The 'just-in-case venflon': effect of surveillance and feedback on prevalence of peripherally inserted intravascular devices.
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Catheters, Indwelling↗
Biomedical subjects
L Goddard
Publications and source records attributed to L Goddard.
Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells.
De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 microM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinib-resistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)delta, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 microM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinib-resistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.
Antineoplastic Agents↗
Effect of an EGF-R selective tyrosine kinase inhibitor and an anti-androgen on LNCaP cells: identification of divergent growth regulatory pathways.
BACKGROUND: The effect of an EGF-R selective tyrosine kinase (EGF-RTK) quinazoline inhibitor ZM252868 was determined on the androgen-sensitive human prostatic tumour cell line LNCaP, which can also respond via the EGF-R-regulated growth pathway for cell proliferation. Potential interaction or 'cross-talk' between steroid and the growth factor mitogen-activated protein kinase (MAPK) signalling pathway was also investigated. METHODS: The responses of LNCaP cells to various growth factors in the absence and presence of the EGF-RTK inhibitor and/or steroid and anti-androgen Casodex, was determined using cell population analysis. The effect of the inhibitor on the expression of androgen receptor, EGF-R and activated MAPK was assessed immunocytochemically and changes in the MAPK signalling cascade were also determined using Western blotting techniques. RESULTS: The ZM252868 inhibitor had no effect on LNCaP basal growth. At 100 nM and 1 microM concentrations, the inhibitor reduced the marked EGF- and TGF-alpha-stimulated LNCaP cell growth by 60% and to basal levels, respectively. Both bFGF- and 5alpha-DHT-stimulated growth were unaffected in this concentration range. The inhibitor (1 microM) decreased the expression of immunoreactive EGF-R but had no effect on androgen receptor levels. Activation of MAPK by EGF was noted, being down-regulated by the inhibitor at a concentration of 1 microM. MAPK was not activated by 5alpha-DHT. The anti-androgen Casodex reduced 5alpha-DHT-stimulated cell growth but had no effect on EGF-R mediated LNCaP growth or EGF-stimulated activated MAPK activity. Treatment with EGF and 5alpha-DHT in combination produced an additive effect on cell proliferation, with the anti-androgen and the EGF-RTK inhibitor only reducing the 5alpha-DHT- or EGF-stimulated portion of growth, respectively. CONCLUSIONS: The study demonstrated the efficacy and selectivity of the ZM252868 inhibitor in inhibiting EGF-R mediated LNCaP cell growth. Additionally, no interaction between androgen and EGF-R mediated growth pathways was determined.
Androgen Antagonists↗
Evaluation of renal function in potential living kidney donors.
BACKGROUND: Most transplant centers in the United States, including our own, use creatinine clearance (Ccr) to estimate glomerular filtration rate (GFR) in potential living kidney donors. The purpose of this study was to evaluate our experience with estimation of donor GFR by Ccr and to explore other potential strategies for evaluation of renal function in donors. METHODS: Potential donors performed one to three outpatient urine collections for Ccr measurement. Those with low or inconsistent results underwent measurement of GFR by a radionuclide method not dependent upon urine collection (rGFR). The ability to determine adequacy of urine volume by creatinine excretion rate (UVcr) was examined. GFR was also predicted from serum creatinine (Scr) by using two prediction equations [Cockcroft-Gault and that from the Modification of Diet in Renal Disease Study (MDRD)]. The effect of indexing GFR by height, as opposed to body surface area (BSA) was explored. RESULTS: Over a 5-year period, 22 potential donors (approximately 10% of total evaluated) had inconsistent or low Ccr. Most had normal rGFR and, presumably, undercollected their urine. However, several female donors had truly low GFR by rGFR. The accuracy of Ccr (compared with rGFR) was not predicted by UVcr in a clinically useful way. The prediction equations did not have sufficient accuracy or precision to replace rGFR in this population. Indexing GFR estimates by BSA introduced a bias toward lower values in females; this was largely overcome by indexing GFR by height. CONCLUSIONS: Evaluation of GFR in potential living donors by Ccr is not very useful. A more promising strategy could be developed predicting GFR from Scr and indexing the results by height rather than BSA. The optimum method for evaluation of renal function in kidney donors deserves further study.
