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At least 901 records · Page 50Linked to original sources
PubMed2000

The MAL proteolipid is necessary for the overall apical delivery of membrane proteins in the polarized epithelial Madin-Darby canine kidney and fischer rat thyroid cell lines.

The MAL proteolipid has been recently demonstrated as being necessary for correct apical sorting of the transmembrane influenza virus hemagglutinin (HA) in Madin-Darby canine kidney (MDCK) cells. The fact that, in contrast to MDCK cells, Fischer rat thyroid (FRT) cells target the majority of glycosylphosphatidylinositol (GPI)-anchored proteins to the basolateral membrane provides us with the opportunity to determine the role of MAL in apical transport of membrane proteins under conditions in which the majority of GPI-anchored proteins are (MDCK cells) or are not (FRT cells) targeted to the apical surface. Using an antisense oligonucleotide-based strategy to deplete endogenous MAL, we have observed that correct transport of apical transmembrane proteins associated (HA) or not (exogenous neurotrophin receptor and endogenous dipeptidyl peptidase IV) with lipid rafts, as well as that of the bulk of endogenous apical membrane, takes place in FRT cells by a pathway that requires normal MAL levels. Even transport of placental alkaline phosphatase, a GPI-anchored protein that is targeted apically in FRT cells, was dependent on normal MAL levels. Similarly, in addition to the reported effect of MAL on HA transport, depletion of MAL in MDCK cells caused a dramatic reduction in the apical delivery of the GPI-anchored gD1-DAF protein, neurotrophin receptor, and the bulk of membrane proteins. These results suggest that MAL is necessary for the overall apical transport of membrane proteins in polarized MDCK and FRT cells.

Animals↗
PubMed2006

Lack of adenomatous polyposis coli protein correlates with a decrease in cell migration and overall changes in microtubule stability.

Most sporadic colorectal tumors carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein is involved in many processes that govern gut tissue. In addition to its involvement in the regulation of beta-catenin, APC is a cytoskeletal regulator with direct and indirect effects on microtubules. Cancer-related truncation mutations lack direct and indirect binding sites for microtubules in APC, suggesting that loss of this function contributes to defects in APC-mutant cells. In this study, we show that loss of APC results in disappearance of cellular protrusions and decreased cell migration. These changes are accompanied by a decrease in overall microtubule stability and also by a decrease in posttranslationally modified microtubules in the cell periphery particularly the migrating edge. Consistent with the ability of APC to affect cell shape, the overexpression of APC in cells can induce cellular protrusions. These data demonstrate that cell migration and microtubule stability are linked to APC status, thereby revealing a weakness in APC-deficient cells with potential therapeutic implications.

Acetylation↗
PubMed1997

Effect of dietary sodium restriction on overall nutrient intake.

Sodium restriction, widely prescribed for hypertensive persons and recommended for the broader US population, may result in nutrient alterations that could either beneficially or detrimentally affect overall diet quality. Most dietary sodium comes from meats (including poultry and fish), grains, and dairy products. These three groups also provide most dietary calcium, iron, magnesium, and vitamin B-6. Thus, reduced consumption of foods that are primary sodium sources could concurrently reduce the dietary content of these other nutrients below recommended daily intakes. This consequence of sodium restriction has not been specifically addressed in clinical trials. Although intake of most food groups was significantly reduced by a sodium-restricted diet in the Hypertension Prevention Trial, three other large clinical trials reported differing effects of sodium restriction on simultaneous energy and nutrient intakes. In the largest study of the effects of a sodium-restricted diet on intake of all major nutrients, sodium reduction was accompanied by lower energy intake and, concomitantly, lower intakes of total fat, saturated fat, protein, carbohydrate, and calcium. Present data are inadequate for determining the potential nutrient alterations of a broad prescription of sodium restriction. Difficulties in interpreting the available data result from the combination of sodium restriction with other interventions, intensive sodium reduction measures that do not reflect clinical implementation, poor compliance with sodium restriction, lack of analysis of changes in patterns of food intake, and interventions that are too short to reflect stable dietary patterns.

