| 191. |
- Alvarez, Mariano J., et al.
(författare)
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A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 979-989
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Tidskriftsartikel (refereegranskat)abstract
- We introduce and validate a new precision oncology framework for the systematic prioritization of drugs targeting mechanistic tumor dependencies in individual patients. Compounds are prioritized on the basis of their ability to invert the concerted activity of master regulator proteins that mechanistically regulate tumor cell state, as assessed from systematic drug perturbation assays. We validated the approach on a cohort of 212 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare malignancy originating in the pancreas and gastrointestinal tract. The analysis identified several master regulator proteins, including key regulators of neuroendocrine lineage progenitor state and immunoevasion, whose role as critical tumor dependencies was experimentally confirmed. Transcriptome analysis of GEP-NET-derived cells, perturbed with a library of 107 compounds, identified the HDAC class I inhibitor entinostat as a potent inhibitor of master regulator activity for 42% of metastatic GEP-NET patients, abrogating tumor growth in vivo. This approach may thus complement current efforts in precision oncology.
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| 192. |
- Antoniou, Antonis C., et al.
(författare)
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
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| 193. |
- Argiropoulos, Bob, et al.
(författare)
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Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:20, s. 4071-82
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Tidskriftsartikel (refereegranskat)abstract
- MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1 target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1 resulted in the rapid and complete eradication of M33-Meis1-transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1 impeded the progression of cells from G(1)-to-S phase, which correlated with significant reduction of cyclin D3 levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3 as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G(1)-phase accumulation and growth suppression induced by M33-Meis1 was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1 to the cyclin D-pRb cell-cycle control pathway.
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| 194. |
- Astély, David, et al.
(författare)
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Spatial signature estimation for uniform linear arrays with unknown receiver gains and phases
- 1999
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Ingår i: IEEE Transactions on Signal Processing. - : Institute of Electrical and Electronics Engineers (IEEE). - 1053-587X .- 1941-0476. ; 47:8, s. 2128-2138
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Tidskriftsartikel (refereegranskat)abstract
- The problem of spatial signature estimation using a uniform linear array (ULA) with unknown receiver gain and phase responses is studied. Sufficient conditions for identifying the spatial signatures are derived, and a closed-Form ESPRIT-like estimator is proposed, The performance of the method is investigated by means of simulations and on experimental data collected with an antenna array in a suburban environment. The results show that the absence of receiver calibration is not critical for uplink signal waveform estimation using a plane wave model.
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| 195. |
- Asztély, David, et al.
(författare)
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A Generalized Array Manifold Model for Local Scattering in Wireless Communications
- 1997
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Ingår i: Proceedings of IEEE International Conference on Acoustics, Speech, and Signal Processing. ICASSP-97. - : IEEE. ; , s. 4021-4024
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Konferensbidrag (refereegranskat)abstract
- In wireless communication scenarios, local scatterers in the vicinity of the mobile sources cause angular spreading. As a result, the spatial signatures will not belong to the conventional array manifold parameterized by direction of arrival (DOA) alone. A parameterized model for spatial signatures applicable in scenarios with localscattering is presented. Several algorithms that exploit this model are proposed, and the performance of signal waveform estimators using the model is investigated via simulations. It is demonstrated that considerable gain may result as compared with using the conventional plane wave model.
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| 196. |
- Asztély, David, et al.
(författare)
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Auto Calibration for Signal Separation with Uniform Linear Arrays
- 1997
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Konferensbidrag (refereegranskat)abstract
- In this paper, the problem of signal waveform estimation using a uniform linear array with unknown receiver gain and phase responses is considered. As is well known, it is not possible to uniquely estimate directions-of-arrival(DOAs) and receiver gain and phase simultaneously. For steering vector and signal separation this ambiguity is notcritical. An ESPRIT-like solution is presented, and the proposed method is examined on data collected with an antenna array in a suburban environment.
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| 197. |
- Asztély, David, et al.
(författare)
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Generalised Array Manifold Model for Wireless Communication Channels with Local Scattering
- 1998
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Ingår i: IEE Proceedings Radar, Sonar and Navigation. - : IEEE. - 1350-2395. ; 145:1, s. 51-57
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Tidskriftsartikel (refereegranskat)abstract
- The authors propose the use of a generalised array manifold for parameterised spatial signature estimation in wireless communication channels with local scattering. The array manifold commonly used for point sources is generalised to include linear combinations of the nominal array response vectors and their derivatives. The motivation behind this idea is to obtain better estimates of the spatial signatures for direction of arrival (DOA) based signal waveform estimation. The estimators proposed exploit the orthogonality between the so-called noise and signal subspaces, leading to a separable solution for the derivative coefficients. As a result, a search is required for the DOAs only. For uniform linear arrays, the spatial signatures are shown to be approximately Vandermonde vectors with damped modes, and a closed-form estimator such as ESPRIT may be used in this case. Simulation examples are included to compare the signal estimation performance obtained using the proposed generalised manifold and the conventional array manifold.
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| 198. |
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| 199. |
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| 200. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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