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Biomedical subjects

G Casey

Publications and source records attributed to G Casey.

At least 73 records · Page 4Linked to original sources
PubMed1996

BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype.

BRCA1 mutations cause increased risk for breast and ovarian cancer, frequently of early onset. Many different mutations occur in BRCA1, including several examples of recurrent mutations, each of which accounts for a significant number of families with heritable cancer predisposition. These common mutations have an etiological role in many breast and ovarian cancer cases and provide the opportunity to examine genotype-phenotype correlations and genotype-environment interactions in individuals with the identical BRCA1 lesion. We report a novel missense change in BRCA1, 2640 C-->T (R841W), found in 3 cases from a subject group of 305 breast and 79 ovarian cancer cases from Orange County, CA. These are consecutive, population-based cases not selected for age or family history. In all three cases, there is a strong family history of breast, ovarian, or other cancers possibly related to a BRCA1 defect and family members showed a high concordance of cancer incidence with the presence of R841W. The age of cancer onset was not always distinct from typical sporadic cases. Testing of a sample of 413 unrelated individuals to examine the hypothesis that R841W might be a rare polymorphism detected one additional instance in a woman with breast cancer diagnosed at age 77 years, and cancer in one parent. R841W is likely to be an etiologically significant lesion with involvement in close to 1% (95% confidence interval of 0-1.7%) of all breast and ovarian cancers in this population.

Adult↗
PubMed1996

Acquisition of doxorubicin resistance in human leukemia HL-60 cells is reproducibly associated with 7q21 chromosomal anomalies.

Tumor cell resistance to doxorubicin (DOX) is usually associated with the overexpression of P-glycoprotein (PGP) in model systems. We have characterized the karyotypic changes in two sublines of HL-60 cells which differ in the induction of differentiation by retinoic acid. The parental sublines, designated HL-60A/S and HL-60Y/S, were selected in increasing concentrations of 0.025-0.1 micrograms/mL DOX. Monosomy 8 in HL-60Y/S was the only karyotypic difference prior to DOX exposure. Both sublines acquired 7q+ markers upon exposure to DOX. In HL-60Y/S, and add(7)(q21) replaced one homologue at 0.025 micrograms/mL DOX, and an add(7)(q32) appeared which replaced the other normal 7 at 0.05 micrograms/mL DOX. The HL-60A/S cells acquired an add(7)(q21) at 0.025 micrograms/mL DOX. The 7q+ abnormalities involved breakpoints in the midregion of 7q. The overexpression of phosphorylated PGP in immunoprecipitates with C-219 antibody was identified in both sublines of DOX-resistant HL-60 cells with 7q+ abnormalities, and this is consistent with the location of mdr-1 sequences to 7q21-21.1. Also, analysis of RNA from parental-sensitive and DOX-resistant sublines by reverse transcriptase-polymerase chain reaction revealed: a) comparable expression of multidrug resistance related protein (MPR) in sensitive and resistant sublines; and b) overexpression of mdr-1 only in the DOX-resistant sublines. Thus, the selection of DOX resistance in two sublines of HL-60 cells which differ in their response to retinoic acid-induced myeloid differentiation is reproducibly associated with overexpression of mdr-1 versus MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

The curriculum evolution and Project 2000: a critical examination.

The changes in nursing education underway in the UK and the USA are designed to educate a new type of practitioner. These new practitioners will be emancipated, critically reflective, creative and autonomous in their practice. This paper looks at the progress of the revolution, with particular reference to the UK, by critically examining the literature arising out of it. The implications for nursing education and educators are examined.

Curriculum↗
PubMed1996

Analysis of Akinsanya's model of bionursing.

A critical analysis of Akinsanya's theory of bionursing is presented. This innovative model, designed to direct nursing education in the biological sciences, explores the link between nursing and these sciences and attempts to disassociate nursing from the dominance of the biomedical model. The underlying assumptions of the model and its main concepts are examined in the light of current beliefs about professional nursing practice and education. Links between the concepts in the model are explored. The utility of the bionursing model for nursing education and practice is examined and some hypotheses for empirical testing of the model are suggested.