Adult↗
PubMed2000

Mediterranean diet and age with respect to overall survival in institutionalized, nonsmoking elderly people.

BACKGROUND: In studies from Italy and Greece, a Mediterranean dietary pattern was shown to favorably affect life expectancy in the elderly population. This pattern is thought to reduce the risk of cancer in addition to being cardioprotective. OBJECTIVE: The objective of this study was to evaluate the interactive effects of the Mediterranean diet and age with respect to survival after controlling for several other variables that could be considered as confounders: age, sex, body mass index, albumin concentration, physical activity, self-assessment of health, and dieting in response to chronic conditions. DESIGN: This was a cohort study involving 161 nonsmoking elderly subjects (74 subjects aged <80 y and 87 subjects aged > or =80 y) living in Spain. The subjects were followed up for > or =9 y. Diet was assessed with a semiquantitative food-frequency questionnaire. RESULTS: A diet score based on 8 characteristics of the traditional diet in the Mediterranean region was associated with a significant reduction in overall mortality in elderly subjects aged <80 y but not in subjects aged > or =80 y. A unit increase in the diet score predicted a 31% reduction in mortality in subjects aged <80 y (95% CI: 7%, 57%). CONCLUSION: Efforts to promote adherence to the Mediterranean dietary pattern appear to be worthwhile in persons aged <80 y, in whom the diet predicts survival, but we do not have any available evidence that such a diet benefits subjects aged > or =80 y.

Aged↗
PubMed2003

Temporary employment and risk of overall and cause-specific mortality.

The number of nonpermanent employees is rising, but mortality in this group has received little attention. The authors examined the associations between temporary employment and all-cause and cause-specific mortality. Longitudinal data from 10 towns in Finland related to 26,592 men and 65,759 women, of whom 1,332 died between 1990 and 2001. Cox proportional hazards models adjusted for age, occupational status, salary, and change in occupational title showed that overall mortality was 1.2-1.6 times higher among male and female temporary employees compared with permanent employees. Temporary employment was associated with increased deaths from alcohol-related causes (hazard ratio (HR) = 2.0, 95% confidence interval (CI): 1.4, 2.9 for men; HR = 1.7, 95% CI: 1.1, 2.5 for women) and, for men, smoking-related cancer (HR = 2.8, 95% CI: 1.3, 6.0). Corresponding risks were greater for the unemployed. Moving from temporary to permanent employment was associated with a lower risk of death than remaining continuously in permanent employment (HR = 0.7, 95% CI: 0.5, 0.9 for men and women combined). These findings suggest that the conventional research practice of treating the employed as a single group may attenuate the associations between employment status and mortality.

Adolescent↗
PubMed2002

Integrated analysis of overall survival in two randomised studies comparing 5-fluorouracil/leucovorin with or without trimetrexate in advanced colorectal cancer.

BACKGROUND: Two randomised studies were performed with trimetrexate (TMTX) as a biochemical modulator of 5-fluorouracil (5-FU)/leucovorin (LV) in advanced colorectal cancer (ACC), one in Europe and one in the United States. Both studies were similarly designed to detect a statistically significant difference in progression-free survival (PFS). Overall survival (OS), however, was later adopted as the primary outcome measure for approvability of agents for first-line treatment of ACC. Therefore, an integrated analysis of survival data from the European and USA trials was performed to detect a clinically relevant difference in survival. PATIENTS AND METHODS: The experimental arm was identical in both studies and consisted of TMTX 110 mg/m2 intravenously (i.v.) followed 24 h later by i.v. LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. The 5-FU dose in the control arm was 600 mg/m2 in the European study and 500 mg/m2 in the USA study, and the USA study was placebo-controlled. Treatment was given weekly for 6 weeks every 8 weeks. RESULTS: A total of 746 patients were analysed. Median OS was 13.0 months for 5-FU/LV and 14.6 months for TMTX/5-FU/LV (P = 0.15; Wilcoxon). Median PFS was 4.4 months and 5.4 months, respectively (P = 0.07; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LV does not improve the outcome for patients with ACC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Is overall survival a realistic primary end point in advanced colorectal cancer studies? A critical assessment based on four clinical trials comparing fluorouracil plus leucovorin with the same treatment combined either with oxaliplatin or with CPT-11.

