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E Anderson

Publications and source records attributed to E Anderson.

At least 91 records · Page 5Linked to original sources
PubMed1997

Assessment of hormone dependence of comedo ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) represents 20%-30% of breast cancers detected by clinical screening (i.e., mammography). More than 50% of DCIS lesions may be estrogen receptor negative and, therefore, hormone independent. However, the role of estrogen in the natural history of DCIS is unknown. PURPOSE: A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth. METHODS: Specimens of breast tissue were collected from 52 women during diagnostic or therapeutic surgical procedures. Portions of each specimen were randomly selected and analyzed by histology and thymidine labeling (to measure cell proliferation). The remainder of each specimen was implanted into five to 18 athymic BALB/c nu/nu mice (depending on the amount of tissue available), with eight pieces of approximately 2 mm x 2 mm x 1 mm implanted at different locations on the back of each mouse. Half of the mice received implants containing estrogen (2 mg 17 beta-estradiol), and the other half received placebo implants. Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specific for the Ki-67 nuclear antigen. Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens. Serum 17 beta-estradiol levels in the mice were measured by radioimmunoassay. RESULTS: Initial levels of cell proliferation were approximately 10-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versus 1.9%, respectively; two-sided P < .001). Xenografts from the majority of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation. Estrogen treatment of the xenograft-bearing mice had no effect on the high level of cell proliferation observed in estrogen receptor-negative, comedo DCIS specimens (two-sided P = .89). In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001). However, even with estrogen treatment, cell proliferation levels in estrogen receptor-positive DCIS specimens did not reach those seen in estrogen receptor-negative DCIS specimens. CONCLUSION AND IMPLICATION: Estrogen receptor-negative, comedo DCIS lesions appear to be estrogen independent; therefore, antiestrogen (e.g., tamoxifen) therapy may not benefit patients with comedo DCIS.

Adult↗
PubMed1997

Differential influence of TGFbeta1 and TGFbeta3 isoforms on cell cycle kinetics and postirradiation recovery of normal and malignant colorectal epithelial cells.

PURPOSE: A clonogenic assay was used to determine the effects of the growth factors TGFbeta1 and TGFbeta3 on the radiation responses of a normal rat epithelial cell line (IEC6) and a human colonic carcinoma epithelial cell line (Widr). METHODS AND MATERIALS: The radiation sensitivity and ability to recover from potentially lethal damage (PLD), of preconfluent monolayer cultures, was assessed in the presence of the growth factors for 24 h prior to, during, and after irradiation. RESULTS: The surviving fractions of both cell lines assessed immediately following irradiation were unaffected by TGFbeta1 or TGFbeta3. However, TGFbeta3 (but not TGFbeta1) significantly reduced the amount of PLD recovery in the Widr cells (but not in the IEC6 cells). This was associated with a reduction in the shoulder region of the survival curve, rather than a change in slope. A comparative analysis of the effects of TGFbetas 1 and 3 on cell cycle events in the two cell lines demonstrated significantly more Widr cells in the S phase, in the presence of TGFbeta3 only, compared to the controls. This remained constant both before and immediately following irradiation. In the IEC6 cell line TGFbeta3 produced an increase in the numbers of G1 phase cells, characteristic of a G1 arrest. CONCLUSION: It seems likely that TGFbeta3-induced radiosensitisation in Widr cells, 6 h after a single dose of irradiation, is related to its effects on cell cycle events such that the failure of these cells to arrest in G1, either before or after irradiation, results in significantly reduced recovery from DNA damage. This, however, may not be the only mechanism by which this growth factor produces this effect. Indeed, it will also be necessary to investigate these effects in in vivo models and to determine the response to fractionated irradiation before the potential therapeutic benefit of both the differential effects observed between the two TGFbeta isoforms and also between the malignant and normal cell lines can be fully assessed.

Animals↗
PubMed1997

Polycystic ovarian condition in the dehydroepiandrosterone-treated rat model: hyperandrogenism and the resumption of meiosis are major initial events associated with cystogenesis of antral follicles.

