PubMed Health⌕ Search

Biomedical subjects

D S Coffey

Publications and source records attributed to D S Coffey.

At least 55 records · Page 3Linked to original sources
PubMed1992

Characterization of nuclear morphology and nuclear matrices in ageing human fibroblasts.

It is believed that the mechanisms for cellular senescence may reside within the genome, however, the changes which occur in the DNA and the surrounding nuclear environment have not been well documented. As the dynamic skeletal framework of the nucleus, the nuclear matrix is poised to play a critical role in the ageing process. The nuclear matrix plays a central role in DNA organization and nuclear structural morphology. The important roles of the nuclear matrix in cell structure and function are demonstrated by its properties of tissue specificity and that it is altered by viral infection, differentiation and carcinogenesis. We therefore undertook a study to investigate the morphologic alterations which occur in ageing nuclei and to determine whether compositional changes in the nuclear matrix occur with age in human skin fibroblasts. We found that as the nucleus increases in size and becomes more round with age, the qualitative pattern of the prominent nuclear matrix proteins does not appear to undergo major changes with age. There do, however, appear to be quantitative alterations in these proteins.

Cell Line↗
PubMed1992

Soy of dietary source plays a preventive role against the pathogenesis of prostatitis in rats.

This study examined the effects of diet on the development of prostatitis in male rats. Adult male rats were placed on either of two specially formulated diets which differed from one another by the presence or absence of soy as the protein source. A third group of rats (control) was fed standard laboratory rat chow which also includes soy as a source of protein. After 11 weeks, it was found that rats maintained on soy-free diet developed prostatitis mainly in the lateral lobe of the prostate. Increased severity and incidence of prostatitis in rats maintained on the soy-free diet coincided with a significant decrease in urinary excretion of various phytoestrogens. There was no evidence of prostatitis in rats maintained on soy-containing diets. Urinary excretion of phytoestrogens in rats maintained on soy-containing diet was also not different from controls. These results suggest that soy as a dietary source plays a protective role against the development of prostatitis in rats, and indicate that the ventral, lateral and dorsal lobes of the rat prostate have different sensitivities to alterations in dietary factors.

Animals↗
PubMed1992

Recombinant human tumor necrosis factor enhances radiosensitivity and improves animal survival in murine neuroblastoma.

An analysis of the potential of recombinant human tumor necrosis factor to enhance the radiosensitivity of C1300 murine neuroblastoma was undertaken. Female A/J mice bearing C1300 murine neuroblastoma (right hindlimb) underwent the following treatments: group 1-0.25 cc normal saline intraperitoneally times 2, group 2-0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2, group 3-400 cGy. right hindlimb, group 4-800 cGy. right hindlimb, group 5-400 cGy. right hindlimb plus 0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2 and group 6-800 cGy. right hindlimb plus 0.5 mcg./gm. recombinant human tumor necrosis factor intraperitoneally times 2. All animals were followed for 21 days after treatment initiation with interval measurements of tumor volume. All single modality treatments were more effective than normal saline in reducing average tumor volumes during the study period (800 cGy. equals recombinant human tumor necrosis factor greater than 400 cGy. greater than normal saline). The addition of recombinant human tumor necrosis factor to radiotherapy moderately augmented antitumor response at radiation doses of 400 cGy. but marked enhancement was attained at radiation doses of 800 cGy. (p less than 0.02). This enhancement was achieved without increased animal morbidity or mortality. Animals receiving recombinant human tumor necrosis factor in addition to 800 cGy. demonstrated increased survival when compared with animals receiving 800 cGy. alone (p less than 0.02). Although statistical synergy was not proved, recombinant human tumor necrosis factor appears to augment significantly radiation-induced tumor regression at no toxic cost to the animal.

Animals↗
PubMed1992

The biology of prostate cancer: new and future directions in predicting tumor behavior.

Because the present ability to treat and cure patients with prostate cancer is limited to those patients with pathologically organ-confined disease, it has become increasingly important to diagnose this disease at an early stage when cure is most likely. Recent advances in imaging may allow the urologist and pathologist to make the diagnosis of prostate cancer much earlier in the natural course of the disease. It therefore becomes imperative to have methods available to predict which patients have a high probability of progressing so that treatment can be assigned logically and appropriately. Our current methods of prognosis determination (stage and grade) do not allow accurate assessment of tumor behavior in the majority of individual patients with prostate cancer. Therefore, more accurate quantification of nuclear and cellular changes that take place as a tumor progresses to take on the aggressive (metastatic) phenotype are urgently needed. Experimental techniques have proven useful in answering these questions in animal models and now seem ready for large-scale testing in clinical studies.