BACKGROUND: The adequacy of overall survival (OS) as study end point in phase III trials for advanced solid tumors is questionable. The present review highlights the limits of OS as study end point to evaluate the efficacy of new drugs. METHODS: Four phase III clinical trials comparing a fluorouracil-based regimen with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal cancer patients were reviewed. The primary aim of the critical assessment was to explain the lack of OS advantage observed in two of the four trials, despite the presence of increased response rate (RR) and time to progression (TTP). Four possible reasons for the lack of OS benefit (i.e. statistical power, cross-over, magnitude of the effect on RR and TTP, non-tumor-related deaths) were systematically reviewed in the trials, and the detectable 1-year OS difference, assuming a statistical power of 80%, was calculated for each. RESULTS: None of these reasons for the lack of OS advantage in presence of RR and TTP benefits convincingly explained the results of the evaluated trials. Three of the four trials had roughly the same statistical power to detect 1-year OS differences, while the fourth trial was underpowered to detect realistic OS differences. The lack of OS advantage observed in the two oxaliplatin trials is therefore likely fortuitous, and due to lack of statistical power. CONCLUSIONS: Although increase in OS remains the ultimate goal of many clinical trials, the choice of OS benefit as a mandatory requirement to register new compounds can lead to a serious underestimation of a drug's real efficacy.

Antimetabolites, Antineoplastic↗
PubMed2004

'Parcours de Femme 2001': a French opinion survey on overall disease and everyday life management in 1870 women presenting with gynecological or breast cancer and their caregivers.

PURPOSE: The aim of the survey 'Parcours de Femmes 2001' was to evaluate the overall management and care of women with female cancers and to determine their needs. METHODS: Women with breast or gynecological cancer who had either received at least 3 months of treatment or had completed treatment <1 year before the study were enrolled in this cross-sectional, observational study. RESULTS: From February to November 2001, 2839 questionnaires were distributed; 1870 were returned (66% response rate), mainly by breast cancer patients (87%). While 92% of women reported having received information at diagnosis, 34% of relapsed patients complained of lack of information concerning their disease and treatment. Only 18% of patients were included in the treatment decision process and 66% of women obtained complementary information from the media, patients and care professionals. Fatigue was the most severe problem quoted (78% of cases) and was poorly managed by caregivers due to diagnostic and treatment difficulties. Problems relating to family and to affective and socio-professional life were poorly identified and remained largely unmanaged. CONCLUSIONS: Information given to female cancer patients must be improved in relapsed patients, particularly regarding the adverse effects of treatment. Psychosocial management requires a more holistic approach through new channels, together with the coordination of existing structures.

Activities of Daily Living↗
PubMed2005

Good clinical response of breast cancers to neoadjuvant chemoendocrine therapy is associated with improved overall survival.

BACKGROUND: We present extended follow-up from a prospective randomised trial evaluating the role of neoadjuvant chemoendocrine therapy in the treatment of operable breast cancer. PATIENTS AND METHODS: 309 women were randomised to primary surgery followed by eight cycles of adjuvant mitoxantrone, methotrexate with tamoxifen (2MT) or 2MT with mitomycin-C (3MT) versus the same regimen for four cycles before followed by four cycles after surgery. For this analysis the median follow-up of patients was 112 months. RESULTS: After 10 years follow-up there is still no statistically significant difference in disease-free survival (DFS) (71% versus 71%) or overall survival (OS) (63% versus 70%) when comparing adjuvant versus neoadjuvant treatment, respectively. Of 144 evaluable patients in the neoadjuvant arm, 74 achieved a good clinical response and 70 patients achieved a poor clinical response. Good responders had a superior DFS (80% versus 64%, P=0.01) and OS (77% versus 63%, P=0.03) compared to poor responders. CONCLUSIONS: At 10 years, neoadjuvant and adjuvant treatment continue to have equivalent OS and DFS. Good clinical response to neoadjuvant chemotherapy is associated with superior DFS and OS. This supports the use of clinical response of primary breast cancer to neoadjuvant therapy as a surrogate marker of survival benefit.