BACKGROUND: The purpose of this study was to elucidate the early effects of dehydroepiandrosterone (DHEA) in the polycystic rat model by charting cytological changes in the early antral follicle of the ovary and constructing a serum hormonal profile. Histological examinations of ovaries from DHEA-treated rats for ten consecutive days revealed that the oocyte of antral follicles, ranging from 1.5 mm to 3.4 mm in diameter, had become activated, i.e., had resumed meiosis. Tabulation and statistical analysis revealed a highly significant difference in the percentage of oocyte activation between the ovaries of DHEA-treated and control rats. Granulosa cells associated with those antral follicles included in our statistical analysis showed no evidence of atresia. A few follicles not included in our analysis contained oocytes that had resumed meiosis and whose associated granulosa cells were atretic. The observed resumption of meiosis occurred in the absence of surges of follicle stimulating hormone (FSH) and luteinizing hormone (LH). During meiosis, a period when many oocytes become activated, levels of serum androgens (DHEA, testosterone, and androstenedione) were high, while FSH, LH, and prolactin (PRL) levels did not differ significantly from those in the controls. Follicles that resume meiosis may be members of a group of follicles that produces a signal(s) when the oocyte becomes uncoupled from the granulosa cell. This signal(s) permit(s) a reprogramming of the accompanying granulosa cells of the follicle to engage in certain developmental processes of cystogenesis. Just what cascade of signals is necessary to achieve this selection remains elusive at this time and is the subject of our continuing investigations.

Androstenedione↗
PubMed1997

Modulation of mRNA levels in the presence of thymocytes and genome mapping for a set of genes expressed in mouse thymic epithelial cells.

Modulation of gene expression in mouse thymic epithelium upon culture in the presence of thymocytes (coculture) was studied by comparison of hybridization signatures on a set of nearly 5000 mouse thymus cDNA clones. Forty-nine differentially expressed clones (usually down-regulated in coculture) were characterized by tag sequencing. Many of them corresponded to entities that had not been described previously in the mouse, and were further characterized by genome mapping. This set of genes appears to be involved in growth regulation and differentiation within the thymus.

Animals↗
PubMed1997

The polycystic ovarian (PCO) condition: apoptosis and epithelialization of the ovarian antral follicles are aspects of cystogenesis in the dehydroepiandrosterone (DHEA)-treated rat model.

This investigation was designed to study apoptosis and epithelialization during cystogenesis of the dehydroepiandrosterone rat model. Using in situ DNA 3'- end-labeling with non-radioactive digoxigenindidesoxy-UTP (dig-ddUTP), apoptosis is initially seen in cumulus granulosa cells and other granulosa cells facing the antrum. During cystogenesis, apoptosis systematically progresses from the cumulus towards the mural granulosa layer. In contrast, granulosa cells of atretic follicles undergo apoptosis in a random manner. The outer layer of mural granulosa cells during cystogenesis escapes apoptosis. Granulosa cells contain vimentin. However, the outer mural granulosa cell layer that lines the cyst acquires keratin. In addition to being associated with each other via gap junctions, the outer layer of granulosa cells acquire tight junctions. With the characterization of the transformation of the outer mural granulosa cells into a characteristic epithelium and the orderly progression of apoptosis, we further the understanding of the multifaceted process of cystogenesis of the ovarian antral follicle.

Androgens↗
PubMed1997

Estrogen sensitivity of normal human breast tissue in vivo and implanted into athymic nude mice: analysis of the relationship between estrogen-induced proliferation and progesterone receptor expression.

High serum concentrations of estradiol (E2) equivalent to those observed in the luteal phase of the menstrual cycle stimulate both epithelial cell proliferation and progesterone receptor (PgR) expression in normal human breast tissue xenografted into athymic nude mice. We report here the results of further investigations designed to determine whether the induction of PgR expression and proliferation require different E2 concentrations and whether proliferating cells expressed the PgR. In untreated normal breast xenografts, the PgR was virtually undetectable and proliferation was at basal levels. Progesterone (Pg) treatment alone had no effect compared to no treatment. Treatment with E2 at follicular phase serum concentrations maximally increased PgR expression but was without effect on proliferation. However, treatment with E2 at luteal phase serum concentrations, alone or in combination with Pg, significantly increased both the PgR content and the proliferation of the breast epithelium. These experimentally derived data reflected the observations made on normal breast tissue at surgical biopsy where PgR content was similar in both halves of the menstrual cycle, whereas proliferation was significantly higher in the luteal phase. Finally, using double labelling techniques, it was demonstrated that proliferating epithelial cells rarely expressed PgR in normal breast tissue obtained at surgical biopsy. These results suggest that the threshold of E2 required to induce PgR expression in normal human breast epithelial cells is lower than that required to induce proliferation and that the majority of proliferating breast cells do not express the PgR.