Biomarkers, Tumor↗
PubMed1991

Identification of nuclear matrix proteins in the cancer and normal rat prostate.

The nuclear matrix is the structural component of the nucleus that determines nuclear morphology and organizes the DNA in a three-dimensional fashion that is tissue specific. Previously, some of the nuclear matrix proteins have been reported to be both tissue and cell type specific and are altered with the state of differentiation and transformation. This study demonstrates that the nuclear matrix is specific for the individual lobes of the normal rat prostate and that the nuclear matrix undergoes changes in protein composition in the Dunning prostate cancer tissue. Additionally, in the Dunning rat prostate adenocarcinoma cell lines, there is a range of tumor phenotypes and the nuclear matrix varies in composition in each tumor cell type. These differences in the nuclear matrix proteins are associated with quantitative changes in nuclear morphology that form the pleiomorphic state of the cancer nucleus.

Adenocarcinoma↗
PubMed1991

Correlation of nuclear morphometry with progression of breast cancer.

Alterations in nuclear structure are the morphologic hallmark of cancer diagnosis. Nuclear size, shape, chromatin pattern, and nucleolar size and number have all been reported to change in breast cancer. Attempts to quantify nuclear alterations to establish grading systems, predict prognosis, and/or set guidelines for therapy have met with varied success. Therefore, the authors quantified the changes that occur with breast cancer with nuclear morphology in several different groups of patients: normal controls, intraductal carcinoma, invasive ductal carcinoma with negative nodes at mastectomy, and invasive ductal carcinoma with positive lymph nodes. Pleomorphism as measured by both nuclear area and intrasample variation increased with invasive histology and metastatic breast cancer. It is still unclear whether node-negative Stage II breast cancer requires adjuvant therapy. This issue would be less complicated if it were possible to identify those women at high risk of recurrence. Therefore, the authors retrospectively identified 30 women with node-negative Stage II infiltrating ductal carcinoma with a long follow-up period of 6 to 12 years. Computer-assisted morphometry of nuclei in routine hematoxylin and eosin-stained pathologic slides was done using the DynaCell Analysis System in a blinded fashion. DynaCell measures 15 nuclear parameters, including perimeter, area volume, roundness, and ellipticity. Although nuclear area and variance were related to breast cancer progression, nuclear morphometry did not predict successfully which patients would have recurrent disease in the women with Stage II, node-negative lesions at the time of mastectomy.

Adult↗
PubMed1991

The effect of extracellular matrix interactions on morphologic transformation in vitro.

There is emerging evidence that the structure and function of a cell is dependent in part on the contacts that cells make with the extracellular matrix. We report here the effect of extracellular matrices secreted from both normal and tumor cells have on the structure of normal rat kidney epithelial cells. Normal rat kidney cells plated on the basement membrane secreted by tumor cells adopt a morphology and phenotype which closely resembles a Kirsten-ras transformed normal rat kidney cell. This morphologic transformation was not observed for cells plated on individual extracellular matrix components or on basement membrane secreted by normal placenta cells. This suggests that tumor derived basement membrane has unique characteristics which may cause morphologic transformation of normal rat kidney cells.

Animals↗
PubMed1991

Modifications of the intermediate filament and nuclear matrix networks by the extracellular matrix.

The tissue matrix system is a dynamic, interacting structural network directly linking the nuclear matrix, cytoskeleton and the extracellular matrix. We report here that interaction of normal rat kidney epithelial cells (NRK) and Kirsten-ras transformed rat kidney cells, with an extracellular matrix secreted by tumor cells, causes modifications to the protein composition of the intermediate filament and nuclear matrix networks. The matrix networks are different between normal and transformed cells; however, these alterations by the tumor extracellular matrix are similar in both cell types. These data represent the first report that modification of the extracellular matrix environment can have an effect on the protein composition of the nuclear matrix.

Animals↗
PubMed1991

Preneoplastic alterations in nuclear morphology that accompany loss of tumor suppressor phenotype.

