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- 2019
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Tidskriftsartikel (refereegranskat)
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- Khatri, B., et al.
(författare)
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Genome-wide association study identifies Sjogren's risk loci with functional implications in immune and glandular cells
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Sjogren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjogren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands. The genetic architecture underlying Sjogren's syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.
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- Eshmvminov, D., et al.
(författare)
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FOLFIRINOX or Gemcitabine-based Chemotherapy for Borderline Resectable and Locally Advanced Pancreatic Cancer: A Multi-institutional, Patient-Level, Meta-analysis and Systematic Review
- 2023
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Ingår i: Annals of Surgical Oncology. - 1068-9265. ; 30:7, s. 4417-4428
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Forskningsöversikt (refereegranskat)abstract
- BackgroundPancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.MethodsWe performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.ResultsA total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.ConclusionsIn patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.
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| 8. |
- Rannikmäe, K., et al.
(författare)
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Reliability of intracerebral hemorrhage classification systems: A systematic review
- 2016
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 11:6, s. 626-636
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems. Methods: We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies’ characteristics, reporting quality and potential for bias; summarized reliability with kappa value forest plots; and performed meta-analyses of the proportion of cases classified into each subtype. Summary of review: We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78–0.97 [six studies, 518 cases], mechanistic 0.89–0.93 [three studies, 510 cases]; intra-rater kappas: anatomical 0.80–1 [three studies, 137 cases], mechanistic 0.92–0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative. Conclusions: Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines. © 2016, © 2016 World Stroke Organization.
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- Flood, Victoria A., et al.
(författare)
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Evaluating modelled tropospheric columns of CH4, CO, and O3 in the Arctic using ground-based Fourier transform infrared (FTIR) measurements
- 2024
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Ingår i: Atmospheric Chemistry and Physics. - 1680-7316 .- 1680-7324. ; 24:2, s. 1079-1118
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluates tropospheric columns of methane, carbon monoxide, and ozone in the Arctic simulated by 11 models. The Arctic is warming at nearly 4 times the global average rate, and with changing emissions in and near the region, it is important to understand Arctic atmospheric composition and how it is changing. Both measurements and modelling of air pollution in the Arctic are difficult, making model validation with local measurements valuable. Evaluations are performed using data from five high-latitude ground-based Fourier transform infrared (FTIR) spectrometers in the Network for the Detection of Atmospheric Composition Change (NDACC). The models were selected as part of the 2021 Arctic Monitoring and Assessment Programme (AMAP) report on short-lived climate forcers. This work augments the model-measurement comparisons presented in that report by including a new data source: column-integrated FTIR measurements, whose spatial and temporal footprint is more representative of the free troposphere than in situ and satellite measurements. Mixing ratios of trace gases are modelled at 3-hourly intervals by CESM, CMAM, DEHM, EMEP MSC-W, GEM-MACH, GEOS-Chem, MATCH, MATCH-SALSA, MRI-ESM2, UKESM1, and WRF-Chem for the years 2008, 2009, 2014, and 2015. The comparisons focus on the troposphere (0-7km partial columns) at Eureka, Canada; Thule, Greenland; Ny Ålesund, Norway; Kiruna, Sweden; and Harestua, Norway. Overall, the models are biased low in the tropospheric column, on average by -9.7% for CH4, -21% for CO, and -18% for O3. Results for CH4 are relatively consistent across the 4 years, whereas CO has a maximum negative bias in the spring and minimum in the summer and O3 has a maximum difference centered around the summer. The average differences for the models are within the FTIR uncertainties for approximately 15% of the model-location comparisons.
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- Berthelsen, A., et al.
(författare)
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Recording marine airgun shots at offsets between 300 and 700 km
- 1991
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 18:4, s. 645-648
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Tidskriftsartikel (refereegranskat)abstract
- This paper demonstrates that - under favorable conditions - by using multichannel recording and subsequent stacking of adjacent records marine airgun shots have been detected at offset distances up to 700 km, the maximum offset at which the authors attempted to record data.^Besides a powerful airgun array, a low noise environment at the recording site and the elimination of static shifts are the prerequisites to obtain refracted and reflected arrivals from the crust and upper mantle at such large offsets.^Primary arrivals detected at offsets between 400 and 700 km image the upper mantle from 70 to about 120 km depth.^Stacking of neighboring shots and/or receivers successfully increases the signal-to-noise ratio, if the traces have been corrected for offset differences, which requires knowledge of the apparent phase velocities.^The data presented here were collected in autumn 1989 during the BABEL Project on the Baltic Shield.
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- Hobbs, R. W., et al.