Adult↗
PubMed2005

FDG-PET after two to three cycles of chemotherapy predicts progression-free and overall survival in high-grade non-Hodgkin lymphoma.

BACKGROUND: Less than 50% of all high-grade non-Hodgkin lymphoma (NHL) patients experience lasting disease-free survival. Risk-adapted treatment strategies require better tools for prediction of outcome. This investigation aimed to assess the value of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) after two to three cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: One hundred and twenty-one patients with high-grade NHL underwent FDG-PET. The therapy response on FDG-PET was correlated to PFS and OS using Kaplan-Meier survival analysis. Cox regression analyses were employed to test for independence of known pretreatment prognostic factors. RESULTS: Fifty FDG-PET scans were negative, 19 scans showed minimal residual uptake (MRU), and 52 scans were positive. The estimated 5 year PFS was 88.8% for the PET-negative group, 59.3% for the MRU group, and 16.2% for the PET-positive group. Kaplan-Meier analyses showed strong associations between FDG-PET results and PFS (P <0.0001) and OS (P <0.01). Early interim FDG-PET was independent of the other prognostic factors. CONCLUSIONS: Early interim FDG-PET is an accurate and independent predictor of PFS and OS. An early assessment of chemotherapy response with FDG-PET could provide the basis for selection of patients for alternative therapeutic strategies.

Adult↗
PubMed1999

Functional promoter modules can be detected by formal models independent of overall nucleotide sequence similarity.

MOTIVATION: Gene regulation often depends on functional modules which feature a detectable internal organization. Overall sequence similarity of these modules is often insufficient for detection by general search methods like FASTA or even Gapped BLAST. However, it is of interest to evaluate whether modules, often known from experimental analysis of single sequences, are present in other regulatory sequences. RESULTS: We developed a new method (FastM) which combines a search algorithm for individual transcription factor binding sites (MatInspector) with a distance correlation function. FastM allows fast definition of a model of correlated binding sites derived from as little as a single promoter or enhancer. ModelInspector results are suitable for evaluation of the significance of the model. We used FastM to define a model for the experimentally verified NFkappaB/IRF1 regulatory module from the major histocompatibility complex (MHC) class I HLA-B gene promoter. Analysis of a test set of sequences as well as database searches with this model showed excellent correlation of the model with the biological function of the module. These results could not be obtained by searches using FASTA or Gapped BLAST, which are based on sequence similarity. We were also able to demonstrate association of a hypothetical GRE-GRE module with viral sequences based on analysis of several GenBank sections with this module. AVAILABILITY: The WWW version of FastM is accessible at: http://www.gsf.de/cgi-bin/fastm. pl and http://genomatix.gsf.de/cgi-bin/fastm2/fastm.pl

Algorithms↗
PubMed2000

A genetic map of tomato based on BC(1) Lycopersicon esculentum x Solanum lycopersicoides reveals overall synteny but suppressed recombination between these homeologous genomes.

