PubMed Health⌕ Search

Biomedical subjects

J W Yates

Publications and source records attributed to J W Yates.

At least 19 recordsLinked to original sources
PubMed2001

Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older.

CONTEXT: Postmenopausal women aged 55 years and older have 66% of incident breast tumors and experience 77% of breast cancer mortality, but other age-related health problems may affect tumor prognosis and treatment decisions. OBJECTIVE: To document the comorbidity burden of postmenopausal breast cancer patients and evaluate its relationship with age on disease stage, treatment, and early mortality. DESIGN AND SETTING: Data were collected on breast cancer patients' comorbidities by retrospective hospital medical records review and merged with information on patients' tumor characteristics collected from 6 regional National Cancer Institute Surveillance, Epidemiology, and End Results cancer registries. Patients were followed up until death or for 30 months from breast cancer diagnosis. PARTICIPANTS: Population-based random sample of 1800 postmenopausal breast cancer patients diagnosed in 1992 stratified by 3 age groups: 55 to 64 years, 65 to 74 years, and 75 years and older. MAIN OUTCOME MEASURES: Extent of disease, therapy received, comorbidity, cause of death, and survival. RESULTS: Seventy-three percent (1312 of 1800) of the sample was diagnosed with stage I and II breast cancer, 10% (n = 188) with stage III and IV breast cancer, and 17% (n = 300) did not have a stage assignment. Of the 1017 patients with stage I and stage II node-negative breast cancer, 95% received therapy in agreement with the National Institutes of Health consensus statement recommendation for early-stage breast cancer. Patients in older age groups were less likely to receive therapy consistent with the consensus statement (P<.001), and women aged 70 years and older were significantly less likely to receive axillary lymph node dissection as determined by logistic regression analysis (P<.01). Diabetes, renal failure, stroke, liver disease, a previous malignant tumor, and smoking were significant in predicting early mortality in a statistical model that included age and disease stage. Breast cancer was the underlying cause of death for 135 decedents (51.3%). Heart disease (n = 45, 17.1%) and previous cancers (n = 22, 8.4%) were the next major underlying causes. In the 30-month follow-up period, 263 patients (15%) died. CONCLUSION: Patient care decisions occur in the context of breast cancer and other age-related conditions. Comorbidity in older patients may limit the ability to obtain prognostic information (ie, axillary lymph node dissection), tends to minimize treatment options (eg, breast-conserving therapy), and increases the risk of death from causes other than breast cancer.

Age Factors↗
PubMed2000

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

Adenosine Triphosphate↗
PubMed1998

The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076.

ATP citrate (pro-S)-lyase (EC 4.1.3.8), a cytosolic enzyme that generates acetyl-CoA for cholesterol and fatty acid synthesis de novo, is a potential target for hypolipidaemic intervention. Here we describe the biological effects of the inhibition of ATP citrate-lyase on lipid metabolism in Hep G2 cells, and plasma lipids in rats and dogs, by using SB-204990, the cell-penetrant gamma-lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076 (Ki=1 microM). Consistent with an important role of ATP citrate-lyase in the supply of acetyl-CoA units for lipid synthesis de novo, SB-204990 inhibited cholesterol synthesis and fatty acid synthesis in Hep G2 cells (dose-related inhibition of up to 91% and 82% respectively) and rats (76% and 39% respectively). SB-204990, when administered orally to rats, was absorbed into the systemic circulation; pharmacologically relevant concentrations of SB-201076 were recovered in the liver. When administered in the diet (0.05-0. 25%, w/w) for 1 week, SB-204990 caused a dose-related decrease in plasma cholesterol (by up to 46%) and triglyceride levels (by up to 80%) in rats. This hypolipidaemic effect could be explained, at least in part, by a decrease (up to 48%) in hepatic very-low-density lipoprotein (VLDL) production as measured by the accumulation of VLDL in plasma after injection of Triton WR-1339. SB-204990 (25 mg/kg per day) also decreased plasma cholesterol levels (by up to 23%) and triglyceride levels (by up to 38%) in the dog, preferentially decreasing low-density lipoprotein compared with high-density lipoprotein cholesterol levels. Overall these results are consistent with the concept that ATP citrate-lyase is an important enzyme in controlling substrate supply for lipid synthesis de novo and a potential enzyme target for hypolipidaemic intervention.

ATP Citrate (pro-S)-Lyase↗
PubMed1998

Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study.