Adult↗
The effects of specific retrieval instruction on social problem-solving in depression.
OBJECTIVES: We examine the proposal that social problem-solving in depression may be improved with the retrieval of specific autobiographical memories. DESIGN AND METHODS: Social problem-solving was assessed with the Means-End Problem-Solving task (MEPS; Platt & Spivack, 1975a). Depressed and non-depressed participants were required either to retrieve a specific memory prior to generating a MEPS solution (primed condition) or to report on the memories retrieved during MEPS performance after giving their MEPS solution (non-primed condition). Participants also judged whether the memories retrieved had been helpful or unhelpful for the process of solution generation. RESULTS: In both depressed and non-depressed individuals, priming increased specific memory retrieval but did not improve MEPS performance. An interaction between depression and priming revealed that priming increased the retrieval of helpful memories in the depressed sample. CONCLUSIONS: Specificity is not, in itself, a sufficient retrieval aim for successful social problem-solving. However specific memory priming may be beneficial in depression because it facilitates the recognition of memories which are helpful for problem-solving.
Adult↗
Expression of androgen receptor and growth factors in premalignant lesions of the prostate.
Analysis of growth factors and receptors in putative premalignant lesions of prostatic adenocarcinoma should aid our understanding of their growth pathways. Sixty prostatic TURP (transurethral resection of the prostate) specimens exhibiting atypical adenomatous hyperplasia (AAH) and/or prostatic intraepithelial neoplasia (PIN) lesions were assayed by immunohistochemistry for androgen receptor (AR), epidermal growth factor receptor (EGFR), c-erbB-2, transforming growth factor-alpha (TGF-alpha), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), MIB-1, E-cadherin, and high molecular weight keratin. Expression of these factors in the lesions was compared with that in the co-existing benign prostatic hyperplasia (BPH) or prostatic adenocarcinoma. Strong AR nuclear staining was observed in the luminal cells, but not the basal cells, of BPH and PIN lesions and in all the carcinomas examined. A similar growth factor and receptor profile was demonstrated in the secretory epithelium of high-grade PIN and carcinoma with a tendency to higher expression of membranous EGFR and c-erbB-2 and cytoplasmic TGF-alpha, and lower levels of FGF-2 than in low-grade PIN or BPH glands. Also, increased rates of proliferation, as estimated by MIB-1 stained cells, were observed in high-grade PIN in comparison with low-grade PIN and BPH and were not confined to the basal layer. AAH lesions resembled neither BPH nor carcinoma. Proliferation was virtually absent (MIB-1 expression); both AR and E-cadherin expression was significantly reduced; and, with the exception of FGF-2, all the other growth factors and receptors studied were absent. The results presented would support a premalignant role for high-grade PIN, whilst AAH would appear to represent a quiescent phenotype unlikely to progress to neoplasia.
Antigens, Nuclear↗
Everyday planning difficulties following traumatic brain injury: a role for autobiographical memory.
The present study examines the role of autobiographical memory in describing how to perform both open-ended and closed everyday activities in 12 patients suffering traumatic brain injury and 12 aged-matched controls. The frequency (high versus low) of performing the activities was also manipulated. Patients seemed less well able to benefit from using specific autobiographical memories; they reported using significantly fewer specific autobiographical memories for describing how to perform low-frequency activities and significantly more such memories for high-frequency activities compared with controls. The quality of their descriptions was also significantly poorer for the open-ended activities. Finally, significant correlations were found between the quality of the descriptions and the retrieval of specific autobiographical memories for the controls only. The importance of the retrieval of specific autobiographical memories for everyday problem-solving is discussed.
Activities of Daily Living↗
Changing attitudes about persons with disabilities: effects of a simulation.
