| 831. |
- Padula, William V., et al.
(författare)
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Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States
- 2016
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 108:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.
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| 832. |
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| 833. |
- Papadimitriou, Nikos, et al.
(författare)
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A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study
- 2020
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Ingår i: European Journal of Nutrition. - : Springer Nature. - 1436-6207 .- 1436-6215. ; 59:7, s. 2929-2937
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.
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| 834. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 835. |
- Patterson, Marc C., et al.
(författare)
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Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C : an observational cohort study
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10, s. 65-65
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat.METHODS: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit.RESULTS: In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data.CONCLUSIONS: Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years.
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| 836. |
- Perdikari, A., et al.
(författare)
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BATLAS: Deconvoluting Brown Adipose Tissue
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 25:3
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
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| 837. |
- Pereira-López, X., et al.
(författare)
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In-beam γ -ray spectroscopy of 94 Ag
- 2023
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Ingår i: European Physical Journal A. - : Springer Science and Business Media LLC. - 1434-6001 .- 1434-601X. ; 59:3
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Tidskriftsartikel (refereegranskat)abstract
- A recoil-beta-tagging experiment has been performed to study the excited T= 0 and T= 1 states in the odd–odd N= Z nucleus 94Ag, populated via the 40Ca(58Ni,1p3n)94Ag reaction. The experiment was conducted using the MARA recoil separator and JUROGAM3 array at the Accelerator Laboratory of the University of Jyväskylä. Through correlating fast, high-energy beta decays at the MARA focal plane with prompt γ rays emitted at the reaction target, a number of transitions between excited states in 94Ag have been identified. The timing characteristics of these transitions confirm that they fall within decay sequences that feed the short-lived T= 1 ground state of 94Ag. The transitions are proposed to proceed within and between the sets of states with T= 0 and T= 1. Possible correspondence between some of these transitions from analog states in 94Pd has been discussed, and shell-model calculations including multipole and monopole electromagnetic effects have been presented, in order to enable predictions of the decay patterns between the T= 0 and T= 1 states and to allow a theoretical set of Coulomb energy differences to be calculated for the A= 94 T= 1 analog states.
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| 838. |
- Persson, B David, et al.
(författare)
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An arginine switch in the species B adenovirus knob determines high-affinity engagement of cellular receptor CD46.
- 2009
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Ingår i: Journal of Virology. - 0022-538X .- 1098-5514. ; 83:2, s. 673-686
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Tidskriftsartikel (refereegranskat)abstract
- Adenoviruses (Ads) are icosahedral, nonenveloped viruses with a double-stranded DNA genome. The 51 known Ad serotypes exhibit profound variations in cell tropism and disease types. The number of observed Ad infections is steadily increasing, sometimes leading to fatal outcomes even in healthy individuals. Species B Ads can cause kidney infections, hemorrhagic cystitis, and severe respiratory infections, and most of them use the membrane cofactor protein CD46 as a cellular receptor. The crystal structure of the human Ad type 11 (Ad11) knob complexed with CD46 is known; however, the determinants of CD46 binding in related species B Ads remain unclear. We report here a structural and functional analysis of the Ad11 knob, as well as the Ad7 and Ad14 knobs, which are closely related in sequence to the Ad11 knob but have altered CD46-binding properties. The comparison of the structures of the three knobs, which we determined at very high resolution, provides a platform for understanding these differences and allows us to propose a mechanism for productive high-affinity engagement of CD46. At the center of this mechanism is an Ad knob arginine that needs to switch its orientation in order to engage CD46 with high affinity. Quantum chemical calculations showed that the CD46-binding affinity of Ad11 is significantly higher than that of Ad7. Thus, while Ad7 and Ad14 also bind CD46, the affinity and kinetics of these interactions suggest that these Ads are unlikely to use CD46 productively. The proposed mechanism is likely to determine the receptor usage of all CD46-binding Ads.
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| 839. |
- Persson, Carina, 1964, et al.
