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Elizabeth R Smith

Publications and source records attributed to Elizabeth R Smith.

15 recordsLinked to original sources
PubMed2025

Mutant p53 disrupts antioxidant defense in fallopian tube epithelium via GSTAs suppression: A pathway to serous tubal carcinogenesis.

High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of epithelial ovarian cancer. The fimbria of the fallopian tube is the likely site of origin based on the presence of distinct precancerous lesions with TP53 signatures known clinically as serous tubal intraepithelial carcinoma (STICs) detected in this region in individuals at genetically high risk or with HGSOC. Previously we identified that matched fallopian tube epithelia (FTE) from fimbria and ampulla of normal fallopian tubes from premenopausal women exhibit differential expression of genes associated with antioxidant and inflammatory pathways. One gene, glutathione S-transferase 2 (GSTA2), showed both higher expression in the fimbria and in the follicular phase (pre-ovulation) compared to the ampulla, suggesting that GSTA2 expression may regulate reactive oxygen homeostasis in these cells in response to ovulation-related stress. Here, to understand how preneoplastic genomic alterations influence regulation of oxidative stress, FTE cells were isolated from healthy tissue and introduced with p53 mutations, from which expression and function of GSTA2 and other antioxidant enzymes were investigated. Mutant p53 downregulated the expression of GSTA2 and subsequently increased DNA damage. The combination of p53 mutation and dysregulated oxidative response likely promotes the genomic instability that initially drives the transformation to high grade serous ovarian carcinoma.

Female↗
PubMed2006

Disabled-2 heterozygous mice are predisposed to endometrial and ovarian tumorigenesis and exhibit sex-biased embryonic lethality in a p53-null background.

Disabled-2 (Dab2) is a phosphoprotein involved in cellular signal transduction and endocytic trafficking. The expression of Dab2 is frequently lost or suppressed in several epithelial tumors, and studies of its cellular function and growth suppressive activity when re-expressed in cancer cells led to the suggestion that Dab2 is a tumor suppressor. A role for Dab2 in epithelial cell positioning organization was derived from study of knockout mice: homozygous deletion of dab2 results in early embryonic lethality due to the disorganization of the primitive endoderm, the first epithelium in early embryos. We now report that dab2 heterozygous mice develop uterine hyperplasia and ovarian preneoplastic morphological changes at a high frequency. Crossing into a p53(-/-) background unexpectedly produced few female dab2(+/-):p53(-/-) mice, while the male dab2(+/-):p53(-/-) were born at the expected Mendelian frequency. The tumor-prone phenotype of dab2(+/-) mice provides additional support for a role of human Dab2 as a tumor suppressor, and the sex-biased embryonic lethality suggests a genetic interaction between p53 and dab2 genes in female mice.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Regulation of Ras-MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells.

In response to retinoic acid, embryonic stem and carcinoma cells undergo differentiation to embryonic primitive endoderm cells, accompanied by a reduction in cell proliferation. Differentiation does not reduce the activation of cellular MAPK/Erk, but does uncouple mitogen-activated protein kinase (MAPK) activation from phosphorylation/activation of Elk-1 and results in inhibition of c-Fos expression, whereas phosphorylation of the cytoplasmic substrate p90RSK remains unaltered. Cell fractionation and confocal immunofluorescence microscopy demonstrated that activated MAPK is restricted to the cytoplasmic compartment after differentiation. An intact actin and microtubule cytoskeleton appears to be required for the restriction of MAPK nuclear entry induced by retinoic acid treatment because the cytoskeletal disrupting agents nocodazole, colchicine, and cytochalasin D are able to revert the suppression of c-Fos expression. Thus, suppression of cell proliferation after retinoic acid-induced endoderm differentiation of embryonic stem and carcinoma cells is achieved by restricting nuclear entry of activated MAPK, and an intact cytoskeleton is required for the restraint.

Active Transport, Cell Nucleus↗
PubMed2004

Using science to assess environmental vulnerabilities.