BACKGROUND: Colon carcinoma primarily affects persons 65 years and older. Seventy-five percent of the incident tumors affect persons in this age group. Because of their advanced age, older patients already may be coping with other concomitant major physical illnesses. This article documents preexisting diseases in older colon carcinoma patients at diagnosis and evaluates the effects of their comorbidity burden on early mortality. METHODS: Prevalence of comorbid conditions was assessed by a retrospective medical records review of an age-stratified random sample of male and female patients aged 55-64 years, 65-74 years, and 75+ years (males, n=799; females, n=811). Data were collected on comorbidity by the National Institute on Aging (NIA) and National Cancer Institute (NCI) and merged with NCI Surveillance, Epidemiology, and End Results (SEER) tumor registry data. RESULTS: Hypertension, high impact heart conditions, gastrointestinal problems, arthritis, and chronic obstructive pulmonary disease emerged as the most prominent comorbid conditions in the NIA/NCI SEER Study sample. The prevalence of comorbidity in the number and type of conditions was similar for both men and women (e.g., 40% of each gender had > or = 5 comorbidities). Within 2 years of diagnosis, 28% (n=454) of the patients had died. The number of comorbid conditions was significant in predicting early mortality in a model including age, gender, and disease stage (P=0.0007). Certain comorbidities, classified as "current problem," added significantly to a basic model (e.g., heart problems, alcohol abuse, liver disease, and deep vein thrombosis). CONCLUSIONS: Although disease stage at time of diagnosis of colon carcinoma is a crucial determinant of patient outcome, comorbidity increases the complexity of cancer management and affects survival duration. Cancer control and treatment research questions should address comorbidity issues pertinent to the age group primarily afflicted with colon carcinoma (i.e., the elderly).

Age Factors↗
PubMed1998

Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs.

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a novel compound, SB 204990 (the 5-ring lactone of +/-(3R*,5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid, CAS 154566-12-8), a potent inhibitor of cholesterol and fatty acid synthesis at the level of ATP-citrate lyase. APOE*3-Leiden mice were fed a saturated fat and cholesterol-rich diet supplemented with either 0.05 or 0.1% w/w of lovastatin, 0.1 or 0.2% w/w of gemfibrozil or 0.1 or 0.2% w/w of SB 204990. Lovastatin showed a dose-related decrease in plasma cholesterol levels (up to -20%) due to a lowering of LDL and HDL (low density resp. high density lipoprotein)-cholesterol (-20 and -18%, respectively), while plasma triglyceride levels were unaffected. Gemfibrozil had no effect on plasma total cholesterol levels but gave significant dose-dependent decreases in plasma (VLDL) triglyceride levels (up to -53%). SB 204990 resulted in a dose-dependent reduction of plasma cholesterol (up to -29%) by lowering VLDL, LDL and HDL-cholesterol (-50, -20 and -20%, respectively). In addition, a strong dose dependent reduction of plasma (VLDL) triglycerides up to -43% was observed with this compound. Although the effects of gemfibrozil and SB 204990 were not simply explained by changes in a single determinant of VLDL metabolism--no effects of these drugs were seen on post-heparin plasma lipoprotein lipase activity, in vivo rate of VLDL synthesis or hepatic apoC-III mRNA levels--APOE*3-Leiden mice were found to give robust hypolipidaemic responses to these test compounds. The responsiveness to hypolipidaemic therapy combined with a clear relationship between aortic lesion size and plasma cholesterol exposure, as demonstrated previously, makes this mouse an attractive model for the testing of anti-atherosclerotic properties of hypolipidaemic drugs.

Animals↗
PubMed1994

Effect of simultaneous exercise and noise exposure (music) on hearing.

Hearing thresholds were measured in 12 subjects prior to and following their participation in three experimental conditions: (a) riding a cycle ergometer for 20 minutes; (b) listening to a selection of music at an equivalent intensity of 96 dB(A) SPL for 20 minutes; and (c) listening to the music while riding the cycle ergometer for 20 minutes. Analysis of the results shows a measurable and statistically greater noise-induced temporary threshold shift (NITTS) for the music plus exercise condition that for either of the other two conditions. The greatest differences were seen in the 3-6 kHz frequency range. These results suggest an increased susceptibility to NITTS and, by extension, to increased potential for permanent hearing loss when noise exposure is coupled with exercise. The results have implications related to contemporary lifestyle issues such as aerobics and the utilization of personal music systems during physical exertion.