The question of whether the use of a teaching strategy employing simulation influences attitudes toward disabled persons over time was addressed in this quasi-experimental intervention study. The experimental group participated in "Sensitivity Day" which incorporated a simulation activity. A total of 77 undergraduate baccalaureate nursing students completed the Attitudes Toward Disabled Persons scale four times: presimulation, immediate postsimulation, six week delayed postsimulation and six month delayed postsimulation. In general, the nursing students had relatively positive scores on the Attitudes Toward Disabled Persons scale in each testing period. The best indicator of postsimulation attitude scores was the presimulation attitude score. Personal and prior nursing experience had no statistical effects on attitude. Improvement that was significant at p = .07 level was noted in the experimental group at the six weeks delayed postsimulation when compared with the presimulation attitude scores. This study supplies data that is useful in constructing learning activities and contributes to the body of knowledge about simulation and attitudes toward persons with disabilities.
Activities of Daily Living↗
Gender differences in the dual-task effects on autobiographical memory retrieval during social problem solving.
A dual-task paradigm was used to explore the effects of cognitive load on social problem solving and autobiographical memory retrieval. The role that gender may play in mediating the relationship was also examined. Participants performed a secondary task concurrently with two primary tasks: (a) a cueing task, and (b) the Means-End Problem-Solving (MEPS) Task, during which they were required to attend to the memories retrieved during solution generation. Two dual-task conditions were employed in order that two levels of secondary task difficulty could be explored. Level of difficulty proved to be an important factor in the effects of resource reduction on the two primary tasks. Retrieval during the MEPS was effected by both the easy and difficult secondary task whereas retrieval on the cueing task was affected by the difficult task only. The results also showed that females (in contrast to males) favoured a more detailed SPS style using a specific memory database. Consequently, under central executive pressure, females' performance was significantly affected while males' performance remained largely unchanged.
Adult↗
Social problem solving and autobiographical memory in non-clinical depression.
OBJECTIVES: We examine the proposal that specific autobiographical memories may play a major role in successful social problem solving (SPS). DESIGN AND METHODS: Depressed and control students report on the types of memories they retrieve while performing an SPS task and a cueing task. RESULTS: The retrieval of specific memories on the cueing task and during SPS was found to be positively related to SPS skill. CONCLUSIONS: Specific memories are important for successful SPS. However, the relationship between a specific memory deficit and poor SPS is mediated by severity of depression.
Adult↗
Comparative analysis of mRNA and protein expression for epidermal growth factor receptor and ligands relative to the proliferative index in human prostate tissue.
The expression of epidermal growth factor receptor (EGF-R), transforming growth factor alpha (TGFalpha), and epidermal growth factor (EGF) was evaluated in a series of prostate cancer (CaP; n = 55) and benign prostate hyperplasia (BPH; n = 44) specimens using immunocytochemistry (ICC) and Northern blotting. In situ hybridization (ISH), performed on a subgroup of these specimens, proved to be a more informative technique for the assessment of messenger RNA (mRNA) in this heterogeneous tissue. A comparative analysis was made in relation to the proliferative index, assessed using the MIB-1 antibody. Elevated levels of EGF-R and TGFalpha, mRNA, and protein were observed in carcinoma cells compared with benign, secretory epithelium using in situ hybridization and immunocytochemistry. In carcinoma specimens evidence of an autocrine growth loop is provided by a correlation between EGF-R and TGFalpha, mRNA (P < .0001), and protein expression (P < .01). A trend toward increased expression of EGF-R and TGFalpha protein with dedifferentiation and a similar trend in the growth fraction suggest a role in tumor progression. Although there was a correlation between EGF-R and the proliferative index (P < .01), no relationship was found between this latter parameter and TGFalpha immunoreactivity (P > .05), indicating that this growth factor may be linked with other aspects of malignant activity rather than directly stimulating proliferation.
Cell Division↗
Role of autobiographical memory in social problem solving and depression.