Beginning in 1995, the U.S. Environmental Protection Agency (U.S. EPA), Office of Research and Development has focused much of its ecological research in the Mid-Atlantic as part of the Mid-Atlantic Integrated Assessment (MAIA). The goal of MAIA is to improve the assessability of scientific information in environmental decision-making. Following the Environmental Monitoring and Assessment Program (EMAP) whose goal is to guide monitoring that effectively reflects current ecosystem condition and trends, MAIA's second, current, phase of research under the Regional Vulnerability Assessment (ReVA) program is designed to target risk management activities using available data and models. The papers presented here are from a conference held in May 2003 that presented results of research in this second phase of MAIA. The conference was organized into the following topics: 1. Assessing Current Impacts and Vulnerabilities 2. Forecasting Environmental Condition and Vulnerabilities 3. Developing Management Strategies to Optimize the Future, and 4. Assessing and Responding to Environmental Vulnerability.

Environmental Monitoring↗
PubMed2004

An overview of data integration methods for regional assessment.

The U.S. Environmental Protections Agency's (U.S. EPA) Regional Vulnerability Assessment(ReVA) program has focused much of its research over the last five years on developing and evaluating integration methods for spatial data. An initial strategic priority was to use existing data from monitoring programs, model results, and other spatial data. Because most of these data were not collected with an intention of integrating into a regional assessment of conditions and vulnerabilities, issues exist that may preclude the use of some methods or require some sort of data preparation. Additionally, to support multi-criteria decision-making, methods need to be able to address a series of assessment questions that provide insights into where environmental risks are a priority. This paper provides an overview of twelve spatial integration methods that can be applied towards regional assessment, along with preliminary results as to how sensitive each method is to data issues that will likely be encountered with the use of existing data.

Animals↗
PubMed2004

Integrated environmental assessment of the Mid-Atlantic region with analytical network process.

A decision analysis method for integrating environmental indicators was developed. This was a combination of Principal Component Analysis (PCA) and the Analytic Network Process (ANP). Being able to take into account the interdependency among variables, the method was capable of ranking ecosystems in terms of environmental conditions and suggesting cumulative impacts across a large region. Using data on land cover, population, roads, streams, air pollution, and topography of the Mid-Atlantic Region of the United States, we were able to point out areas which were in relatively poor condition and/or vulnerable to future deterioration regarding various environmental aspects. The method offered an easy and comprehensive way to combine the strengths of conventional multivariate statistics (PCA) and decision-making science tool (ANP) for integrated environmental assessment.

Conservation of Natural Resources↗
PubMed2003

Self-organizing maps for integrated environmental assessment of the Mid-Atlantic region.

A new method has been developed to perform environmental assessment at regional scale. This involves a combination of a self-organizing map (SOM) neural network and principal component analysis (PCA). The method is capable of clustering ecosystems in terms of environmental conditions and suggesting relative cumulative environmental impacts of multiple factors across a large region. Using data on land-cover, population, roads, streams, air pollution, and topography of the Mid-Atlantic region, the method was able to indicate areas that are in relatively poor environmental condition or vulnerable to future deterioration. Combining the strengths of SOM with those of PCA, the method offers an easy and useful way to perform a regional environmental assessment. Compared with traditional clustering and ranking approaches, the described method has considerable advantages, such as providing a valuable means for visualizing complex multidimensional environmental data at multiple scales and offering a single assessment or ranking needed for a regional environmental assessment while still facilitating the opportunity for more detailed analyses.

Environmental Monitoring↗
PubMed2002

Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis.

