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Biomedical subjects

L Moore

Publications and source records attributed to L Moore.

At least 73 records · Page 4Linked to original sources
PubMed1999

Regulation of transcription at the Saccharomyces cerevisiae start transition by Stb1, a Swi6-binding protein.

In Saccharomyces cerevisiae, gene expression in the late G(1) phase is activated by two transcription factors, SBF and MBF. SBF contains the Swi4 and Swi6 proteins and activates the transcription of G(1) cyclin genes, cell wall biosynthesis genes, and the HO gene. MBF is composed of Mbp1 and Swi6 and activates the transcription of genes required for DNA synthesis. Mbp1 and Swi4 are the DNA binding subunits for MBF and SBF, while the common subunit, Swi6, is presumed to play a regulatory role in both complexes. We show that Stb1, a protein first identified in a two-hybrid screen with the transcriptional repressor Sin3, binds Swi6 in vitro. The STB1 transcript was cell cycle periodic and peaked in late G(1) phase. In vivo accumulation of Stb1 phosphoforms was dependent on CLN1, CLN2, and CLN3, which encode G(1)-specific cyclins for the cyclin-dependent kinase Cdc28, and Stb1 was phosphorylated by Cln-Cdc28 kinases in vitro. Deletion of STB1 caused an exacerbated delay in G(1) progression and the onset of Start transcription in a cln3Delta strain. Our results suggest a role for STB1 in controlling the timing of Start transcription that is revealed in the absence of the G(1) regulator CLN3, and they implicate Stb1 as an in vivo target of G(1)-specific cyclin-dependent kinases.

Blotting, Western↗
PubMed1999

Dietary fat and prostate cancer progression and survival.

BACKGROUND: The association between dietary factors and the occurrence of prostate cancer has been studied extensively, but there is, as yet, no published study on the relationship between diet and disease progression among prostate cancer patients. We studied the association between dietary fat intake and prostate cancer survival. METHODS: We prospectively followed 384 men diagnosed with prostate cancer between 1990 and 1992 in the Quebec City area who participated in a case-control study of diet in relation to prostate cancer occurrence. Trained nutritionists interviewed the men on their usual diet using a diet history questionnaire. Deaths in the follow-up were documented through record linkage with the provincial mortality file and review of hospital records. The cause of death was taken as written on the death certificate. Cox proportional hazards models were used to estimate the relative risk of dying from prostate cancer associated with terciles of fat intake, expressed as percent of dietary energy, while controlling for prognostic factors and total energy. RESULTS: The median duration of follow-up was 5.2 years. During the follow-up period, 32 patients died of prostate cancer and 39 died of other causes. The 5-year disease-specific survival was 91%. After controlling for grade, clinical stage, initial treatment, age and total energy intake, we found that saturated fat consumption was significantly associated with disease-specific survival (p = 0.008). Compared to men in the lower tercile of saturated fat, those in the upper tercile had three times the risk of dying from prostate cancer (hazards ratio 3.13, 95% confidence interval 1.28-7.67). CONCLUSION: Our findings suggest that, if saturated fat is causally related to disease-specific survival, a moderate reduction of its intake below 10% of energy should reduce the risk of dying from prostate cancer. This dietary goal is already recommended for health promotion and primary prevention of heart disease and cancer.

Aged↗
PubMed1999

The trithorax group gene osa encodes an ARID-domain protein that genetically interacts with the brahma chromatin-remodeling factor to regulate transcription.

The trithorax group gene brahma (brm) encodes the ATPase subunit of a chromatin-remodeling complex involved in homeotic gene regulation. We report here that brm interacts with another trithorax group gene, osa, to regulate the expression of the Antennapedia P2 promoter. Regulation of Antennapedia by BRM and OSA proteins requires sequences 5' to the P2 promoter. Loss of maternal osa function causes severe segmentation defects, indicating that the function of osa is not limited to homeotic gene regulation. The OSA protein contains an ARID domain, a DNA-binding domain also present in the yeast SWI1 and Drosophila DRI proteins. We propose that the OSA protein may target the BRM complex to Antennapedia and other regulated genes.