Depressed patients frequently exhibit deficiencies in social problem solving (SPS). A possible cause of this deficit is an impairment in patients' ability to retrieve specific autobiographical memories. A clinically depressed group and a hospital control group performed the Means-End Problem-Solving (MEPS; J. J. Platt & G. Spivack, 1975a) task, during which they were required to attend to the memories retrieved during solution generation. Memories were categorized according to whether they were specific, categoric, or extended and whether the valence of the memories was positive or negative. Results support the general hypothesis that SPS skill is a function of autobiographical memory retrieval as measured by a cuing task and by the types of memories retrieved during the MEPS. However, the dysfunctional nature of categoric memories in SPS, rather than the importance of specific memories, was highlighted in the depressed group. Valence proved to be an unimportant variable in SPS ability. The cyclical links among autobiographical memory retrieval, SPS skills, and depression are discussed.
Adaptation, Psychological↗
Vascular endothelial growth factor (VEGF) expression in prostatic tumours and its relationship to neuroendocrine cells.
Vascular endothelial growth factor (VEGF) expression was examined by immunohistochemistry in 45 prostatic carcinoma specimens and ten benign prostatic tumours (BPH). The majority of carcinoma specimens exhibited cytoplasmic staining for VEGF and showed a trend of increasing expression with dedifferentiation (2p = 0.003). Immunoreactive VEGF was also seen in the prostatic carcinoma cell lines, the order of staining intensity was PC3 > DU145 > LNCaP. Intense granular cytoplasmic staining for VEGF was observed in neuroendocrine-like cells which were seen focally in many of the prostatic specimens. Consecutive sections were incubated with a chromogranin A antibody to confirm the neuroendocrine phenotype of these cells. A significant correlation (P < 0.0001) between the total number of intensely stained VEGF-positive cells and chromogranin A-positive cells was found. A subpopulation of neuroendocrine-like cells also showed intense immunoreactivity for transforming growth factor alpha (TGF-alpha). A correlation was observed (2p = 0.0092) between the intensity of VEGF and TGF-alpha immunostaining in carcinoma cells which were not of neuroendocrine differentiation. The presence of these two angiogenic factors may aid the neovascularisation of carcinomas and their increased expression in tumour-associated neuroendocrine cells may contribute to a more aggressive phenotype.
Chromogranin A↗
Epidermal growth factor receptor expression by northern analysis and immunohistochemistry in benign and malignant prostatic tumours.
Epidermal growth factor receptor (EGFR) expression in 44 benign prostatic hyperplasia (BPH) and 55 prostatic carcinoma specimens has been investigated using Northern blot analysis and immunohistochemistry. The values obtained for the EGFR mRNA in the BPH and carcinoma specimens were not significantly different and in the latter there was no correlation with grade. In the immunohistochemical assays, two antibodies to the external and one to the internal domain of EGFR were used. The former ones stained the basal cell membranes intensely whilst cytoplasmic staining of secretory epithelium was seen in BPH specimens with the latter. In the carcinoma specimens, the intensity of membrane staining correlated with the two external domain antibodies, r = 0.640, P < 0.001, but neither of these correlated with the EGFR mRNA results. All three antibodies demonstrated a trend towards elevated expression of EGFR with dedifferentiation which reached significance only with the internal domain antibody results, P < 0.02. No correlation was observed with tumour EGFR mRNA values and the EGFR immunohistochemical results. The EGFR immunoreaction with the external domain antibody in 14 treated high-grade tumours was comparable to that obtained in 15 untreated anaplastic prostatic tumours. In 5 patients, both pre- and post-treatment samples were available and these exhibited little or no difference in EGFR expression with therapy.
Blotting, Northern↗
Cell proliferation in prostatic carcinoma: comparative analysis of Ki-67, MIB-1 and PCNA.