(författare)
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Nitrogen hydrides in interstellar gas II. Analysis of Herschel/HIFI observations towards W49N and G10.6-0.4 (W31C)
- 2012
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 543:Article Number: A145, s. 145-179
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Tidskriftsartikel (refereegranskat)abstract
- As a part of the Herschel key programme PRISMAS, we have used the Herschel-HIFI instrument to observe interstellar nitrogen hydrides along the sight-lines towards eight high-mass star-forming regions in order to elucidate the production pathways leading to nitrogen-bearing species in diffuse gas. Here, we report observations towards W49N of the NH N = 1 - 0, J = 2 - 1, and J = 1 - 0, ortho-NH2 N_(Ka, K_c) J = 1_(1,1) 3/2 - 0_(0,0) 1/2, ortho-NH3 J_K = 1_0 - 0_0 and 2_0 - 1_0, para-NH3 J_K = 2_1 - 1_1 transitions, and unsuccessful searches for NH+. All detections show absorption by foreground material over a wide range of velocities, as well as absorption associated directly with the hot-core source itself. As in the previously published observations towards G10.6-0.4, the NH, NH2 and NH3 spectra towards W49N show strikingly similar and non-saturated absorption features. We decompose the absorption of the foreground material towards W49N into different velocity components in order to investigate whether the relative abundances vary among the velocity components, and, in addition, we re-analyse the absorption lines towards G10.6-0.4 in the same manner. Abundances, with respect to molecular hydrogen, in each velocity component are estimated using CH, which is found to correlate with H2 in the solar neighbourhood diffuse gas. The analysis points to a co-existence of the nitrogen hydrides in diffuse or translucent interstellar gaswith a high molecular fraction. Towards both sources, we find that NH is always at least as abundant as both o-NH2 and o-NH3, in sharp contrast to previous results for dark clouds. We find relatively constant N(NH)/N(o-NH3) and N(o-NH2)/N(o-NH3) ratios with mean values of 3.2 and 1.9 towards W49N, and 5.4 and 2.2 towards G10.6-0.4, respectively. The mean abundance of o-NH4 is ~2x10^-9 towards both sources. The nitrogen hydrides also show linear correlations with CN and HNC towards both sources, and looser correlations with CH. The upper limits on the NH+ abundance indicate column densities
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| 840. |
- Persson, Magnus V., 1983, et al.
(författare)
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The ALMA-PILS Survey: Formaldehyde deuteration in warm gas on small scales toward IRAS 16293-2422 B
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 610
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Tidskriftsartikel (refereegranskat)abstract
- Context. The enhanced degrees of deuterium fractionation observed in envelopes around protostars demonstrate the importance of chemistry at low temperatures, relevant in pre- and protostellar cores. Formaldehyde is an important species in the formation of methanol and more complex molecules. Aims. Here, we aim to present the first study of formaldehyde deuteration on small scales around the prototypical low-mass protostar IRAS 16293-2422 using high spatial and spectral resolution Atacama Large Millimeter/submillimeter Array (ALMA) observations. We determine the excitation temperature, abundances and fractionation level of several formaldehyde isotopologues, including its deuterated forms. Methods. Excitation temperature and column densities of formaldehyde in the gas close to one of the components of the binary were constrained through modeling of optically thin lines assuming local thermodynamical equilibrium. The abundance ratios were compared to results from previous single dish observations, astrochemical models and local ISM values. Results. Numerous isotopologues of formaldehyde are detected, among them H 2 C 17 O, and D 2 13 CO for the first time in the ISM. The large range of upper energy levels covered by the HDCO lines help constrain the excitation temperature to 106 ± 13 K. Using the derived column densities, formaldehyde shows a deuterium fractionation of HDCO/H 2 CO = 6.5 ± 1%, D 2 CO/HDCO = 12.8 -4.1 +3.3 %, and D 2 CO/H 2 CO = 0.6(4) ± 0.1%. The isotopic ratios derived are 16 O/ 18 O = 805 -79 +43 , 18 O/ 17 O = 3.2 -0.3 +0.2 , and 12 C/ 13 C = 56 -11 +8 . Conclusions. The HDCO/H 2 CO ratio is lower than that found in previous studies, highlighting the uncertainties involved in interpreting single dish observations of the inner warm regions. The D 2 CO/HDCO ratio is only slightly larger than the HDCO/H 2 CO ratio. This is consistent with formaldehyde forming in the ice as soon as CO has frozen onto the grains, with most of the deuteration happening toward the end of the prestellar core phase. A comparison with available time-dependent chemical models indicates that the source is in the early Class 0 stage.
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