Animals↗
PubMed1999

The Drosophila kismet gene is related to chromatin-remodeling factors and is required for both segmentation and segment identity.

The Drosophila kismet gene was identified in a screen for dominant suppressors of Polycomb, a repressor of homeotic genes. Here we show that kismet mutations suppress the Polycomb mutant phenotype by blocking the ectopic transcription of homeotic genes. Loss of zygotic kismet function causes homeotic transformations similar to those associated with loss-of-function mutations in the homeotic genes Sex combs reduced and Abdominal-B. kismet is also required for proper larval body segmentation. Loss of maternal kismet function causes segmentation defects similar to those caused by mutations in the pair-rule gene even-skipped. The kismet gene encodes several large nuclear proteins that are ubiquitously expressed along the anterior-posterior axis. The Kismet proteins contain a domain conserved in the trithorax group protein Brahma and related chromatin-remodeling factors, providing further evidence that alterations in chromatin structure are required to maintain the spatially restricted patterns of homeotic gene transcription.

Amino Acid Sequence↗
PubMed1999

Downward trend in prostate cancer mortality in Quebec and Canada.

PURPOSE: If new treatment strategies and screening for prostate cancer are effective they should reduce prostate cancer mortality. In this review we monitored prostate cancer mortality rates in Quebec and in Canada. MATERIALS AND METHODS: We obtained data on all deaths from prostate cancer between 1976 and 1997 in Quebec, and 1976 and 1996 in Canada. We calculated age standardized mortality rates and assessed changes with time. RESULTS: Prostate cancer mortality rates increased regularly until 1991 in Quebec and Canada. After 1991 the rates decreased moderately until 1995 and then more markedly in 1996. There was a further decline in 1997 in Quebec. Overall, age standardized prostate cancer mortality rates declined by 23% in Quebec between 1991 and 1997, and by 9.6% in Canada between 1991 and 1996. The mortality decline was observed for all age groups but was more pronounced among men younger than 75 years. CONCLUSIONS: Until 1995 the trends in prostate cancer mortality in Quebec and Canada were similar to those observed in the United States. Our data suggest that a sharper decline has occurred since 1995. It is of primary importance to identify the causes of the mortality decline. As prostate cancer mortality rates declined relatively early after the initiation of widespread screening with prostate specific antigen, it is unlikely that screening has as yet contributed in a major way to the decline. It is more likely that the mortality reduction is a consequence of better prostate cancer management or improved treatment modalities.

Age Distribution↗
PubMed1999

Peer consultation reflection exercise.

OBJECTIVE: To explore participants' overall perception of the value of the Peer Consultation Reflection Exercise (PCRE); of barriers and facilitators to participation and learning during a PCRE; and of the transferability of the experience to participants' own settings. DESIGN: This study used the qualitative techniques of key informant interviews and a focus group. SETTING: Focus group and key informant interviews at the 1996 Annual Meeting of the College of Family Physicians of Canada's Section of Teachers. PARTICIPANTS: Family medicine teachers attending a PCRE. METHOD: Five key informant interviews and one focus group composed of five participants were conducted to explore participants' experience of participating and learning during a PCRE. MAIN FINDINGS: Participants viewed the PCRE as a valuable opportunity to interact and learn from colleagues a were especially impressed with the opportunity to listen. Confidentiality and the important role of the facilitator were identified as key components. The greatest perceived barrier was the formal structure of the PCRE. CONCLUSIONS: The PCRE is an innovative strategy for personal and professional development. It could be used in other settings.

Adult↗
PubMed1999

Predictive value of cell cycle markers p53, MDM2, p21, and Ki-67 in superficial bladder tumor recurrence.

