| 31. |
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| 32. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 33. |
- Gonzalez-Ericsson, Paula, et al.
(författare)
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The path to a better biomarker: application of a risk management framework for the implementation of PD‐L1 and TILs as immuno‐oncology biomarkers into breast cancer clinical trials and daily practice
- 2020
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Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 250:5, s. 667-684
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Forskningsöversikt (refereegranskat)abstract
- Immune checkpoint inhibitor therapies targeting PD‐1/PD‐L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD‐L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab‐paclitaxel. However, concerns regarding variability between immunohistochemical PD‐L1 assay performance and inter‐reader reproducibility have been raised. High tumor‐infiltrating lymphocytes (TILs) have also been associated with response to PD‐1/PD‐L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin–stained slides and have shown reliable inter‐reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD‐L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD‐L1 and TIL analyses as a more comprehensive immuno‐oncological biomarker for patient selection for PD‐1/PD‐L1 inhibition‐based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk‐management framework that may help mitigate the risks of suboptimal patient selection for immuno‐therapeutic approaches in clinical trials and daily practice based on combined TILs/PD‐L1 assessment in BC.
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| 34. |
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| 35. |
- Mathews, M. V., et al.
(författare)
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A marriage of the Director Musices program and the conductor program
- 2003
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Ingår i: Proceedings of the Stockholm Music Acoustics Conference, August 6-9, 2003 (SMAC 03), Stockholm, Sweden. ; , s. 13-16
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Konferensbidrag (refereegranskat)abstract
- This paper will describe an ongoing collaboration between the authors to combine the Director Musices and Conductor programs in order to achieve a more expressive and socially interactive performance of a midi file score by an electronic orchestra. Director Musices processes a “square” midi file, adjusting the dynamics and timing of the notes to achieve the expressive performance of a trained musician. The Conductor program and the Radio-baton allow a conductor, wielding an electronic baton, to follow and synchronize with other musicians, for example to provide an orchestral accompaniment to an operatic singer. These programs may be particularly useful for student soloists who wish to practice concertos with orchestral accompaniments.
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| 36. |
- Mathews, T.S, et al.
(författare)
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Integration of functional reliability analysis with hardware reliability : An application to safety grade decay heat removal system of Indian 500 MWe PFBR
- 2009
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Ingår i: Annals of Nuclear Energy. - : Elsevier BV. - 0306-4549 .- 1873-2100. ; 36:4, s. 481-492
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Tidskriftsartikel (refereegranskat)abstract
- A passive system can fail either due to classical mechanical failure of components, referred to as hardware failure, or due to the failure of physical phenomena to fulfill the intended function, referred to as functional failure. In this paper a methodology is discussed for the integration of these two kinds of unreliability and applied to evaluate the integrated failure probability of the passive decay heat removal system of Indian 500 MWe prototype fast breeder reactor (PFBR). The probability of occurrence of various system hardware configurations is evaluated using the fault tree method and functional failure probabilities on the corresponding configurations are determined based on the overall approach reported in the reliability methods for passive system (RMPS) project. The variation of functional reliability with time, which is coupled to the probability of occurrence of various hardware system configurations is studied and incorporated in the integrated reliability analysis. It is observed that this consideration of the dependence of functional reliability on time will give significant advantages on system reliability. The integrated reliability analysis is also explained using an event tree. The impact of the provision for forced circulation in the primary circuit on functional reliability is also studied with this procedure and it is found that the forced circulation capability helps to bring down the total decay heat removal failure probability by lowering the peak temperatures after the reactor shut down.
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| 37. |
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| 38. |
- Wang, Sheng, et al.
(författare)
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De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis
- 2018
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 24:13, s. 3441-
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Tidskriftsartikel (refereegranskat)abstract
- We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.
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| 39. |
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| 40. |
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