Biological Science Disciplines↗
PubMed1996

Resistance to interleukin 6 in human non-small cell lung carcinoma cell lines: role of receptor components.

The role of interleukin 6 (IL-6) in regulating the growth of three human non-small cell lung carcinoma (NSCLC) cell lines (NSCLC-3, NSCLC-5, and NSCLC-7, derived from a primary lesion, a brain lesion, and lymph node metastases, respectively) was examined. Although IL-6 alone did not alter the growth of these cells, the addition of soluble IL-6 receptor (sIL-6R) led to the inhibition of proliferation of one of the NSCLC cell lines, NSCLC-5. This antiproliferative effect was neutralized by antibodies to IL-6 and the IL-6R binding and signaling component (gp130). The IL-6-related cytokines, leukemia inhibitory factor and oncostatin M, inhibited proliferation of NSCLC-5 cells but were ineffective in NSCLC-3 and NSCLC-7 cells. NSCLC-7 cells (but not NSCLC-3 or NSCLC-5 cells) secreted biologically active IL-6 and expressed IL-6R. However, antibodies to IL-6 or gp130 failed to alter the proliferation of NSCLC-7 cells. All three cell lines expressed gp130 mRNA and protein. The level of expression of gp130 protein varied in the three cell lines (NSCLC-7 > NSCLC-3 > NSCLC-5). The examination of tyrosine phosphorylation of gp130 (as an early event in IL-6 signal transduction) revealed that gp130 could be phosphorylated in all cell lines after stimulation with IL-6 and/or IL-6 + sIL-6R. These results demonstrate that the mechanisms responsible for IL-6 resistance in different NSCLC cell lines vary and involve defects at either one or more levels of the IL-6 signaling cascade. In the NSCLC-5 cell line, IL-6 resistance (which can be reversed in the presence of sIL-6R) is due to the transcriptional inactivation of the IL-6R gene. In contrast, in the other two cell lines (NSCLC-3 and NSCLC-7), defect(s) in the signaling cascade downstream of gp130 phosphorylation, together with a lack of expression of IL-6R in NSCLC-3 cells, result in IL-6 resistance.

Antigens, CD↗
PubMed1995

Lysophospholipids activate ovarian and breast cancer cells.

We have investigated the effects of phospholipids on activation and proliferation of ovarian and breast cancer cells. Lysophosphatidic acid (LPA), lysophosphatidylserine (LPS) and sphingosylphosphorylcholine (SPC) all induce transient increases in cytosolic free Ca2+ ([Ca2+]i) in both ovarian and breast cancer cell lines. The ability of LPA, LPS and SPC to induce increases in [Ca2+]i in ovarian and breast cancer cells is likely to be due to an interaction with cell-surface receptors as the increases in [Ca2+]i were: (1) due to release of calcium from intracellular stores and not from transmembrane uptake due to changes in permeability; (2) blocked by lanthanum and suramin which do not enter cells; (3) blocked by phorbol esters which interrupt increases in [Ca2+]i induced through a number of different receptors; and (4) not detected in freshly isolated peripheral blood mononuclear cells, indicating cell type specificity. In addition, increases in [Ca2+]i induced by LPA, LPS and SPC in ovarian and breast cancer cells completely self-desensitized and cross-desensitized each other, but did not block increases in [Ca2+]i induced by thrombin. Lysophosphatidylglycerol (LPG), but not other lysophospholipids, inhibited LPA- but not LPS- or SPC-induced increases in [Ca2+]i, suggesting that LPA may interact with a different receptor(s) to LPS or SPC and that their downstream signalling pathways converge or interact. LPA, SPC and LPS also induced rapid increases in tyrosine phosphorylation of specific cellular proteins, including p125FAK. Strikingly, LPA, but not LPS or SPC, induced activation of mitogen-activated protein (MAP) kinases. Despite an ability to activate similar intracellular signaling events, LPA, LPS and SPC exhibited markedly different effects on cell proliferation. Whereas LPA induced a significant increase in cell proliferation, LPS did not substantially alter cell proliferation and SPC inhibited cell proliferation. Surprisingly, phosphatidic acid (PA), which did not induce increases in [Ca2+]i, p125FAK activation or activation of MAP kinases, did induce proliferation of ovarian cancer cells, albeit at higher concentrations that LPA. The discordance between sensitivity to LPG, early biochemical events stimulated, and the eventual proliferation response combine to suggest that LPA probably utilizes a different receptor from LPS, SPC and PA. Therefore ovarian and breast cancer cells are sensitive to the effects of a number of different phospholipids which may play a role in the growth of these tumour cells in the cancer patient and are thus potential targets for therapy.