The aim of the study was to determine whether the expression of the cell cycle markers p53, MDM2, p21, and Ki-67 was predictive of superficial bladder cancer recurrence and to compare the relative predictive power for tumor recurrence of a cell cycle index based on the number of abnormally expressed cell cycle markers with a clinicopathological index based on primary clinical tumor characteristics. The expression of p53, MDM2, and p21 proteins and the value of the Ki-67 index were analyzed for 244 patients. One hundred ninety-four lesions were determined to be superficial papillary tumors (pTa), whereas 50 tumors invaded the lamina propria (pT1). Tumor grade was noted low (grade 1) in 83 cases and high (grades 2-3) in 161 cases. An avidin-biotin peroxidase method was performed using monoclonal antibodies against p53, MDM2, p21, and Ki-67 antigens after antigen retrieval treatment of formalin-fixed specimens. The cell cycle marker index was created using the number of abnormally expressed cell cycle markers according to the following cutoff points: p53 (>5%), MDM2 (>20%), p21 (<5%), and Ki-67 (>10%). The clinicopathological index was created using the following adverse tumor characteristics: grades G2-G3, stage pT1, multifocality, and diameter of tumors > 3 cm. Cox regression models were used to calculate the relative risks and their 95% confidence intervals associated with disease recurrence for the clinicopathological index and the cell cycle marker index. The chi2 test was performed to describe the correlation between the Ki-67 index and p53, MDM2, and p21 protein expression. Kaplan-Meier survival curves were generated to demonstrate the disease-free survival according to these two prognostic indexes. The clinicopathological index was a strong, independent predictor of disease recurrence where tumors with three or four adverse tumor characteristics at initial resection had over four times the risk of recurrence than tumors with no risk factors (P for trend = 0.0001). A strong correlation was observed between the Ki-67 index >10% and both MDM2 and p21 proteins. MDM2 was overexpressed in 106 tumors (43%), and p53 was overexpressed in 47 (19%); Ki-67 was >10% in 171 cases (70%). Thirty-nine tumors (16%) were p21 negative. The risk of recurrence increased slightly with the number of abnormally expressed cell cycle markers, but when the clinicopathological index was taken into account in multivariate analysis, the cell cycle marker index was not predictive of disease recurrence (P for trend = 0.72). The cell cycle markers studied provided no added prognostic information on disease recurrence after initial resection of papillary superficial tumors when the clinicopathological parameters were taken into account.

Aged↗
PubMed1998

Interaction of yeast Rvs167 and Pho85 cyclin-dependent kinase complexes may link the cell cycle to the actin cytoskeleton.

BACKGROUND: . PHO85 encodes the catalytic subunit of a cyclin-dependent kinase (Cdk) in budding yeast and functions in phosphate and glycogen metabolism. Pho85 associated with the G1 cyclins Pcl1 and Pcl2 is also required for cell cycle progression in the absence of the Cdc28 cyclins Cln1 and Cln2. Loss of Pcl1, Pcl2 and related Pho85 cyclins results in budding defects, suggesting that Pcl-Pho85 complexes function in cell morphogenesis early in the cell cycle; their precise role is not clear, however. RESULTS: . To identify targets for Pcl-Pho85 kinases, we performed yeast two-hybrid interaction screens using Pcl2 and the related cyclin Pcl9. We identified RVS167, a gene involved in endocytosis, organization of the actin cytoskeleton, and cell survival after starvation. Like rvs167Delta mutants, pho85 mutants or strains deleted for the Pcl1,2-type Pho85 cyclins showed abnormal cell morphology on starvation, sensitivity to salt, random budding in diploids, and defects in endocytosis and in the actin cytoskeleton. Overexpression of Rvs167 in wild-type cells caused morphological abnormalities and growth arrest at high temperatures; these phenotypes were exacerbated by deleting PHO85. Rvs167 has a Src homology 3 (SH3) domain and five potential Pho85 phosphorylation sites; recombinant Rvs167 was phosphorylated by the Pcl2-Pho85 kinase in vitro. Maximal phosphorylation of Rvs167 in vivo required Pho85 and the Pcl1,2-type cyclins. CONCLUSIONS: . Rvs167 interacts with Pho85 cyclins and is implicated as a target of Pho85 kinases in vivo. Our results identify a connection between Cdks and the actin cytoskeleton; interaction of Rvs167 and Pcl-Pho85 Cdks might contribute to actin cytoskeleton regulation in response to stresses such as starvation.

