroscopy, electrical impedance spectroscopy, and microwave imaging spectroscopy-to serve as potential benchmarks for future investigation. The breasts of 23 women without clinical or mammographic findings of disease were imaged in the coronal plane with nonionizing radiation of varying frequencies. Average electromagnetic property values were reconstructed at each frequency on the basis of computational models of light diffusion, current flow, and microwave propagation. Electromagnetic properties were correlated with subject characteristics and between techniques. Each technique yielded information on breast tissue features (eg, conductivity, permittivity, light scattering, and absorption) that had not previously all been measured in the same individuals.

Adult↗

PubMed2004

Analysis of the microvasculature and tissue type ratios in normal vs. benign and malignant breast tissue.

OBJECTIVE: To analyze the microvasculature and tissue type ratios in normal vs. benign and malignant breast tissue to establish a baseline for expected values against which future imaging studies can be benchmarked. STUDY DESIGN: Using computer-assisted techniques on immunostained breast tissue (normal [n = 28], fibrocystic [n = 37], fibroadenomas [n = 19], invasive carcinomas [n = 19]), values were obtained for microvessel density (MVD), mean vessel area (MVA), vessel orientation (shape) and epithelial:stromal ratio (E:S). Measurement reproducibility and the effects of fibroadenoma stromal hyalinization and fibrocystic disease severity were also tested. RESULTS: Value ranges for the 4 diagnostic groups were significantly different (P < .001). For invasive breast carcinomas, E:S and MVD were significantly higher (P < .001) but MVA was smaller as compared to that in fibroadenomas. Peripherally vs. centrally there was no significant difference in MVD, MVA or vessel shape in the neoplasms. Decreases in E:S and MVD correlated with fibroadenoma stromal hyalinization. Increases in E:S and MVA correlated with more severe fibrocystic disease. Correlation coefficients for measurement reproducibility were high across the diagnostic categories. CONCLUSION: This study established a specific, reproducible, computer-assisted technique and baseline of expected values for morphologic criteria in normal, benign and malignant breast tissue that may be used in the future to correlate new breast imaging responses with these underlying biologic properties.

Adult↗

PubMed2002

Leiomyosarcoma of the popliteal vein.

Primary vascular leiomyosarcomas are rare tumors arising from the media of vessel walls, involving the extremities in about one third of reported cases, and the popliteal vein even less frequently. We report a case of popliteal vein leiomyosarcoma in a 62-year old man who presented with leg pain and edema 4 weeks following spine surgery. Findings on ultrasound, MRI and CT angiography are reviewed, with particular emphasis on the value of CT angiography in fully evaluating the extent of the mass and in assisting percutaneous biopsy.

Angiography↗

PubMed2002

Multispectral near-infrared tomography: a case study in compensating for water and lipid content in hemoglobin imaging of the breast.

Images of hemoglobin concentration and oxygen saturation are presented from multispectral near-infrared tomographic measurements in the breast of a woman with an invasive cancer. Images of the absorption coefficient and reduced scattering coefficient are recovered from the measured data using a finite element reconstruction algorithm based on the frequency-domain diffusion equation. Three methods of recovering the hemoglobin concentration and oxygen saturation images are presented which compensate for water and lipid absorption in different ways: (1) an assumed bulk content of water and lipids is used, (2) four chromophores are imaged, and (3) scattering power data are applied to deduce water and lipid images. In all three cases, a large increase in the hemoglobin concentration (3:1) is observed at the location of the cancer while a maximum of 15% difference is observed in the hemoglobin images between each of these methods for water and lipid compensation.

Aged↗

PubMedDate not supplied

Approximation of Mie scattering parameters in near-infrared tomography of normal breast tissue in vivo.

A method for estimating Mie theory scattering parameters from diffuse light tomography measurements in breast tissue is discussed. The approach provides an estimate of the mean particle size and number density given assumptions about the index of refraction change expected in lipid-membrane-bound scatterers. When using a sparse number of wavelengths in the reduced scattering spectra, the parameter extraction technique is limited to representing a continuous distribution of scatterer sizes that appears to be dominated by an exponential decrease with increasing particle size. The fitting method is tested on simulated data and then on Intralipid-based tissue-phantom data, giving a mean particle size of 93+/-17 nm, which is in excellent agreement with expectations. The approach is also applied retrospectively to breast tissue spectra acquired from normal healthy volunteers, where the average particle size and number density were found to be in the range of 20 to 1400 nm. Grouping of the data based on radiographic breast density, as a surrogate measure of tissue composition yielded values of 20 to 65, 25 to 200, 140 to 1200, and 150 to 1400 nm, respectively, for the four BI-RADS (American College of Radiology Breast Imaging Reporting and Data System) density classifications of extremely dense, heterogeneously dense, scattered, and fatty. These results are consistent with the microscopic characteristics of each breast type given the expected progression from predominantly collagenous connective tissue (extremely dense category) to increasing proportions of glandular epithelium and fat (intermediate density categories) to predominantly fat (fatty category).

Breast↗

PubMedDate not supplied

Image reconstruction of effective Mie scattering parameters of breast tissue in vivo with near-infrared tomography.

A method for image reconstruction of the effective size and number density of scattering particles is discussed within the context of interpreting near-infrared (NIR) tomography images of breast tissue. An approach to use Mie theory to estimate the effective scattering parameters is examined and applied, given some assumptions about the index of refraction change expected in lipid membrane-bound scatterers. When using a limited number of NIR wavelengths in the reduced scattering spectra, the parameter extraction technique is limited to representing a continuous distribution of scatterer sizes, which is modeled as a simple exponentially decreasing distribution function. In this paper, image formation of effective scatterer size and number density is presented based on the estimation method. The method was evaluated with Intralipid phantom studies to demonstrate particle size estimation to within 9% of the expected value. Then the method was used in NIR patient images, and it indicates that for a cancer tumor, the effective scatterer size is smaller than the background breast values and the effective number density is higher. In contrast, for benign tumor patients, there is not a significant difference in effective scatterer size or number density between tumor and normal tissues. The method was used to interpret magnetic resonance imaging-coupled NIR images of adipose and fibroglandular tissues, and it indicated that the fibroglandular tissue has smaller effective scatterer size and larger effective number density than the adipose tissue does.

Algorithms↗