F(1) hybrids between the cultivated tomato (Lycopersicon esculentum) and the wild nightshade Solanum lycopersicoides are male sterile and unilaterally incompatible, breeding barriers that impede further crosses to tomato. Meiosis is disrupted in 2x hybrids, with reduced chiasma formation and frequent univalents, but is normal in allotetraploid hybrids, indicating the genomes are homeologous. In this study, a partially male-fertile F(1) was backcrossed to tomato, producing the first BC(1) population suitable for genetic mapping from this cross. BC(1) plants were genotyped at marker loci to study the transmission of wild alleles and to measure rates of homeologous recombination. The pattern of segregation distortion, in favor of homozygotes on chromosomes 2 and 5 and heterozygotes on chromosomes 6 and 9, suggested linkage to a small number of loci under selection on each chromosome. Genome ratios nonetheless fit Mendelian expectations. Resulting genetic maps were essentially colinear with existing tomato maps but showed an overall reduction in recombination of approximately 27%. Recombination suppression was observed for all chromosomes except 9 and 12, affected both proximal and distal regions, and was most severe on chromosome 10 (70% reduction). Recombination between markers on the long arm of this chromosome was completely eliminated, suggesting a lack of colinearity between S. lycopersicoides and L. esculentum homeologues in this region. Results are discussed with respect to phylogenetic relationships between the species and their potential use for studies of homeologous pairing and recombination in a diploid plant genome.

Crosses, Genetic↗
PubMed1999

Effects of hypercholesterolaemia on Leydig and Sertoli cell secretory function and the overall sperm fertilizing capacity in the rabbit.

The effects of hypercholesterolaemia on testicular endocrine and exocrine function were evaluated. The influence of hypercholesterolaemia on sperm quality, quantity, and fertilizing potential was also determined. Ten mature rabbits (group A) were fed chow containing 3% cholesterol for 12 weeks. Ten control rabbits (group B) were fed normal chow for the same period. At the end of the experimental period testosterone profiles and sperm parameters were evaluated and the sperm reproductive potential was assessed by in vitro fertilization (IVF) techniques. Peripheral serum testosterone responses to testicular stimulation with human chorionic gonadotrophin, androgen-binding protein activity in testicular cytosols, sperm concentration, sperm motility, length of sperm midpiece, and IVF outcome were all significantly lower in group A than in group B. In contrast, serum cholesterol concentrations were significantly higher in group A. There were no significant differences in either testicular versus intra-abdominal temperature differences or cholesterol concentrations in seminal plasma or testicular tissue between groups A and B. The results suggest that hypercholesterolaemia has a detrimental effect on Leydig and Sertoli cell secretory function, spermatogenesis, epididymal sperm maturation process, and the overall sperm fertilizing capacity.

Animals↗
PubMed2006

Effect of education on overall and cause-specific mortality in injecting drug users, according to HIV and introduction of HAART.

BACKGROUND: We assessed the impact of education on long-term overall and cause-specific mortality among 6575 injecting drug users (IDUs) according to HIV status and introduction of highly active antiretroviral therapy (HAART). METHODS: Community-based cohort study of IDUs recruited in three AIDS prevention centres (1987-1996). Causes of death were ascertained in clinical centres and Mortality Registry and classified as AIDS, drug use related, injuries, or liver diseases. Poisson regression models including education and calendar period interaction and adjusted by sex, age, and HIV were used. RESULTS: In 73 901 person-years of follow-up, there were 1493 deaths (20.2/1000 person-years): 761 related to AIDS, 234 to drug use, 179 to injuries, and 93 to liver diseases. IDUs with university studies had a lower risk of death (RR 0.52; 95% CI 0.36-0.77) than those without studies: this difference was higher after (RR 0.45; 95% CI 0.25-0.80) than before 1997 (RR 0.68; 95% CI 0.41-1.13). Compared to before 1997, while decreases in the risk of AIDS mortality were seen during 1997-2004 for both lower (RR 0.49; 95% CI 0.41-0.58) and higher (RR 0.33; 95% CI 0.23-0.48) educated, only those higher educated experienced a reduction in drug-use mortality (RR 0.54; 95% CI 0.28-1.05) and death from injuries (RR 0.52; 95% CI 0.23-1.21). CONCLUSIONS: Independently of HIV status, lower education predicts a higher risk of death in IDUs and its impact is stronger after 1997. Education has a protective effect on most causes of death and it cannot be entirely attributable to the access or use of HAART.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Split-course accelerated hyperfractionation radiotherapy for advanced head and neck cancer: influence of split time and overall treatment time on local control.