Actins↗
PubMed1998

Theoretical analysis of cell separation based on cell surface marker density.

A theoretical analysis was performed to determine the number of fractions a multidisperse, immunomagnetically labeled cell population can be separated into based on the surface marker (antigen) density. A number of assumptions were made in this analysis: that there is a proportionality between the number of surface markers on the cell surface and the number of immunomagnetic labels bound; that this surface marker density is independent of the cell diameter; and that there is only the presence of magnetic and drag forces acting on the cell. Due to the normal distribution of cell diameters, a "randomizing" effect enters into the analysis, and an analogy between the "theoretical plate" analysis of distillation, adsorption, and chromatography can be made. Using the experimentally determined, normal distribution of cell diameters for human lymphocytes and a breast cancer cell line, and fluorescent activated cell screening data of specific surface marker distributions, examples of theoretical plate calculations were made and discussed.

Antigens, Surface↗
PubMed1998

Effects of the Heartbeat Wales programme over five years on behavioural risks for cardiovascular disease: quasi-experimental comparison of results from Wales and a matched reference area.

OBJECTIVE: To assess the net 5 year effects of intervention of a community based demonstration project, the Heartbeat Wales programme, on modifiable behavioural risks for prevention of cardiovascular disease. DESIGN AND SETTING: Quasi-experimental design comparing results from two independent cross sectional population surveys conducted in 1985 and 1990 in Wales and a matched reference area in north east England. SUBJECTS: Random, stratified samples of people aged 18-64 years (18,538 in 1985 and 13,045 in 1990) in Wales and in north east England (1483 and 4534, respectively). INTERVENTION: A coordinated range of activities for heart health promotion in Wales entailing public education campaigns along with supportive policy and infrastructure change. In the reference area no additional community heart health promotion was planned, though considerable activity did take place, "contaminating" the reference area. MAIN OUTCOME MEASURES: Fifteen self reported behavioural indicators relating to dietary choice, smoking, frequency of exercise, and weight. RESULTS: Positive changes (for health) in behavioural outcomes were observed among the population in Wales, including a reduction in reported smoking prevalence and improvements in dietary choice. There was no net intervention effect for the programme over and above observed change in the reference area. CONCLUSIONS: No definite conclusions can be drawn concerning the efficacy of the programme in terms of behavioural outcomes. With hindsight, the difficulties of evaluating such a complex multifaceted intervention were underestimated. Further debate on the most appropriate methods for assessing the effectiveness of community based health promotion programmes is called for.

Adolescent↗
PubMed1998

Can the urea breath test for H.pylori replace endoscopy for the assessment of dyspepsia in primary care?

AIMS: The urea breath test may have value in the initial assessment of dyspepsia in primary care. This pilot study tracks patient and general practitioner behaviour which cannot be predicted with modelling studies. METHODS: The urea breath test was made available over a period of 18 months. The test was requested when general practitioners would normally have used a trial of medication or referred for endoscopy. Patients with a positive urea breath test had early endoscopy before treatment. Patients with a negative urea breath test were treated according to symptom response. A follow-up questionnaire was given 6-24 months after the urea breath test. RESULTS: Urea breath tests were requested on 249 patients; clinical notes and follow-up interview data were available for 207 patients (83%). The urea breath test was positive for 89 patients (43%); 70 were referred for endoscopy and peptic ulcer disease was found in 33 (47%). The urea breath test was negative for 118 patients; 14 were follow-up tests after previous H.pylori treatment. For the 104 patients with dyspepsia, a negative test and no previous treatment, 42% had 1 or more previous investigations for dyspepsia and 66% had dyspepsia symptoms for more than one year. During follow-up, 21 patients had endoscopy. Dyspepsia symptom scores were significantly lower at follow-up (p < 0.01). Using a global assessment, 66% had fewer symptoms, 22% same and 12% had more symptoms. The symptom improvement was greater if the duration of symptoms was less than one year (p < 0.05). Medication use did not change significantly. Twelve patients were dissatisfied with management; most of these would have preferred endoscopy. CONCLUSIONS: A negative urea breath test appears to have some reassurance value. The use of the urea breath test as initial assessment for dyspespia may prevent the need for some endoscopy. Further controlled studies of breath testing compared with early endoscopy are required.