Breast Neoplasms↗
PubMed1995

Cloning and mapping of a human gene (TBX2) sharing a highly conserved protein motif with the Drosophila omb gene.

We have identified and cloned a human gene (TBX2) that exhibits strong sequence homology within a putative DNA binding domain to the drosophila optomotor-blind (omb) gene and lesser homology to the DNA binding domain of the murine brachyury or T gene. Unlike omb, which is expressed in neural tissue, or T, which is not expressed in adult animals, TBX2 is expressed primarily in adult in kidney, lung, and placenta as multiple transcripts of between approximately 2 and 4 kb. At least part of this transcript heterogeneity appears to be due to alternative polyadenylation. This is the first reported human member of a new family of highly evolutionarily conserved DNA binding proteins, the Tbx or T-box proteins. The human gene has been mapped by somatic cell hybrid mapping and chromosomal in situ hybridization to chromosome 17q23, a region frequently altered in ovarian carcinomas.

Adult↗
PubMed1995

Analysis of the Wilms tumor suppressor gene WT1 in endometrial carcinoma.

This study reports on the evaluation of the Wilms tumor suppressor gene WT1 in 14 endometrial carcinomas. Despite the fact that several endometrial carcinomas were shown to express WT1, we were unable to demonstrate mutations in the MT1 zinc finger region, suggesting that WT1 does not play a prominent role in the etiology of this malignancy.

Base Sequence↗
PubMed1995

Effect of lysophospholipids on signaling in the human Jurkat T cell line.

Lysophospholipids have recently been demonstrated to induce activation and proliferation of fibroblasts and other cell lineages by interacting with high affinity cell surface receptors leading to specific intracellular signaling events. Platelet activation, likely at the site of injury or inflammation, results in increased production of lysophospholipids suggesting a possible source of lysophospholipids. We have recently demonstrated that high concentrations of lysophospholipids are present in ascites and plasma from ovarian cancer patients, suggesting that physiologically produced lysophospholipids could interact with cells present in these fluids, including lymphocytes, and alter their function. We demonstrate herein that lysophosphatidic acid (LPA), lysophosphatidylserine (LPS), and sphingosylphosphorylcholine (SPC) activate the Jurkat T cell line. Each of the lysophospholipids induced a transient increase in cytosolic free calcium ([Ca2+]i) in Jurkat cells. Increases in [Ca2+]i were cross-desensitized by LPA, LPS and SPC, suggesting that the lysophospholipids share the same receptor(s) or that their downstream signaling pathways converge or interact. Lysophosphatidylglycerol (LPG), a competitive inhibitor of the putative LPA receptor, inhibited the calcium releasing activity of LPA, but not that of LPS and SPC, suggesting that these lysophospholipids interact with different receptors and that desensitization is due to interactions in downstream signaling pathways. The ability of the lysophospholipids to induce increases in [Ca2+]i was attenuated, but not completely blocked, by increases in [Ca2+]i induced by activation of the thrombin receptor. In contrast, increases in [Ca2+]i induced by the lysophospholipids and cross-linking the CD3 component of the T cell receptor complex with the UCHT1 antibody did not undergo heterologous desensitization. Strikingly, LPA is sufficient to stimulate proliferation of Jurkat cells in serum-free medium or in synergy with low concentrations of fetal bovine serum. In addition, LPA also increased the production of the T cell growth factor, interleukin 2 (IL-2), by Jurkat cells treated with phorbol esters. LPS, in contrast, inhibited Jurkat proliferation while increasing IL-2 production and SPC inhibited both processes. Thus, although all three lysophospholipids were sufficient to induce a transient increase in [Ca2+]i in Jurkat cells, they induced markedly different physiological consequences.