The signal transduction adapter protein Disabled-2 (Dab2) is one of the two mammalian orthologs of the Drosophila Disabled. The brain-specific Disabled-1 (Dab1) functions in positional organization of brain cells during development. Dab2 is widely distributed and is highly expressed in many epithelial cell types. The dab2 gene was interrupted by in-frame insertion of beta-galactosidase (LacZ) in embryonic stem cells and transgenic mice were produced. Dab2 expression was first observed in the primitive endoderm at E4.5, immediately following implantation. The homozygous Dab2-deficient mutant is embryonic lethal (earlier than E6.5) due to defective cell positioning and structure formation of the visceral endoderm. In E5.5 dab2 (-/-) conceptus, visceral endoderm-like cells are present in the deformed primitive egg cylinder; however, the visceral endoderm cells are not organized, the cells of the epiblast have not expanded, and the proamniotic cavity fails to form. Disorganization of the visceral endodermal layer is evident, as cells with positive visceral endoderm markers are scattered throughout the dab2 (-/-) conceptus. Only degenerated remains were observed at E6.5 for dab2 (-/-) embryos, and by E7.5, the defective embryos were completely reabsorbed. In blastocyst in vitro culture, initially cells with characteristics of endoderm, trophectoderm, and inner cell mass were observed in the outgrowth of the hatched dab2 (-/-) blastocysts. However, the dab2 (-/-) endodermal cells are much more dispersed and disorganized than those from wild-type blastocysts, the inner cell mass fails to expand, and the outgrowth degenerates by day 7. Thus, Dab2 is required for visceral endodermal cell organization during early mouse development. The absence of an organized visceral endoderm in Dab2-deficient conceptus leads to the growth failure of the inner cell mass. We suggest that Dab2 functions in a signal pathway to regulate endodermal cell organization using endocytosis of ligands from the blastocoel cavity as a positioning cue.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Dynamic alterations of the extracellular environment of ovarian surface epithelial cells in premalignant transformation, tumorigenicity, and metastasis.

BACKGROUND: Ovarian surface epithelial cells are positionally organized as a single cell layer by a sheet of basement membrane. It is believed that the contact of the ovarian surface epithelial cells with the basement membrane regulates cell growth and ensures the organization of the epithelium. Disabled-2 (Dab2), a signal transduction protein and a candidate tumor suppressor of ovarian carcinoma, functions in positional organization of ovarian surface epithelial cells. In ovarian carcinomas, genetic and epigenetic changes enable the tumor cells to escape positional control and proliferate in a disorganized fashion. Alterations in the extracellular environment may also be critical for tumor initiation and progression. METHODS: We analyzed and compared the presence of collagen IV and laminin, the scaffold proteins of the basement membrane, and Dab2 in 50 ovarian tumors that are restricted to the ovaries and in 50 metastases of ovarian tumors by immunohistochemistry. Expression of collagen IV, laminin, and Dab2 was also analyzed by Northern blotting in a panel of human ovarian surface epithelial and cancer cell lines. RESULTS: The basement membrane is often absent in morphologically benign ovarian surface and cyst epithelium and low-grade tumors and collagen IV and laminin are absent in the extracellular matrix of most of the primary tumors tested. Of the 50 ovarian tumors confined to the ovaries, 6% (3 of 50) were collagen IV positive and 24% (12 of 50) were laminin positive tumors. Of the 50 metastatic tumors, 16% (8 of 50) are collagen IV positive and 86% (43 of 50) are laminin positive. In addition, even in the metastatic ovarian tumors that are largely collagen IV negative, there are pockets of local areas in which the tumor cells are surrounded by collagen IV-positive staining. Dab2 is absent in the majority of ovarian tumors found in both ovaries and metastatic sites. In both nontumorigenic human ovarian surface epithelial and cancer cell lines, collagen IV, laminin, and Dab2 are expressed aberrantly. CONCLUSIONS: Loss of the basement membrane may be an early event in the preneoplastic transformation of ovarian surface epithelium and in the early stages of tumorigenesis before tumor invasion and metastasis. The majority of primary ovarian tumors examined lack collagen IV and laminin in their extracellular matrix. However, expression of laminin is restored in the majority of metastatic tumors. Reexpression of collagen IV may also contribute to tumor metastasis. The ability of tumor cells to dynamically alter the expression of collagen IV and laminin may facilitate the shedding of cancer cells into the peritoneal spaces and subsequent attachment to the metastatic sites. We propose that loss of collagen IV and laminin may be an initial event in ovarian tumorigenicity and that restoration of collagen IV and laminin expression in the later stages of tumor development may promote metastasis of ovarian tumors.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Ras/MAPK pathway confers basement membrane dependence upon endoderm differentiation of embryonic carcinoma cells.