Alterations of nuclear shape are frequently observed in tumor cells, but the genes controlling these changes and the stage in the neoplastic process at which they occur are unknown. We have studied nuclear shape changes in chemically immortalized, nontumorigenic Syrian hamster embryo cell clones that had either retained (supB+) or lost (supB-) the ability to suppress the tumorigenic phenotype when they were hybridized with a tumor cell line (BP6T). Quantitative morphometric analysis of the nuclei of cells from each of two pairs of supB+/supB- variants indicated that the nuclei of supB- cells were significantly more out of round than those of their corresponding supB+ clones. These data indicate that modification of nuclear structure may represent an early, preneoplastic event in multistep chemical carcinogenesis and that loss of a tumor suppressor gene function may regulate alterations in nuclear morphology.

Animals↗
PubMed1991

Nuclear structure and the three-dimensional organization of DNA.

The organization of DNA within the nucleus has been demonstrated to be both cell and tissue specific and is arranged in a non-random fashion in both sperm and somatic cells. Nuclear structure has a pivotal role in this three-dimensional organization of DNA and RNA and contributes as well to forming fixed organizing sites for nuclear functions, such as DNA replication, transcription, and RNA processing. In sperm, DNA is also organized in a specific fashion by the nuclear matrix and DNA-protamine interactions. Within somatic cells, the nuclear matrix provides a three-dimensional framework for the tissue specific regulation of genes by directed interaction with transcriptional activators. This differential organization of the DNA by the nuclear matrix, in a tissue specific manner, contributes to tissue specific gene expression. The nuclear matrix is the first link from the DNA to the entire tissue matrix system and provides a direct structural linkage to the cytomatrix and extracellular matrix. In summary, the tissue matrix serves as a dynamic structural framework for the cell which interacts to organize and process spatial and temporal information to coordinate cellular functions and gene expression. The tissue matrix provides a structural system for integrating form and function.

Animals↗
PubMed1991

Influence of age, strain, and the testes on rat prostate hormone sensitivity.

There are conflicting reports in the literature regarding the response of the rat prostate to various androgen/estrogen combinations. The reason for these conflicting results has been unclear. The purpose of the present study was to assess factors that may determine the effect of sex hormones on rat prostate growth. The results of this study demonstrate that the prostates of Lewis rats respond differently to sex hormone combinations than do those of Sprague Dawley rats. Young rats have a different prostate hormone responsiveness than do old rats. The presence or absence of the testes alters the responsiveness of the prostate gland to androgen-estrogen combinations. These results suggest that strain, age, and the presence of the testes are important factors which will influence the response of the rat prostate to hormonal manipulation. The importance of these factors should be considered in the design of experiments which deal with the response of the rat prostate to hormone manipulation.

Aging↗
PubMed1991

Cellular harmonic information transfer through a tissue tensegrity-matrix system.

Cells and intracellular elements are capable of vibrating in a dynamic manner with complex harmonics, the frequency of which can now be measured and analyzed in a quantitative manner by Fourier analysis. Cellular events such as changes in shape, membrane ruffling, motility, and signal transduction occur within spatial and temporal harmonics that have potential regulatory importance. These vibrations can be altered by growth factors and the process of carcinogenesis. It is important to understand the mechanism by which this vibrational information is transferred directly throughout the cell. From these observations we propose that vibrational information is transferred through a tissue tensegrity-matrix which acts as a coupled harmonic oscillator operating as a signal transucing system from the cell periphery to the nucleus and ultimately to the DNA. The vibrational interactions occur through a tissue matrix system consisting of the nuclear matrix, the cytoskeleton, and the extracellular matrix that is poised to couple the biologic oscillations of the cell from the peripheral membrane to the DNA through a tensegrity-matrix structure. Tensegrity has been defined as a structural system composed of discontinuous compression elements connected by continuous tension cables, which interact in a dynamic fashion. A tensegrity tissue matrix system allows for specific transfer of information through the cell by direct transmission of vibrational chemomechanical energy through harmonic wave motion.

Animals↗
PubMed1991

The effects of basic fibroblast growth factor and suramin on cell motility and growth of rat prostate cancer cells.