Calcium↗
PubMed1995

Microsatellite instability at a single locus (D11S988) on chromosome 11p15.5 as a late event in mammary tumorigenesis.

Replication errors at microsatellite repeats are markers for genomic instability in hereditary nonpolyposis colon carcinoma and in some sporadic cancers. Microsatellite sequences may show alterations in one or both alleles in some tumors, suggesting an error in the DNA replication of dinucleotide repeats. We have investigated microsatellite instability (MSI) in sporadic breast tumors at several loci on the short arm of chromosome 11. Among microsatellites studied we found a high frequency of MSI at one specific locus, D11S988 on chromosome 11p15.5. Most colorectal tumors that exhibit MSI display abnormalities of at least one other locus and usually more. By contrast we have detected only one abnormal microsatellite in all the tumors examined. This marker lies between the TH and HBB genes, a subregion previously suggested to harbor a putative tumor suppressor gene for breast cancer. Loss of heterozygosity for chromosome markers at 11p15 has earlier been correlated with poor prognosis. In an unselected panel of primary breast tumors, we observed that 20 of 69 showed mobility shifts of D11S988 in tumor compared with corresponding normal DNA samples. Tumors with instability at D11S988 were rapidly proliferating compared with tumors without MSI. DNA aneuploidy, estrogen receptor positivity and moderate to poorly differentiated tumor phenotype were also characteristics of tumors with MSI at this locus and the majority also exhibited loss of heterozygosity at one or more of the six 11p loci analyzed. Taken together these data suggest that MSI at the D11S988 locus is a late event in mammary tumorigenesis and may be associated with progression of breast carcinomas.

Alleles↗
PubMed1995

Detailed mapping and loss of heterozygosity analysis suggests a suppressor locus involved in sporadic breast cancer within a distal region of chromosome band 17p13.3.

The chromosome region 17p13.3 is thought to encode a tumour suppressor gene involved in sporadic breast cancer and other malignancies. Physical ordering of markers has been carried out by a series of multicolour fluorescent in situ hybridisation (FISH) experiments, using isolated yeast artificial chromosomes (YACs) and cosmids. Eight polymorphic markers ordered within this new physical map and one external marker were used to investigate the pattern of loss of heterozygosity in a panel of 40 sporadic breast tumour patients. The data revealed a region of high loss (60%) within distal 17p13.3, defined by markers D17S926, D17S695 and D17S849 which mapped close together. A contig of YACs was constructed physically linking these three markers.

Base Sequence↗
PubMed1995

Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients.