Adult↗
PubMed1997

Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone.

The epithelial proliferation of normal human breast tissue xenografts implanted into athymic nude mice is significantly increased from basal levels by oestradiol (E2), but not progesterone (Pg) treatment at serum concentrations similar to those observed in the luteal phase of the human menstrual cycle. Type I IGF receptor (IGFR-I) mRNA and protein have been shown to be up-regulated by E2 in MCF-7 breast cancer cells in vitro in which IGF-I and E2 act synergistically to stimulate proliferation. We have investigated the expression of the IGFR-I mRNA in normal human breast xenografts treated with or without E2 or Pg alone and in combination. Northern analysis of 20 micrograms of RNA extracted from the breast xenograft samples showed no hybridization with 32P-labelled IGFR-I probe, although an 11-kb species of IGFR-I mRNA could be seen when 20 micrograms of RNA extracted from either MCF-7 breast cancer cells or human breast carcinomas was examined in this way. In order to analyse the expression of IGFR-I mRNA in breast xenografts, a quantitative reverse transcription-polymerase chain reaction (RT-PCR) was employed in which RNA loading, reverse transcription and PCR efficiencies were internally controlled. The data indicate that the IGFR-I mRNA is up-regulated by two to threefold compared with untreated levels by 7 and 14 days E2 treatment. In contrast, 7 or 14 days Pg treatment down-regulates the receptor mRNA to approximately half that of untreated levels, whereas combination E2 and Pg treatment produced a twofold increase in IGFR-I mRNA levels compared with untreated tissue. The results are consistent with the suggestion that E2 may act to stimulate proliferation indirectly via a paracrine mechanism involving IGFs in normal as well as malignant human breast epithelial cells.

Animals↗
PubMed1997

Influence of dehydroepiandrosterone on the expression of insulin-like growth factor-1 during cystogenesis in polycystic rat ovaries and in cultured rat granulosa cells.

This study was designed to investigate the expression of insulin-like growth factor-1 (IGF-1) during cystogenesis in the dehydroepiandrosterone (DHEA)-induced rat polycystic ovarian syndrome (PCO) model. IGF-1 expression patterns in DHEA-treated rat ovaries were compared with those in control ovaries. In situ hybridization revealed a similar distribution of IGF-1 mRNA in DHEA-treated and control ovaries: in both, IGF-1 mRNA expression was confined to the granulosa cells of preantral and small antral follicles. Some hybridization signals for IGF-1 mRNA were also found in theca and infrequently in the interstitial cells. No signal was observed in larger antral follicles, atretic follicles, or cysts. This similarity indicates that there might be a shared mechanism in the early follicular development of normal folliculogenesis and DHEA-induced cystogenesis. The effects of DHEA on granulosa cells were analyzed in vitro in their quiescent, proliferative, differentiative, and preovulatory stages. Northern analysis revealed three transcripts for IGF-1 (7.5 kilobases [kb], 1.6 kb, and a group of signals between 0.4 and 0.9 kb) in cells at all stages except the preovulatory. The strongest signal was observed in cells of the proliferative stage of control cultures, while expression of IGF-1 increased only in the DHEA-treated cells cultured in the differentiative stage (when they secrete estrogen). Increase in IGF-1 expression may contribute to the hypersteroidogenism observed in the DHEA-treated rat PCO model.

Animals↗
PubMed1997

Steroidogenic acute regulatory (StAR) protein (p25) and prohibitin (p28) from cultured rat ovarian granulosa cells.