The formation of extraembryonic endoderm is one of the earliest steps in the differentiation of pluripotent cells of the inner cell mass during the early stages of embryonic development. The primitive endoderm cells and the derived parietal and visceral endoderm cells gain the capacity to produce collagen IV and laminin. The deposition of these components results in the formation of basement membrane and epithelium of the endoderm, with polarized cells covering the inner surface of the blastocoels. We used retinoic acid-induced endoderm differentiation of stem cell-like F9 embryonic carcinoma cells to study the role of the Ras pathway and its regulation in the formation of the visceral endoderm. Upon endoderm differentiation of F9 cells induced by retinoic acid, c-Fos expression, the downstream target of the Ras pathway, is suppressed by uncoupling Elk-1 phosphorylation/activation to MAPK activity. However, attachment to matrix gel greatly enhances the activation of MAPK in endoderm cells but not in undifferentiated F9 cells. Enhanced MAPK activation as a result of contact with basement membrane is able to compensate for reduced Elk-1 phosphorylation and c-Fos expression. We conclude that endoderm differentiation renders the activation of the Ras pathway basement membrane dependent, contributing to the epithelial organization of the visceral endoderm.

Animals↗
PubMed2002

Molecular events associated with dysplastic morphologic transformation and initiation of ovarian tumorigenicity.

BACKGROUND: Disabled-2 (Dab2), a candidate tumor suppressor of ovarian carcinoma, frequently (around 80%) loses its expression in ovarian tumors. Expression of exogenous Dab2 in tumor cell lines negatively regulates growth and suppresses the downstream signal of the Ras/mitogen activated protein kinase mitogenic pathway. The inactivation of Dab2 is believed to be an early event in ovarian tumorigenicity. METHODS: The authors analyzed the correlation among expression of Dab2, presence of basement membrane (collagen IV and laminin), morphologic alteration of the surface epithelial cells, and expression of the mitotic index marker Mib-1 in 50 archived ovarian tumors by an immunohistochemical approach. The stainings of Dab2, Mib-1, collagen IV, and laminin in premalignant lesions bordering both normal and neoplastic ovarian surface epithelium from adjacent slides were analyzed in 50 ovarian tumors. RESULTS: In these 50 ovarian tumors, the percentage of Mib-1 positive tumor cells distributed in a wide range, from 1% to 75%, and there has no strong correlation with the expression of Dab2. However, in the premalignant regions bordering tumor and normal ovarian surface epithelium, the loss of Dab2 expression closely correlated with the dysplastic morphologic transition and Mib-1 expression of the ovarian surface epithelial cells. In 20 foci in 12 out of the 50 tumors, a transition from normal to neoplastic morphology within a contiguous epithelium was observed, and in all cases the morphologic change correlated with the loss of Dab2 staining. In addition, the collagen and laminin staining of the basement membrane were absent or weakened in pre-malignant epithelium prior to loss of Dab2 expression in all these 20 cases. Nevertheless, collagen IV and laminin were detectable in established adenomas on the same tumor slides. CONCLUSIONS: The loss of Dab2 is closely associated with the transition of ovarian surface epithelial cells to premalignant states and is likely involved in the initiation of ovarian tumorigenicity. Transient loss of collagen IV and laminin in the basement membrane of the premalignant epithelium and subsequent inactivation of Dab2 are common early events associated with tumorigenicity of the ovarian surface epithelium.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Fuzzy decision analysis for integrated environmental vulnerability assessment of the mid-Atlantic Region.

A fuzzy decision analysis method for integrating ecological indicators was developed. This was a combination of a fuzzy ranking method and the analytic hierarchy process (AHP). The method was capable of ranking ecosystems in terms of environmental conditions and suggesting cumulative impacts across a large region. Using data on land cover, population, roads, streams, air pollution, and topography of the Mid-Atlantic region, we were able to point out areas that were in relatively poor condition and/or vulnerable to future deterioration. The method offered an easy and comprehensive way to combine the strengths of fuzzy set theory and the AHP for ecological assessment. Furthermore, the suggested method can serve as a building block for the evaluation of environmental policies.

Air Pollution↗
PubMedDate not supplied

Diagnosis and treatment frequency for overweight children and adolescents at well child visits.

Obesity in children is a rapidly growing problem and may be underrecognized by pediatricians. We reviewed 473 consecutive well child visits to assess frequency of correctly identifying overweight children. Of children with a body mass index greater than the 95th percentile for gender and age, only 27 (29%) were diagnosed as overweight by the physician. Our results suggest that the frequency of diagnosing children as overweight at well child visits is critically low.

Adolescent↗