Adult↗
PubMed1993

Dietary ethanol reduces phosphatidylcholine levels and inhibits the uptake of dietary choline in Drosophila melanogaster larvae.

1. Low to moderate concentrations of dietary ethanol (200 mM to 600 mM) significantly increased the level of phosphatidylethanolamine (PE), while phosphatidylcholine (PC) levels decreased in third instar larvae. This was seen in both ethanol tolerant and intolerant strains of Drosophila melanogaster, indicating that the reduction of PC is not associated with a high level of ethanol tolerance. 2. The phospholipid changes were not ethanol-specific. Larvae fed ethanol, n-butanol, isopropanol, methanol, and n-propanol exhibited similar changes. 3. At 200 mM concentrations, dietary ethanol acted as a competitive inhibitor for the larval uptake of dietary choline. At higher concentrations, dietary ethanol acted as a noncompetitive inhibitor. This ethanol-induced inhibition of dietary choline uptake can only partially explain the ethanol-induced reductions in larval PC.

Alcohols↗
PubMed1993

Dietary ethanol stimulates the activity of phosphatidylcholine-specific phospholipase D and the formation of phosphatidylethanol in Drosophila melanogaster larvae.

When administered in the diet to third instar Drosophila melanogaster larvae, short chain primary alcohols reduce phosphatidylcholine (PC) levels. The ethanol-induced reductions in larval PC may be in part due to an increase in the activity of PC-specific phospholipase D (PC-specific PLD, EC 3.1.4.4). PC-specific PLD not only hydrolyzes PC, but it also apparently catalyzes the formation of phosphatidylethanol. PC-specific PLD activity was also stimulated by 200 mM ethanol, methanol, isopropanol, n-butanol, and n-propanol. In vitro studies indicated that Drosophila PC-specific PLD activities were enhanced by submicromolar concentrations of Ca2+ and by GTP-gamma S. In vivo studies utilizing [14C]lyso-palmitoyl phosphatidylcholine indicated that dietary ethanol promoted the flux of label into triacylglycerol, 1,2 diacylglycerol, and fatty acid ethyl esters, while the label in PC decreased.

Animals↗
PubMed1992

Testing the progressive nature of alcoholism.

The authors employed a new data collection methodology to assess Jellinek's progressive model of alcoholism. Data were collected to explore whether (a) symptoms occurred in four distinct phases, one phase following another, as described by Jellinek's model; (b) the phase markers and the phases of the symptom progression follow one another as predicted in the Jellinek model; and (c) the sequence of each of the 46 individual symptoms is as described by a serial interpretation of Jellinek's model. The authors also compared male participants with female participants on the conditions described above.

Adaptation, Psychological↗
PubMed1991

Cancer staging may have different meanings in academic and community hospitals.

We investigated differences in lung cancer care and outcome between academic and community settings for all lung cancer patients diagnosed during 1973-1976 in New Hampshire and Vermont. Trained abstracters reviewed hospital charts to record personal, diagnostic, and clinical information, and survival was determined for all patients through the end of 1979. Patients diagnosed in university hospital cancer centers underwent more staging procedures and tended to be assigned to a higher stage than similar patients diagnosed in community hospitals. When tumor stage was considered as a covariable in a survival analysis, these patients appeared to have a lower mortality rate both for non-small cell tumors (mortality rate ratio, 95% confidence interval = 0.81, 0.71-0.91) and for small cell tumors (0.71, 0.55-0.91). When functional status rather than tumor stage was used to adjust for disease severity, there was no apparent survival advantage for university patients with non-small cell cancer (0.96, 0.85-1.09) and the lower mortality for small cell cancers (0.76, 0.59-0.97) was attenuated, although still statistically significant. We conclude that inconsistently-collected data on clinical stage can complicate comparisons of prognosis between cancer patients from different types of hospitals and that measures of performance status may be more useful indicators of disease severity in population based studies.

Academic Medical Centers↗
PubMed1990

Results of a national survey of characteristics of hospital tumor conferences.