We analyzed 52 patients with stage III and IV head and neck cancer who were given split-course accelerated hyperfractionated radiotherapy with curative intent, focusing particularly on the influence of split-time on local control. An initial complete response was achieved in 16 patients (31%), and the rate of persistent local control at 3 years was 23%. The cause specific survival rate at 3 years was 29%. Univariate analysis of local control according to the split-time duration and overall treatment time showed that shorter duration (< or = 14 days or < or = 45 days, respectively) had a significantly positive impact on local control (P < 0.05). Multivariate analysis using local control as an endpoint also demonstrated that gender (women showing a better outcome than men) and split-time (< or = 14 days was better than > 14 days) were statistically significant factors for local control. These results suggest that shortening the split-time during radiotherapy might improve local control in accelerated hyperfractionation.

Adult↗
PubMed2001

Can lack of improvement in vitamin A status indicators be explained by little or no overall change in vitamin A status of humans?

Changes in vitamin A status using conventional indicators, i.e., serum and breast milk retinol concentrations and the modified relative dose response test, following a vitamin A intervention have not always been shown. A simplified model to predict calculated changes in vitamin A status after intervention is described. The model shows that changes in indicator values cannot be expected if the change in vitamin A status is only marginal. A critical review of several papers using vitamin A status assessment indicators was undertaken. Assumptions that included current knowledge concerning vitamin A absorption and metabolism were made and applied to the data. Based on current recommended daily allowances for women and children, one cannot necessarily expect a change in indicators if an overall change in vitamin A status was not achieved. Thus, when designing vitamin A intervention studies, the following parameters should be considered if applicable to the population to be enrolled in the study: average body weight, estimated liver weight, amount of vitamin A administered, estimated loss in breast milk and study duration.

Female↗
PubMed2004

Overall adherence to the dietary guidelines for americans is associated with reduced prevalence of early age-related nuclear lens opacities in women.

Few studies have examined the efficacy of the Dietary Guidelines for Americans in the prevention of age-related chronic disease, such as age-related cataract. We examined whether adherence to the Guidelines was associated with a lower prevalence of age-related nuclear lens opacities in women. Eye exams were conducted in 479 Nurses' Health Study participants aged 52 to 73 y without previously diagnosed cataract or diabetes living in the Boston, MA area. Four FFQs, collected during a 9- to 11-y period before evaluation of lens status, were used to define diet quality according to the following: 1) daily number of servings of fruits, vegetables, and whole grains; 2) Recommended Foods Score (RFS); and 3) Healthy Eating Index (HEI). Nuclear opacities were defined as scores >/= 2.5 using the Lens Opacification Classification System III. After adjusting for age, smoking, and other risk factors, women in the highest quartile category of HEI scores were significantly less likely to have nuclear opacities than those in the lowest category [odds ratio (OR) = 0.47; 95% CI: 0.26-0.84]. This association appeared to be stronger among nonusers of supplemental vitamin C (OR = 0.23; 95% CI: 0.10-0.52). Decreased prevalence odds of nuclear opacities were also observed with high intake of fruit (OR = 0.58; 95% CI: 0.32-1.05) and whole grains (OR = 0.64; 95% CI: 0.36-1.15). These results suggest that overall compliance with the Dietary Guidelines, as measured by the HEI, protects against nuclear opacities.

Adult↗
PubMed1986

Anisotropic overall and internal motions of short DNA fragments.

Anisotropic motions of DNA fragments in the size range 6-118 base pairs are studied by the steady-state fluorescence polarization of different excitation transitions in the intercalated ethidium cation. Calculated effective tumbling and twisting times are found to be shorter than predicted for overall motions of rigid DNA, indicating that internal motions and/or dye wobbling contribute to the depolarization. The data are consistent with a model where the DNA fragments are considered to be rigid against bending but torsionally flexible, and where the dye can wobble within the intercalated site. We also discuss the possibility of correlated out-of-plane motions of the dye and the DNA bases.

DNA↗