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| 2. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 3. |
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| 4. |
- 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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| 5. |
- Fossum, E., et al.
(författare)
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The effect of losartan versus atenolol on cardiovascular morbidity and mortality in patients with hypertension taking aspirin: the Losartan Intervention for Endpoint Reduction in hypertension (LIFE) study
- 2005
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Ingår i: J Am Coll Cardiol. - : Elsevier BV. - 0735-1097. ; 46:5, s. 770-5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study to determine whether aspirin interacted with the properties of losartan, an angiotensin-II receptor antagonist. BACKGROUND: Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported. There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin. METHODS: The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan- or atenolol-based therapy for a mean of 4.7 years, with 1,970 (21.4%) taking aspirin at baseline. The primary composite end point (CEP) included cardiovascular death, stroke, and myocardial infarction (MI). The present cohort was stratified by aspirin use at baseline. RESULTS: Blood pressures were reduced similarly in the losartan with aspirin (n = 1,004) and atenolol with aspirin (n = 966) groups. The CEP was reduced by 32% (95% confidence interval 0.55 to 0.86, p = 0.001) with losartan with aspirin compared to atenolol with aspirin, adjusted for Framingham risk score and LVH. The test for treatment versus aspirin interaction, excluding other covariates, was significant for the CEP (p = 0.016) and MI (p = 0.037). CONCLUSIONS: There was a statistical interaction between treatment and aspirin in the LIFE study, with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline. Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment.
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| 6. |
- Fyhrquist, F., et al.
(författare)
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Pulse pressure and effects of losartan or atenolol in patients with hypertension and left ventricular hypertrophy
- 2005
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Ingår i: Hypertension. - 1524-4563. ; 45:4, s. 580-5
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Tidskriftsartikel (refereegranskat)abstract
- In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the primary composite end point of cardiovascular death, stroke, and myocardial infarction was reduced by losartan versus atenolol in patients with hypertension and left ventricular hypertrophy. The objective of this post hoc analysis was to determine the influence of pulse pressure on outcome. Patients were divided into quartiles of baseline pulse pressure. Cox regression, including baseline Framingham risk score as a covariate, was used to compare risk in the quartiles. In the atenolol group, there were significantly higher risks in the highest versus lowest quartile for the composite end point 28% (confidence interval [CI], 2% to 62%; P=0.035), stroke 84% (CI, 32% to 157%; P<0.001), and total mortality 41% (CI, 7% to 84%; P=0.013). Risk for myocardial infarction was 44% higher (CI, -5% to 120%; P=0.089). The risks in the losartan group also increased with increasing quartile, but were lower than in the atenolol group, and differences between the highest and lowest quartiles were not significant: composite end point 12% (CI, -13% to 44%; P>0.2), stroke -5% (CI, -34% to 37%; P>0.2), myocardial infarction 30% (CI, -13% to 94%; P>0.2), and total mortality 32% (CI, -1% to 76%; P=0.062). In patients with hypertension and left ventricular hypertrophy in the LIFE study, there were significantly higher risks, adjusted for the Framingham risk score, for the primary composite end point, stroke, and total mortality in the highest versus lowest quartile of pulse pressure with atenolol-based treatment. The risks in the losartan group also increased with increasing pulse pressure quartile, but were lower than those in the atenolol group, and were not significant.
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| 7. |
- Kizer, J. R., et al.
(författare)
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Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study
- 2005
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Ingår i: Hypertension. - 1524-4563. ; 45:1, s. 46-52
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Tidskriftsartikel (refereegranskat)abstract
- The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that treatment with the angiotensin II type-1 receptor antagonist losartan reduces overall stroke risk compared with conventional therapy with the beta-blocker atenolol. We conducted secondary analyses in LIFE to determine the extent to which the cerebrovascular benefits of losartan apply to different clinical subgroups and stroke subtypes and to assess the dependence of these benefits on baseline and time-varying covariates. Among 9193 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy, random allocation to losartan-based treatment lowered the risk of fatal (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43 to 0.96; P=0.032) and atherothrombotic stroke (HR, 0.72; 95% CI, 0.59 to 0.88; P=0.001) compared with atenolol-based therapy. Although comparable risk reductions occurred for hemorrhagic and embolic stroke, these were not statistically significant. The number of neurological deficits per stroke was similar, but there were fewer strokes in the losartan group for nearly every level of stroke severity. Effects were consistent in all clinical subgroups except for those defined by age and ethnicity. The benefits of losartan on all strokes were independent of baseline and time-varying risk factors, including blood pressure. The number needed to treat for 5 years to prevent 1 stroke was 54 for the average participant, declining to 25, 24, and 9 for patients with cerebrovascular disease, isolated systolic hypertension, and atrial fibrillation, respectively. In conclusion, substantial cerebrovascular benefit could be realized with the institution of losartan-based therapy over conventional therapy among hypertensive patients with left ventricular hypertrophy across the spectrum of cardiovascular risk.
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| 8. |
- Kjeldsen, S. E., et al.
(författare)
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The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study
- 2005
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Ingår i: J Clin Hypertens (Greenwich). - 1524-6175. ; 7:3, s. 152-8
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Tidskriftsartikel (refereegranskat)abstract
- The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan-based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55-80 years with blood pressures 160-200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non-ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagic/other strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan-treated compared to the atenolol-treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan-based treatment is more effective than an atenolol-based treatment for patients with ISH and a high risk for stroke.
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| 9. |
- Adewumi, Oluseun, et al.
(författare)
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
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Tidskriftsartikel (refereegranskat)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
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| 10. |
- Ibsen, H., et al.
(författare)
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Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study
- 2005
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Ingår i: Hypertension. - 1524-4563. ; 45:2, s. 198-202
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Tidskriftsartikel (refereegranskat)abstract
- Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient's current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.
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