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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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- Galluzzi, L, et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes.
- 2009
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Ingår i: Cell death and differentiation. - : Springer Science and Business Media LLC. - 1476-5403 .- 1350-9047. ; 16:8, s. 1093-107
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Forskningsöversikt (refereegranskat)abstract
- Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.
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- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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- Lindblad-Toh, Kerstin, et al.
(författare)
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Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
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Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
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- Packer, M., et al.
(författare)
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Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study
- 2005
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Ingår i: Journal of cardiac failure. - : Elsevier BV. - 1071-9164. ; 11:1, s. 12-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Endothelin receptor antagonism produces favorable short-term hemodynamic effects in heart failure, but the clinical effects of longer term therapy have not been evaluated. METHODS AND RESULTS: Three hundred and seventy patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction <35% were randomly assigned (double-blind) to placebo (n = 126) or the endothelin receptor antagonist bosentan, titrated slowly (n = 121) or rapidly (n = 123) to a target dose of 500 mg twice daily. Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant. Safety concerns led to early termination of the trial when only 174 patients had had an opportunity to complete 26 weeks of therapy. Bosentan exerted no apparent benefit when all randomized patients were analyzed (P = .709). However, in the first 174 patients who were recruited at least 26 weeks before study termination and who could therefore be followed for the planned duration of the trial, patients in the bosentan groups were more likely to be improved (26% versus 19%) and were less likely to be worse (28% versus 43%), P = .045. When compared with placebo-treated patients, bosentan-treated patients had a increased risk of heart failure during the first month of treatment but a decreased risk of heart failure during the fourth, fifth, and sixth months of therapy. The major noncardiac adverse effects of bosentan included an increase in hepatic transaminases (in 15.6% of patients) and a decrease in hemoglobin (of about 1 g/L). CONCLUSION: Although bosentan exerted no favorable effects in the overall study, our findings suggest that the clinical responses to endothelin antagonism with bosentan in patients with severe chronic heart failure may be dependent on the duration of treatment.
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- Lassen, Michael R, et al.
(författare)
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Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty
- 2008
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Ingår i: The New England journal of medicine. - 0028-4793. ; 358:26, s. 86-2776
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We investigated the efficacy of rivaroxaban, an orally active direct factor Xa inhibitor, in preventing venous thrombosis after total knee arthroplasty.METHODS: In this randomized, double-blind trial, 2531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban, 10 mg once daily, beginning 6 to 8 hours after surgery, or subcutaneous enoxaparin, 40 mg once daily, beginning 12 hours before surgery. The primary efficacy outcome was the composite of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery. Secondary efficacy outcomes included major venous thromboembolism (i.e., proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death related to venous thromboembolism) and symptomatic venous thromboembolism. The primary safety outcome was major bleeding.RESULTS: The primary efficacy outcome occurred in 79 of 824 patients (9.6%) who received rivaroxaban and in 166 of 878 (18.9%) who received enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P<0.001). Major venous thromboembolism occurred in 9 of 908 patients (1.0%) given rivaroxaban and 24 of 925 (2.6%) given enoxaparin (absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P=0.01). Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin (P=0.005). Major bleeding occurred in 0.6% of patients in the rivaroxaban group and 0.5% of patients in the enoxaparin group. The incidence of drug-related adverse events, mainly gastrointestinal, was 12.0% in the rivaroxaban group and 13.0% in the enoxaparin group.CONCLUSIONS: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding. (ClinicalTrials.gov number, NCT00361894.)
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- Baddley, J W, et al.
(författare)
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Candida infective endocarditis.
- 2008
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Ingår i: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 0934-9723. ; 27:7, s. 519-29
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Tidskriftsartikel (refereegranskat)abstract
- Candida infective endocarditis (IE) is uncommon but often fatal. Most epidemiologic data are derived from small case series or case reports. This study was conducted to explore the epidemiology, treatment patterns, and outcomes of patients with Candida IE. We compared 33 Candida IE cases to 2,716 patients with non-fungal IE in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS). Patients were enrolled and the data collected from June 2000 until August 2005. We noted that patients with Candida IE were more likely to have prosthetic valves (p < 0.001), short-term indwelling catheters (p < 0.0001), and have healthcare-associated infections (p < 0.001). The reasons for surgery differed between the two groups: myocardial abscess (46.7% vs. 22.2%, p = 0.026) and persistent positive blood cultures (33.3% vs. 9.9%, p = 0.003) were more common among those with Candida IE. Mortality at discharge was higher in patients with Candida IE (30.3%) when compared to non-fungal cases (17%, p = 0.046). Among Candida patients, mortality was similar in patients who received combination surgical and antifungal therapy versus antifungal therapy alone (33.3% vs. 27.8%, p = 0.26). New antifungal drugs, particularly echinocandins, were used frequently. These multi-center data suggest distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different and mortality is increased. Newer antifungal treatment options are increasingly used. Large, multi-center studies are needed to help better define Candida IE.
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- Fredriksson, Robert, et al.
(författare)
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The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain
- 2008
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 149:5, s. 2062-71
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Tidskriftsartikel (refereegranskat)abstract
- Gene variants of the FTO (fatso) gene have recently been strongly associated with body mass index and obesity. The FTO gene is well conserved and found in a single copy in vertebrate species including fish and chicken, suggesting that the ancestor of this gene was present 450 million years ago. Surprisingly, the FTO gene is present in two species of algae but not in any other invertebrate species. This could indicate that this gene has undergone a horizontal gene transfer. Quantitative real-time PCR showed that the gene is expressed in many peripheral and central rat tissues. Detailed in situ hybridization analysis in the mouse brain showed abundant expression in feeding-related nuclei of the brainstem and hypothalamus, such as the nucleus of the solitary tract, area postrema, and arcuate, paraventricular, and supraoptic nuclei as well as in the bed nucleus of the stria terminalis. Colabeling showed that the FTO gene is predominantly expressed in neurons, whereas it was virtually not found in astrocytes or glia cells. The FTO was significantly up-regulated (41%) in the hypothalamus of rats after 48-h food deprivation. We also found a strong negative correlation of the FTO expression level with the expression of orexigenic galanin-like peptide, which is mainly synthesized in the arcuate nucleus. These results are consistent with the hypothesis that FTO could participate in the central control of energy homeostasis.
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