(författare)
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Integrated seismic studies of the Baltic shield using data in the Gulf of Bothnia region
- 1993
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Ingår i: Geophysical Journal International. - 0956-540X .- 1365-246X. ; 112:3, s. 305-324
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Tidskriftsartikel (refereegranskat)abstract
- In the autumn of 1989 a co-operative experiment involving 12 research institutions in northwestern Europe collected 2268 km of deep seismic reflection profiles in the Gulf of Bothnia and the Baltic Sea. the 121 litre airgun array used for this profiling was also recorded by 62 muiticomponent land stations to provide coincident refraction surveys, fan-spreads, and 3-D seismic coverage of much of the Gulf of Bothnia. We thus have potentially both high-resolution impedance contrast images as well as more regional 3-D velocity models in both P- and S-waves. In the Bothnian Bay a south-dipping, non-reflective zone coincides with the conductive Archaean-Proterozoic boundary onshore in Finland. Between the Bothnian Bay and Bothnian Sea observed reflectivity geometries and velocity models at Moho depths suggest structures inherited from a 1.9Ga subduction zone; the upper crust here appears to have anomalously low velocity. Within the Bothnian Sea, reflectivity varies considerably beneath the metasedimentary/granitoid rocks of the Central Svecofennian Province (CSP) and the surrounding metavolcanic-arc rocks. Numerous dipping reflectors appear throughout the metavolcanic crust, whereas the CSP has little reflectivity. Wide-angle reflections indicate that the metasedimentary crust of the Bothnian Basin is 10 km thicker than the neighbouring Svecofennian subprovinces. Near the Åland archipelago Rapakivi granite plutons exhibit bright reflections, a contrast to the usual non-reflective plutons elsewhere in western Europe. Additional dipping reflections deep in the crust of this area may support models of rifting and crustal thinning during emplacement of the 1.70-1.54 Ga Rapakivi granites. Coeval gabbroic/anorthositic magmatism may explain the high reflectivity and high velocity of these plutons. the c. 1.25 Ga mafic sills and feeder dykes of the Central Scandinavian Dolerite Group also produce clear reflections on both near- and far-offset seismic sections. Continued modelling will produce better velocity models of the crust and better constrained contour maps of crustal thickness in this part of the Baltic shield.
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| 14. |
- Wagner, M, et al.
(författare)
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Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 1147-
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Tidskriftsartikel (refereegranskat)abstract
- The human ovary orchestrates sex hormone production and undergoes monthly structural changes to release mature oocytes. The outer lining of the ovary (cortex) has a key role in defining fertility in women as it harbors the ovarian reserve. It has been postulated that putative oogonial stem cells exist in the ovarian cortex and that these can be captured by DDX4 antibody isolation. Here, we report single-cell transcriptomes and cell surface antigen profiles of over 24,000 cells from high quality ovarian cortex samples from 21 patients. Our data identify transcriptional profiles of six main cell types; oocytes, granulosa cells, immune cells, endothelial cells, perivascular cells, and stromal cells. Cells captured by DDX4 antibody are perivascular cells, not oogonial stem cells. Our data do not support the existence of germline stem cells in adult human ovaries, thereby reinforcing the dogma of a limited ovarian reserve.
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- Öhlander, Björn, et al.
(författare)
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Delineation and character of the Archaean-Proterozoic boundary in northern Sweden
- 1993
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Ingår i: Precambrian Research. - 0301-9268 .- 1872-7433. ; 64:1-4, s. 67-84
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Tidskriftsartikel (refereegranskat)abstract
- Before the deposition of a Proterozoic cover and the repeated Proterozoic reworking of the older rocks, the presently exposed Archaean areas in northern Sweden formed part of a coherent craton. In the present study, we have used Sm---Nd isotopic analyses of Proterozoic granitoids and metavolcanics to delineate the Archaean palaeoboundary. In a regional context, the transition from strongly negative εNd(t) values in the northeast to positive values in the southwest is distinct, and approximately defines the border of the old craton. The Archaean palaeoboundary extends in a WNW direction, and is subparallel to the longitudinal axis of the Skellefte sulphide ore district but it is situated ≈ 100 km farther to the north. The ≈ 1.9 Ga old granitoids on the two sides of the palaeoboundary were all formed in compressional environments, but those situated to the north have higher contents of LILE and LREE at similar contents of Si. This indicates that they were generated in an area with thicker crust and supports the location of the Archaean-Proterozoic palaeoboundary. There is no simple correlation between the Archaean palaeoboundary, as defined by the isotopic results, and any of the major fracture systems as interpreted from regional geophysical measurements. Reflection seismic work indicates that juvenile volcanic-arc terrains to the south have been thrust onto the Archaean craton. Possible thrust faults have been identified from aeromagnetic measurements. Rifting of the Archaean craton created a passive margin ≈ 2.0 Ga ago. Spreading shifted to convergence with subduction beneath the Archaean continent ≈ 1.9 Ga ago. Subsequently, the resulting juvenile volcanic arc collided with the old continent, and the Archaean palaeoboundary as existing today was formed by a collision characterized by overthrusting. The boundary then was disturbed by later deformation predominantly along NNE-trending fracture systems.
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- Blasch, J., et al.
(författare)
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New clean energy communities in polycentric settings : Four avenues for future research
- 2021
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Ingår i: Energy Research and Social Science. - : Elsevier BV. - 2214-6296. ; 82
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Tidskriftsartikel (refereegranskat)abstract
- Given the gaps between EU ambitions regarding energy community development and the current reality of clean energy communities in Europe, we explore a research framework enabling viable multi- and interdisciplinary research into new clean energy communities. We offer a definition of new clean energy communities, discuss their potential for wider dissemination and identify four factors that contribute to the current mismatch between ambitions and reality in energy community development. As a broader framework for interdisciplinary research into the field of new clean energy communities, we propose polycentric governance theory, considering the fact that the area of community energy systems is essentially multi-scalar, and that the rules of engagement in such systems are of great significance. This opens up four avenues for research on energy communities, which we outline in terms of enabling institutional contexts, potential for learning and transferability, business models and value propositions, and evaluation of outcomes and processes.
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| 18. |
- Boswell, M. T., et al.
(författare)
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Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS
- 2022
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Ingår i: Virus Evolution. - : Oxford University Press (OUP). - 2057-1577. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors – synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.
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- Gennemark, Peter, et al.
(författare)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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