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| 142. |
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| 143. |
- Wang, Yifan, et al.
(författare)
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The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin
- 2016
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Ingår i: Cancer Research. - 0008-5472. ; 76:9, s. 2778-2790
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Tidskriftsartikel (refereegranskat)abstract
- Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1- Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance.
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| 144. |
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| 145. |
- Aguilera-Lizarraga, J., et al.
(författare)
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Expression of immune-related genes in rectum and colon descendens of Irritable Bowel Syndrome patients is unrelated to clinical symptoms
- 2019
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 31:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mucosal immune activation has been postulated to play an important role in the pathogenesis of irritable bowel syndrome (IBS). However, data are conflicting and often based on small patient cohorts. Here, we aimed to evaluate the gene expression of a large set of immune-related genes in mucosal biopsies from IBS patients and healthy volunteers (HV). Methods: A total of 171 IBS patients and 127 HV were included in the study. Rectum biopsies were collected from a cohort of 70 HV and 77 IBS patients (Rome III) and colon descendens biopsies from another cohort of 57 HV and 94 IBS patients (Rome II). Gene expression was assessed using OpenArray technology, and validated questionnaires were used to evaluate clinical characteristics (GI symptoms, somatization, anxiety, and depression). Key Results: A subset of IBS patients (33%) with increased immune activation in the colon descendens was identified using multivariate analysis and displayed increased gene expression of IL1B (3-fold change), prostaglandin synthase PTGS2 (2.1-fold change), and the G-protein-coupled receptor MRGPRX2 (10.7-fold change). Clinical characteristics in this subgroup were however similar to the rest of the patient cohort. Analysis of rectal biopsies failed to identify such subgroup of “immuno-active” IBS patients in the other patient cohort. Conclusion: A subset of IBS patients reveals evidence of immune activation in the colon descendens, but not in the rectum; however, gene expression is unrelated to clinical symptoms. To what extent this subgroup might however respond to anti-inflammatory therapy remains to be investigated. © 2019 John Wiley & Sons Ltd
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| 146. |
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| 147. |
- Bolton, Kelly L., et al.
(författare)
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Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
- 2012
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
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Tidskriftsartikel (refereegranskat)abstract
- Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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| 148. |
- Bosman, Arthur D., et al.
(författare)
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A Potential Site for Wide-orbit Giant Planet Formation in the IM Lup Disk
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 944:2
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Tidskriftsartikel (refereegranskat)abstract
- The radial transport, or drift, of dust has taken a critical role in giant planet formation theory. However, it has been challenging to identify dust drift pileups in the hard-to-observe inner disk. We find that the IM Lup disk shows evidence that it has been shaped by an episode of dust drift. Using radiative transfer and dust dynamical modeling we study the radial and vertical dust distribution. We find that high dust drift rates exceeding 110 M ⊕ Myr−1 are necessary to explain both the dust and CO observations. Furthermore, the bulk of the large dust present in the inner 20 au needs to be vertically extended, implying high turbulence (α z ≳ 10−3) and small grains (0.2-1 mm). We suggest that this increased level of particle stirring is consistent with the inner dust-rich disk undergoing turbulence triggered by the vertical shear instability. The conditions in the IM Lup disk imply that giant planet formation through pebble accretion is only effective outside of 20 au. If such an early, high-turbulence inner region is a natural consequence of high dust drift rates, then this has major implications for understanding the formation regions of giant planets including Jupiter and Saturn.
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| 149. |
- Broz, M., et al.
(författare)
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Dynamics of multiple protoplanets embedded in gas and pebble discs and its dependence on Σ and ν parameters
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 620
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Tidskriftsartikel (refereegranskat)abstract
- Protoplanets of super-Earth size may get trapped in convergence zones for planetary migration and form gas giants there. These growing planets undergo accretion heating, which triggers a hot-Trail effect that can reverse migration directions, increase planetary eccentricities, and prevent resonant captures of migrating planets. In this work, we study populations of embryos that are accreting pebbles under different conditions, by changing the surface density, viscosity, pebble flux, mass, and the number of protoplanets. For modelling, we used the FARGO-THORIN two-dimensional (2D) hydrocode, which incorporates a pebble disc as a second pressure-less fluid, the coupling between the gas and pebbles, and the flux-limited diffusion approximation for radiative transfer. We find that massive embryos embedded in a disc with high surface density (Σ = 990 g cm-2 at 5.2 au) undergo numerous "unsuccessful" two-body encounters that do not lead to a merger. Only when a third protoplanet arrives in the convergence zone do three-body encounters lead to mergers. For a low-viscosity disc (ν = 5 × 1013 cm2 s-1), a massive co-orbital is a possible outcome, for which a pebble isolation develops and the co-orbital is further stabilised. For more massive protoplanets (5 MâŠ), the convergence radius is located further out, in the ice-giant zone. After a series of encounters, there is an evolution driven by a dynamical torque of a tadpole region, which is systematically repeated several times until the co-orbital configuration is disrupted and planets merge. This may be a way to solve the problem that co-orbitals often form in simulations but they are not observed in nature. In contrast, the joint evolution of 120 low-mass protoplanets (0.1 MâŠ) reveals completely different dynamics. The evolution is no longer smooth, but rather a random walk. This is because the spiral arms, developed in the gas disc due to Lindblad resonances, overlap with each other and affect not only a single protoplanet but several in the surrounding area. Our hydrodynamical simulations may have important implications for N-body simulations of planetary migration that use simplified torque prescriptions and are thus unable to capture protoplanet dynamics in its full glory.
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