Ascites from ovarian cancer patients contain potent growth-promoting activity toward human ovarian cancer cells both in vitro and in vivo. This activity is associated with rapid increases in cytosolic free calcium ([Ca2+]i) as a consequence of phosphoinositide hydrolysis. In this study, we describe the purification, characterization, and identification of an ovarian cancer activating factor (OCAF) from ascites of ovarian cancer patients. We have isolated OCAF by a combination of solvent extraction, silica gel chromatography, and TLC. Mass spectral analysis, phospholipase sensitivity, and gas chromatographic behavior of purified OCAF indicate that OCAF is composed of various species of lysophosphatidic acid (LPA), including LPAs with polyunsaturated fatty acyl chains (linoleic, arachidonic, and docosahexaenoic acids). However, OCAF is more potent than sn-1 palmitoyl, oleoyl, or stearoyl LPA in increasing [Ca2+]i in ovarian cancer cells. The ability of OCAF to alter [Ca2+]i is sensitive to the effects of lipoxidase, whereas the activity of sn-1 oleoyl, stearoyl, or palmitoyl LPA is not, suggesting that polyunsaturated bonds in the fatty acyl chain of OCAF may account for its increased ability to activate ovarian cancer cells. Furthermore, a sn-2 linoleoyl LPA generated by phospholipase A1 treatment of synthetic phosphatidic acid is much more active than are sn-1 palmitoyl, stearoyl, or oleoyl LPA in increasing [Ca2+]i in ovarian cancer cells. Taken together, these data suggest that the ability of OCAF to increase cellular calcium may reside in the structure and/or location of the fatty acyl chain of LPA. Purified OCAF, at concentrations similar to those present in ascites from ovarian cancer patients, was sufficient to induce proliferation of ovarian cancer cells, as indicated by thymidine incorporation, reduction of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, or colony formation. However, even at optimal concentrations of OCAF, proliferation was lower than that induced by FCS or ascites from ovarian cancer patients, indicating that, although OCAF may be a major regulator of ovarian cancer cells in vivo, it is not the sole mediator present in ascites, and it likely functions in concert with other growth factor activities.

Ascites↗
PubMed1994

Evidence that wild-type TP53, and not genes on either chromosome 1 or 11, controls the tumorigenic phenotype of the human fibrosarcoma HT1080.

The specific transfer of normal chromosomes via microcell fusion has been instrumental in identifying putative tumor suppressor gene loci in a variety of human cancers. Using this same technique it has been proposed that the tumorigenicity of the human fibrosarcoma cell line HT1080 is controlled by functionally distinct tumor suppressor genes on human chromosomes I and II. To address these results and perhaps further localize the suppressive effect to particular regions on these two chromosomes, we transferred into HT1080 seven different fibroblast-derived human chromosomes containing either intact or discrete portions of chromosome I or II. Interestingly, we found no evidence of genes on these chromosomes that could alter the growth of HT1080 either in vitro or in vivo. Based on these results we were left with the possibility that a gene, or genes, residing on an entirely different chromosome(s) was involved in the tumorigenesis of HT1080. Since TP53 mutation has been documented in a variety of human tumor types, and we found both copies of TP53 to be mutated in HT1080, we were prompted to examine its role by both cDNA transfection and chromosome transfer. Although by cDNA transfection we found that expression of exogenous wild-type TP53 was incompatible with continued proliferation of HT1080 cells in vitro, chromosome 17 transfer studies revealed that a more physiologic expression of exogenous wild-type TP53 could be tolerated in vitro while being completely incompatible with growth in vivo. These studies demonstrate a differential effect of TP53 growth inhibition and clearly show that TP53 tumor suppressing function can be independent from its potent growth suppressing effect in vitro.

Animals↗
PubMed1994

The effect of two nursing interventions on families of ICU patients.

Although much research has addressed family needs of ICU patients, only a few studies have examined interventions aimed at meeting these family needs. Therefore, the purpose of this study was to examine the effects of two interventions, a family information pamphlet and a family group session, on 60 family members of ICU patients. Results revealed no statistically significant differences between the family member groups on Critical Care Family Needs Inventory scores (p = .45), which assessed important needs, or State Trait Anxiety scores (p = .61). Consistent with previous research on families' needs, the majority of the needs identified as most important by all family members related to receiving information. Small sample sizes may have contributed to nonsignificant differences between family member groups, and study replication with larger sample sizes is recommended.

Clinical Nursing Research↗