This study has identified and characterized two intracellular proteins (25 and 28 kDa) during ongoing differentiation of rat granulosa cells isolated from preantral and early antral follicles. The identity of p25 was confirmed as the mitochondria associated StAR protein by western blotting analysis. In the culture conditions used, this protein was expressed only when granulosa cells were stimulated with FSH to produce progesterone. It is apparent that the steroidogenic differentiation of granulosa cells affects StAR expression. Amino acid sequence analysis of p28 identified it as prohibitin and was corroborated by western blot analysis with antibodies specific for rat prohibitin. During the ongoing differentiation of granulosa cells there were changes in the expression of p28/prohibitin. Although prohibitin is constitutively expressed in granulosa cells, there is an increase in the more acidic isoform of prohibitin when oestrogen concentrations are raised by increased production or exogenous addition. This increase in this acidic isoform of prohibitin is due to phosphorylation. It is possible that oestrogen induces phosphorylation of prohibitin and, thus, may be involved in the regulation of granulosa cell proliferation and the ontogeny of the ovarian follicle.

Androstenedione↗
PubMed1997

Fish vaccine antigens produced or delivered by recombinant DNA technologies.

Current efforts to develop vaccines, particularly for aquacultured species, have turned largely to biotechnology because it provides the means to inexpensively produce sufficient quantities of the immunoprotective antigen. These efforts have resulted in several prototype vaccines for fish and the publication of a large number of articles on the subject. However, there are only a few recombinant DNA-based vaccines for aquaculture in the licensing pipeline. Continued funding of research on recombinant DNA vaccines comes from the recognition by industry and government funding agencies that this research can lead to an increased understanding of the mechanisms in protective immunity. This is especially important for fish and shellfish species since our knowledge of the immune mechanisms in these animals is pitifully meagre. This presentation discusses the relative merits of the different recombinant DNA technologies that have been used to produce viral vaccines for fish and the promising approaches that are under consideration to increase the efficacy of these vaccines. There are many approaches to antigen production by recombinant DNA techniques including: (i) the preparation of purified antigenic proteins produced from the cloned viral genes in a variety of vector/host expression systems, (ii) chemical synthesis or the use of fusion vectors to produce peptides corresponding to known epitopes, (iii) defined attenuations, i.e. specific genetic alterations, of live virus vaccines, (iv) the use of live bacterial or viral vectors to deliver resistance genes or viral antigens, (v) anti-idiotype antibodies, and (vi) DNA vaccines where purified plasmid DNA expressing the pathogen gene under a eucaryotic promoter is injected. All of these technologies have been used more or less successfully in the development of vaccines for aquacultured species. However, the requirements for safety, effectiveness, ease of application and low cost/dose restrict their commercial development for aquaculture. The ideal viral vaccine for aquaculture must be effective in preventing death, be inexpensive to produce and license, provide immunity of long duration, and be easily administered. In addition, these vaccines must not only provide protection against the lethal effects of virus infection but prevent the formation of virus persistence. This is especially true for infectious haematopoietic necrosis virus (IHNV) which has been shown to persist in survivors in the presence of high antibody levels. Since resolution of virus persistence is thought to be correlate with cell-mediated immunity, vaccines designed to augment the cell-mediated immunity must be developed for fish. Approaches that are being considered include the use of cytokines in combination with subunit vaccines and the use of specific MHC-I inducer adjuvants with the vaccine. The "tailoring" of vaccine immunogenicity using different combinations of antigen and adjuvant will be presented.

Animals↗
PubMed1996

Spatial Response of Mammals to Late Quaternary Environmental Fluctuations

Analyses of fossil mammal faunas from 2945 localities in the United States demonstrate that the geographic ranges of individual species shifted at different times, in different directions, and at different rates in response to late Quaternary environmental fluctuations. The geographic pattern of faunal provinces was similar for the late Pleistocene and late Holocene, but differing environmental gradients resulted in dissimilar species composition for these biogeographic regions. Modern community patterns emerged only in the last few thousand years, and many late Pleistocene communities do not have modern analogs. Faunal heterogeneity was greater in the late Pleistocene.