Adult↗
PubMed1998

Are giant ganglia a reliable marker of intestinal neuronal dysplasia type B (IND B)?

It has been suggested that giant ganglia are a marker for a developmental bowel disorder, intestinal neuronal dysplasia of the submucosal plexus (IND B), diagnosed in a proportion of patients with severe intractable constipation. Diagnosis of this condition, however, remains controversial with a wide variation in the frequency of diagnosis in different centres. Our aim was to assess the frequency with which giant ganglia could be found in the bowel of individuals who did not give a history of life-long constipation. We also aimed to assess the reproducibility of giant ganglia counts. For this two pathologists independently assessed pieces of normal bowel taken away from the site of the lesion in patients who had undergone surgery for colorectal carcinoma. Giant ganglia containing seven or more ganglion cells were found in 76 and 78% of subjects by each of the two pathologists. There was 1 giant ganglion per 10 ganglia counted in those patients in whom they were identified and 1 giant ganglion per 10.9 ganglia overall. Sections from eight patients in whom there was a history of constipation and/or melanosis coli did not show a greater number of giant ganglia. We conclude therefore that so-called "giant ganglia" are a common feature in the submucosa of normal bowel and that the presence of occasional giant ganglia cannot be considered diagnostic of IND B.

Colorectal Neoplasms↗
PubMed1998

Aerosolization of novel nitric oxide donors selectively reduce pulmonary hypertension.

OBJECTIVES: Inhaled nitric oxide (NO) reduces pulmonary hypertension in acute respiratory failure. Soluble nitric oxide donors (NO/nucleophile adducts-NONOates) are less cumbersome to deliver and may offer clinical advantage compared with inhaled NO. The objective of this study was to examine the pulmonary and systemic hemodynamic effects of tracheal aerosolization of a new class of NONOates in a porcine model of experimentally induced pulmonary hypertension. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory. SUBJECTS: Yorkshire pigs (n = 18), weighing 11.4 to 16.4 kg. INTERVENTIONS: In anesthetized, mechanically ventilated, instrumented pigs, steady-state pulmonary hypertension (SSPH) was induced using a thromboxane agonist (U46619). Control animals received tracheal aerosolization of saline (n = 6); EP/NO animals received tracheal aerosolization of ethylputreanine NONOate (EP/ NO, n = 6); and DMAEP/NO animals received aerosolized 2-(dimethylamino) ethylputreanine NONOate (DMAEP/NO, n = 6). MEASUREMENTS AND MAIN RESULTS: Mean pulmonary (MPAP) and mean systemic arterial pressures (MAP), atrial pressures, cardiac output, and arterial blood gases were measured following drug instillation. DMAEP/NO animals had significant reductions in pulmonary vascular resistance index (PVRI) and MPAP at all time points compared with SSPH and control animals (p < .05), while systemic vascular resistance index did not change. EP/NO animals had a significant reduction in PVRI and MPAP at some time points compared with SSPH and control animals. For both NONOate-treated animal groups, MAP and cardiac index did not change significantly compared with SSPH and control animals (p < .05). CONCLUSIONS: In this porcine model of pulmonary hypertension, intratracheal aerosolization of soluble NO donors results in sustained reduction of pulmonary hypertension without reducing systemic arterial pressure. Intermittent aerosolization of NONOates may be an alternative to continuously inhaled NO in the treatment of acute pulmonary hypertension.