A descriptive survey of hospital tumor conferences, which are also referred to as tumor boards, was conducted by the National Cancer Institute in collaboration with the American College of Surgeons and Roswell Park Memorial Institute. The survey was done to assess the involvement of the tumor conference in the care of the patient with cancer and to lay the groundwork for additional studies of the conference. The data from the descriptive survey are based on questionnaires sent to 1,700 hospitals in the United States. The questionnaires requested information about frequency, attendance, composition, role of the chairman, agenda and other variables that relate to the format and purpose of the conference. From the results, we conclude that tumor conferences are an accepted and established institution for the multidisciplinary care of patients with cancer. They are a major source of consultation and education for physicians and for other professionals involved in oncology. Tumor conferences are conducted in a wide spectrum of hospitals and related institutions that vary in size and function.

Clinical Protocols↗
PubMed1989

Breast cancer in aging women. A population-based study of contrasts in stage, surgery, and survival.

Over 43% of the newly diagnosed breast cancers in the US occur in women 65 years or older. Yet little attention is devoted to the age-associated aspects of this malignancy. This study uses data on more than 125,000 women diagnosed from 1973 to 1984 to examine the influence of advancing age on breast cancer. The National Cancer Institute's Surveillance, Epidemiology, and End Results Program provides information on disease stage, surgery, histologic type, and survival time to compare and contrast women in all age groups. Women who present initially with distant disease are more likely to be elderly. Certain surgical procedures are used less frequently for older women. No unusual age variations in histologic features are noted. Elderly women do as well as younger patients in survival time for localized and regional stages of breast cancer; for distant disease, they fare worse. Results emphasize the need to focus on elderly women for screening, early detection, diagnostic evaluation, and therapy.

Age Factors↗
PubMed1988

The elderly population. Opportunities for cancer prevention and detection.

Interest in the elderly population, persons 65 years of age or older, as a target group for cancer control has not been great. Age recommendations rarely are made for prevention and early detection of cancer for elderly persons. However, cancer incidence and mortality rates are known to rise rapidly with increasing age. This paper takes a long-term public-health perspective to look toward the year 2030 to discuss the challenges of organizing and implementing prevention and early detection incentives for our nation's current and future elderly population. Cancer prevalence estimates in the context of the geriatric imperative of the 21st century are provided for three cancers--breast, prostate, and lung and bronchus. The sheer magnitude of numbers created by the aged population expansion can greatly increase the number of cancer survivors and newly diagnosed cases. Current efforts in cancer prevention and early detection should anticipate the health-care demands of the elderly in the first three decades of the next century.

Adult↗
PubMed1988

The long-term impact of a training program in maxillofacial prosthodontics.

A follow-up survey of trainees in a National Cancer Institute-sponsored program in maxillofacial prosthodontics was conducted. Information about the trainees' current professional activities indicated that the majority work in private practice or a dental school, are primarily involved in clinical work or teaching, and see few cancer patients. Inadequate reimbursement and lack of collaboration with surgeons were cited as barriers to involvement in cancer patient care. It is suggested that barriers to applying training expertise in actual practice settings require emphasis in the planning and curricula of training programs.

Career Choice↗
PubMed1987

Quality of life.

The term quality of life (QL) is a global characterization usually consisting of the following factors: physical function, symptoms from disease and/or treatment, occupational and social interactions, and psychological parameters, including mood with some overall assessment of well-being, such as happiness or satisfaction. For the purposes of individual patient management, the physician often assesses many of these in the process of making decisions about cancer care. The aggregate assessment of QL in groups of patients is more difficult. The increasing subjectivity and difficulty in measurement as medical observers move from the physical (objective parameters) to the psychosocial (subjective parameters) has hindered our ability to study QL. The changing status of the patient from initial symptomatic disease, to the incapacitation related to the treatment and/or the ongoing course of the disease often leading to death makes the measurement of QL a moving target. One must be very specific as to the malignancy, the status of disease, the treatments with their side effects and sequela, and the time of measurement in this dynamic spectrum, if the data is to be comparable and to permit generalizations. For the purposes of clinical trials the emphasis remains with the physical factors: function and symptom control. Even these factors are difficult to assess consistently, making the aggregation of such data from similarly treated groups of patients sometimes suspect. The ability to determine the impact of disease and treatment on these factors in a reliable manner could make possible, with aggregated data from many patients, more objective assessment of the advantages and disadvantages of a particular therapy. Late sequelae of treatment may also be important. When cure or prolonged survival are not likely or possible then the ability to determine the probable effects, physical and psychosocial, of a specific treatment on an individual patient is valuable. Treatment then can be guided to some extent by QL considerations.

Humans↗