Journal Article↗
PubMed1996

The Seismic Structure of the Sun

Global Oscillation Network Group data reveal that the internal structure of the sun can be well represented by a calibrated standard model. However, immediately beneath the convection zone and at the edge of the energy-generating core, the sound-speed variation is somewhat smoother in the sun than it is in the model. This could be a consequence of chemical inhomogeneity that is too severe in the model, perhaps owing to inaccurate modeling of gravitational settling or to neglected macroscopic motion that may be present in the sun. Accurate knowledge of the sun's structure enables inferences to be made about the physics that controls the sun; for example, through the opacity, the equation of state, or wave motion. Those inferences can then be used elsewhere in astrophysics.

Journal Article↗
PubMed1996

Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes.

Effects of the pure antiestrogen ICI182780 and tamoxifen on ER-protein, ER-mRNA, and estrogen-regulated mRNA expression were analysed using matched pretreatment core-cut biopsies and post-treatment mastectomy samples from 43 ER positive human breast cancers. Sixteen controls received either no preoperative treatment (n = 9) (7 days) or placebo (n = 7) (median 21 days) prior to primary surgery. Nineteen patients received ICI182780 6 mg/day (n = 10) or 18 mg/day (n = 9) for 7 days. Eight patients were given preoperative tamoxifen (4 x 40 mg-day 1, 20 mg/day thereafter, median 21 days). ER-protein expression was assessed on pre and post treatment samples by immunocytochemistry. ER, pS2, pLIV1, and actin-mRNA expression was determined by northern analysis on post-treatment samples only. ER-mRNA levels were similar to controls following ICI182780 or tamoxifen treatment. However ER-protein levels were significantly suppressed by ICI182780, particularly at the higher dosage (p = 0.0013). Tamoxifen had no significant effect on ER-protein levels. The ER-mRNA and ER-protein contents of control tumors were linearly related (Spearman r = 0.719, p = 0.006). A similar relationship between pretreatment protein and post ICI182780 treatment mRNA levels was observed (r = 0.652, p = 0.005). However, comparison of post ICI182780 treatment protein and mRNA results shows a loss of linearity through a reduction in protein without concurrent loss of mRNA (r = 0.28, p = 0.257). pS2 mRNA hybridization was lower in ICI182780 treated samples than controls (Mann-Whitney p = 0.035) but was unaffected by tamoxifen. pLIV1 mRNA hybridization was uninfluenced by either treatment. Short term exposure of breast tumors to ICI182780 appears to produce a greater inhibition of estrogen-induced transcriptional events than tamoxifen. These effects appear to occur without a concurrent reduction in ER mRNA levels.

Antineoplastic Agents, Hormonal↗
PubMed1996

New endocrine therapies for breast cancer.

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.

Animals↗
PubMed1996

The effects of dehydroepiandrosterone (DHEA) and its metabolites on the polycystic ovarian condition (PCO): cystogenic changes of rat granulosa cells in vitro.

During mammalian folliculogenesis, granulosa cells (GCs) are initially steroidogenically quiescent, later proliferate, and subsequently commence to hormonally differentiate, first producing estrogen and later, in the preovulatory stage, secreting both estrogen and progesterone. In this study and elsewhere, we have used follicle-stimulating hormone with a combination of growth factors in vitro to simulate the above in vivo conditions. In a previous study, we used dehydroepiandrosterone (DHEA) to accomplish the polycystic ovary condition (PCO) in rats. In the latter model, there were high circulating levels of DHEA and its metabolite, androstenedione. In the present study, we investigated the effects of high levels of DHEA (10(-5) M) and its metabolites, androstenedione, androstenediol and dehydroepiandrosterone sulfate on the quiescent, proliferative, and steroidogenically differentiating stages of GCs cultured in a serum-free medium for up to 10 days. In addition to possessing the regularly occurring organelles, when cultured with the aforementioned androgens, the GCs acquired endoplasmic reticulum of the smooth variety which is associated with steroidogenesis. The radioimmunoassay data showed that GCs cultured in the quiescent and proliferative stages in the presence of the androgens, no longer remain in these stages but proceed to differentiate in a preovulatory direction by producing both estrogen and progesterone. This study supports our hypothesis that high circulating levels of DHEA and/or its metabolites have most effect during the quiescent and proliferative stages of granulosa cells, with regard to their structure and their steroidogenic activities.

Androstenediols↗