Acute Disease↗
PubMed1998

Follow up after successful eradication of Helicobacter pylori: symptoms and reinfection.

The important long-term outcomes after Helicobacter pylori eradication are the proportion of patients with continuing symptoms, and the rate of recrudescence of the infection. Patients with proven H. pylori infection prior to treatment and a negative urea breath test at least 4 weeks after completing treatment were invited to return for a further urea breath test and a questionnaire. There were 167 patients and the mean interval since the post-treatment urea breath test was 16 months. The endoscopic diagnoses were duodenal ulcer 72, duodenitis 17, gastric ulcer 26, normal or oesophagitis 52. The ethnic groups were European 86, Maori 25, Pacific Island 28 and other ethnic groups 28. Ten patients (6%) had a positive urea breath test at follow up. The proportion of patients showing recrudescence of H. pylori was related to the delta value (delta) of the post-treatment urea breath test: delta 0-2, five of 146 (3.4%); delta 2-3, two of 18 (11%); and delta 3-4, three of five (60%). A symptom questionnaire was given to 147/157 patients with a persistently negative breath test; 60 had no symptoms, 31 had heartburn, 30 had epigastric pain, 15 had both heartburn and epigastric pain, and 11 had nausea or other symptoms. There were fewer symptoms in patients with gastric ulcer (GU) compared with patients with duodenal ulcer (DU) and non-ulcer patients. Twenty-four patients (16%) were taking H2-antagonists (including seven DU and five GU), 15 were taking antacids and four were taking omeprazole. There was no difference in medication use between diagnostic groups. Eighteen of the 46 patients (39%) with heartburn stated that this was a new symptom. Heartburn was a common symptom for duodenal ulcer patients after eradication (24/74, 32%). A second urea breath test 6-12 months after eradication is required to definitely prove eradication. Patients with a breath test delta value of 2-4 should have a repeat urea breath test.

Anti-Bacterial Agents↗
PubMed1998

Cyclin partners determine Pho85 protein kinase substrate specificity in vitro and in vivo: control of glycogen biosynthesis by Pcl8 and Pcl10.

In Saccharomyces cerevisiae, PHO85 encodes a cyclin-dependent protein kinase (Cdk) with multiple roles in cell cycle and metabolic controls. In association with the cyclin Pho80, Pho85 controls acid phosphatase gene expression through phosphorylation of the transcription factor Pho4. Pho85 has also been implicated as a kinase that phosphorylates and negatively regulates glycogen synthase (Gsy2), and deletion of PHO85 causes glycogen overaccumulation. We report that the Pcl8/Pcl10 subgroup of cyclins directs Pho85 to phosphorylate glycogen synthase both in vivo and in vitro. Disruption of PCL8 and PCL10 caused hyperaccumulation of glycogen, activation of glycogen synthase, and a reduction in glycogen synthase kinase activity in vivo. However, unlike pho85 mutants, pcl8 pcl10 cells had normal morphologies, grew on glycerol, and showed proper regulation of acid phosphatase gene expression. In vitro, Pho80-Pho85 complexes effectively phosphorylated Pho4 but had much lower activity toward Gsy2. In contrast, Pcl10-Pho85 complexes phosphorylated Gsy2 at Ser-654 and Thr-667, two physiologically relevant sites, but only poorly phosphorylated Pho4. Thus, both the in vitro and in vivo substrate specificity of Pho85 is determined by the cyclin partner. Mutation of PHO85 suppressed the glycogen storage deficiency of snf1 or glc7-1 mutants in which glycogen synthase is locked in an inactive state. Deletion of PCL8 and PCL10 corrected the deficit in glycogen synthase activity in both the snf1 and glc7-1 mutants, but glycogen synthesis was restored only in the glc7-1 mutant strain. This genetic result suggests an additional role for Pho85 in the negative regulation of glycogen accumulation that is independent of Pcl8 and Pcl10.

Cyclin-Dependent Kinases↗