Suramin, a new type of cancer chemotherapeutic agent with growth factor antagonist properties, has been reported to affect growth of prostate cancer metastatic lesions. Partin et al. have previously reported that prostate cancer cell motility was essential for tumor cell metastasis. We have studied the effects of suramin on cell motility and cell growth in a prostate cancer cell model. We have demonstrated that suramin has differential effects on rat prostate cancer cells in vitro. The effects of suramin on cell growth were biphasic. At low concentrations of 0.01 mM and 0.1 mM, suramin stimulated growth while it was inhibitory at a higher concentration of 1.0 mM, and 10 mM suramin resulted in cell death. Cell motility was inhibited at a suramin concentration above 0.1 mM. The inhibition of cell motility by suramin may be through the blockage of growth factor effects. Reducing serum growth factor concentration reduced cell motility and the motility was restored by the addition of basic fibroblast growth factor (bFGF) to the media. Motility which had been restored by bFGF could then be blocked by the presence of suramin. The inhibition of cell motility by suramin is reversible on washout of the drug. Suramin inhibits cell motility in both the human prostate cancer cells (LNCaP) and the rat (MLL).

Animals↗
PubMed1991

DNA packaging and organization in mammalian spermatozoa: comparison with somatic cells.

Mammalian sperm DNA is the most tightly compacted eukaryotic DNA, being at least sixfold more highly condensed than the DNA in mitotic chromosomes. To achieve this high degree of packaging, sperm DNA interacts with protamines to form linear, side-by-side arrays of chromatin. This differs markedly from the bulkier DNA packaging of somatic cell nuclei and mitotic chromosomes, in which the DNA is coiled around histone octamers to form nucleosomes. The overall organization of mammalian sperm DNA, however, resembles that of somatic cells in that both the linear arrays of sperm chromatin and the 30-nm solenoid filaments of somatic cell chromatin are organized into loop domains attached at their bases to a nuclear matrix. In addition to the sperm nuclear matrix, sperm nuclei contain a unique structure termed the sperm nuclear annulus to which the entire complement of DNA appears to be anchored when the nuclear matrix is disrupted during decondensation. In somatic cells, proper function of DNA is dependent upon the structural organization of the DNA by the nuclear matrix, and the structural organization of sperm DNA is likely to be just as vital to the proper functioning of the spermatozoa.

Animals↗
PubMed1991

Cell motility as a chemotherapeutic target.

The major cause of failure in the treatment of patients with solid malignancies is failure to prevent or control the spread of metastases. The metastatic process is a series of interrelated steps that must be accomplished before distant tumour foci can be established. Tumour cell motility is a complex process, which is involved in many of these steps. The mechanisms by which motility is stimulated and physically generated are complex and as yet poorly understood. Viewing the cell as a chemomechanical engine that relies on a tension based system for movement allows us to design chemotherapeutic strategies to inhibit tumour cell motility directly. Chemotherapeutic agents that block stimulation, interfere with cell-ECM interactions and interfere with cytoskeletal mechanics are already being tested. Further studies will be needed to define their efficacy.

Animals↗
PubMed1990

Specific organization of genes in relation to the sperm nuclear matrix.

We have recently reported that mammalian sperm DNA, the most highly condensed and functionally inert eukaryotic DNA, is organized into DNA loop domains attached at their bases to a sperm nuclear matrix (Chromosoma, 98: 153, 1989). We report here the specific arrangement of genes within the sperm loop domains by measuring the proximity of six hamster genes to the sperm nuclear matrix. After restriction endonuclease treatment of sperm nuclear matrices, five genes were clearly not associated with the sperm nuclear matrix and only one, alpha A-crystallin, was within 2 Kb of the matrix. This suggests that sperm DNA is organized in a specific manner in relation to the sperm matrix.

Animals↗
PubMed1990

The prostate: an increasing medical problem.

The prostate gland is the major site of medical problems in the U.S. male. Surgery for benign prostatic hyperplasia is the most common surgical procedure performed in males, and the total cost for this surgery exceeds 1 billion dollars per year. The incidence of and mortality from prostate cancer are increasing yearly. Prostate cancer now exceeds lung cancer as the most commonly diagnosed cancer in males and is the second leading cause of male cancer deaths. Of all tumors, the prevalence of prostate cancer increases the most rapidly with age. A shift in age distribution favoring an older population will lead to an increase in the number of patients diagnosed with prostate cancer in the United States. It is estimated that by the year 2000 there will be a 37% increase in prostate cancer deaths per year and a 90% increase in prostate cancer cases per year. Although the factors responsible for the development and progression of prostate cancer to a clinically manifest form are not known, there is evidence that environmental factors may play a role. It will be important for the future to focus on the etiological factors that may lead to a decrease in the prevalence of prostatic tumors.

Adult↗