Antibodies to assess the proliferative index of tumours are being increasingly employed together with established markers for prognostic evaluation. This study set out to compare three cell proliferation markers, Ki-67, MIB-1 and PCNA, utilizing a semi-quantitative method of assessment, in 20 human prostatic carcinomas. The streptavidin-biotin immunostaining system was used for the monoclonal antibodies MIB-1 and PCNA and an indirect immunoperoxidase assay for the monoclonal antibody Ki-67. Significant correlations were found between the expression of Ki-67 in frozen tissues and MIB-1 in formal saline-fixed wax-embedded tissues (p = 0.0003); between Ki-67 and PCNA expression in Bouin's-fixed tissues (p < or = 0.0001); and MIB-1 (formalin-saline-fixed tissues) and PCNA (Bouin's-fixed tissues) (p < or = 0.0001). A more intense nuclear staining pattern with less heterogeneity was observed for MIB-1 compared with PCNA, suggesting the antibody of choice, on formal saline-fixed tissues, is MIB-1, which closely correlated with Ki-67, a marker we have previously shown to be of prognostic value in prostatic carcinoma.
Antibodies, Monoclonal↗
Transforming growth factor beta 1 expression in benign and malignant prostatic tumors.
The expression of transforming growth factor beta 1 (TGF-beta 1) in prostate specimens obtained from patients with benign prostatic hyperplasia (BPH, n = 32) and prostate carcinoma (n = 66) was investigated using Northern blot analysis and immunohistochemistry. Northern blot analysis revealed TGF-beta 1 message (2.5 kb) in virtually all of the samples examined, reflecting the ubiquitous nature of this growth factor. No statistical difference was found between the levels of mRNA detected in benign and malignant tissues due, in part, to the inherent heterogeneity of prostate tissue. Immunohistochemical methods using an antibody to native TGF-beta 1 revealed a novel pattern of immunoreactivity. Staining observed only in certain epithelial cells of benign glands was associated with areas of infection rather than tumorigenesis. Interestingly, intense staining was also seen in polymorphonuclear leukocytes. No correlation was found with the mRNA results, suggesting that this antibody is binding to TGF-beta 1 activated in response to infection rather than detecting sites of synthesis of latent TGF-beta 1.
Blotting, Northern↗
An immunocytochemical analysis of TGF alpha expression in benign and malignant prostatic tumors.
Transforming growth factor alpha (TGF alpha) expression was analyzed immunocytochemically on formalin-fixed wax-embedded sections obtained from 24 benign prostatic hyperplasia (BPH) specimens and 76 prostatic carcinoma tissues, 3 human prostatic tumor xenografts, normal kidney, and salivary gland. Low amounts of TGF alpha immunopositivity were encountered in the epithelium of BPH glandular tissues, whereas in the prostatic adenocarcinoma samples, a greater heterogeneity and intensity of TGF alpha immunostaining was observed. The most intense staining was exhibited by the least differentiated tumors, although a few of these were weakly stained. Statistical analysis of the relationship of histopathological grade of tumor with TGF alpha expression in the carcinomas showed a significant correlation of these parameters, 0.01 > P > 0.001. The expression of the proliferation markers Ki-67 and PCNA was also analyzed in the carcinoma specimens, and the relationship of these to TGF alpha expression indicated that there was no significant correlation in this series of tumors between increased growth activity and TGF alpha expression (p approximately 0.25 with both markers). The prostatic carcinoma xenografts TEN12 and TEN15 contained low levels of immunoreactive TGF alpha, which was uniformly distributed, whilst heterogeneous immunostaining was observed in the uroepithelial xenograft TEN16. In the normal human kidney, TGF alpha was concentrated in the epithelium of the distal convoluted tubules (DCT) and the collecting tubules (CT), and lower amounts were identified in the proximal convoluted tubules (PCT). As in the prostatic carcinomas, the immunostaining was eliminated by prior absorption of the antibody with pure TGF alpha and not with human or mouse EGF. No crossreactivity of the TGF alpha antibody with salivary EGF was demonstrated. This study concludes that, in prostate carcinoma, the least differentiated tumors more often expressed greater amounts immunoreactive TGF alpha; however, no relationship between TGF alpha expression and cellular proliferation markers was found.
Adenocarcinoma↗
The Honors Program: pathway to excellence.
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Achievement↗